| 1. |
- Isaksson, Rebecka, et al.
(författare)
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A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
- 2019
-
Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
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Tidskriftsartikel (refereegranskat)abstract
- We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.
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| 2. |
- Pipkorn, Bengt, 1963, et al.
(författare)
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Mathematical human body models in side impacts- A validation study with particular emphasis on the torso and shoulder and their influence on head and neck motion
- 2008
-
Ingår i: Int. Res. Counc. Biomech. Inj. - Int. IRCOBI Conf. Biomech. Inj., Proc.. - 9783033015807 ; , s. 99-114, s. 99-114
-
Konferensbidrag (refereegranskat)abstract
- The ability of three mathematical human body models to predict previously published human responses in two different side impact loading configurations was evaluated using an objective rating method. In particular the kinematics of the shoulder, T1 and head were evaluated. The human body models evaluated were THUMS, HUMOS 2 and the GM model. The impact loading configurations used were pendulum impact tests and sled tests. In the pendulum configurations, the closest correlation to the published responses was shown by THUMS followed by the GM model. In the sled configuration, closest correlation to the published responses was shown by HUMOS 2 followed by THUMS. According to the objective rating method the published responses in the pendulum configuration were predicted by all human body models. The published responses in the sled configuration were predicted by HUMOS 2 and THUMS.
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| 3. |
- Wannberg, Johan, et al.
(författare)
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N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
- 2024
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 265
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Tidskriftsartikel (refereegranskat)abstract
- Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tertbutylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT(2)R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT(2)R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT(2)R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t(1/2) of less than 10 min in human liver microsomes. The most promising ligand, with an AT(2)R K-i value of 4.9 nM and with intermediate stability in human hepatocytes (t(1/2) = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
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| 4. |
- Wannberg, Johan, et al.
(författare)
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N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands
- 2021
-
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 29
-
Tidskriftsartikel (refereegranskat)abstract
- A series of meta-substituted acetophenone derivatives, encompassing N-(alkyloxycarbonyl)thiophene sulfonamide fragments have been synthesized. Several selective AT2 receptor ligands were identified, among those a tert-butylimidazole derivative (20) with a Ki of 9.3 nM, that demonstrates a high stability in human liver microsomes (t½ = 62 min) and in human hepatocytes (t½ = 194 min). This methyloxycarbonylthiophene sulfonamide is a 20-fold more potent binder to the AT2 receptor and is considerably more stable in human liver microsomes, than a previously reported and broadly studied structurally related AT2R prototype antagonist 3 (C38). Ligand 20 acts as an AT2R agonist and caused an AT2R mediated concentration-dependent vasorelaxation of pre-contracted mouse aorta. Furthermore, in contrast to imidazole derivative C38, the tert-butylimidazole derivative 20 is a poor inhibitor of CYP3A4, CYP2D6 and CYP2C9. It is demonstrated herein that smaller alkyloxycarbonyl groups make the ligands in this series of AT2R selective compounds less prone to degradation and that a high AT2 receptor affinity can be retained after truncation of the alkyloxycarbonyl group. Binding modes of the most potent AT2R ligands were explored by docking calculations combined with molecular dynamics simulations.
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| 5. |
- Ackerley, Rochelle, 1980, et al.
(författare)
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Case Studies in Neuroscience: Sensations elicited and discrimination ability from nerve cuff stimulation in an amputee over time
- 2018
-
Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 120:1, s. 291-295
-
Tidskriftsartikel (refereegranskat)abstract
- The present case study details sensations elicited by electrical stimulation of peripheral nerve axons using an implanted nerve cuff electrode, in a participant with a transhumeral amputation. The participant uses an osseointegrated electromechanical interface, which enables skeletal attachment of the prosthesis and long-term, stable, bidirectional communication between the implanted electrodes and prosthetic arm. We focused on evoking somatosensory percepts, where we tracked and quantified the evolution of perceived sensations in the missing hand. which were evoked from electrical stimulation of the nerve, for over 2 yr. These sensations included small, pointlike areas of either vibration or pushing, to larger sensations over wider areas, indicating the recruitment of a few and many afferents, respectively. Furthermore, we used a two-alternative forced choice paradigm to measure the level of discrimination between trains of brief electrical stimuli, to gauge what the participant could reliably distinguish between. At best, the participant was able to distinguish a 05-Hz difference and on average acquired a 3.8-Hz just-noticeable difference at a more stringent psychophysical level. The current work shows the feasibility for long-term sensory feedback in prostheses, via electrical axonal stimulation, where small and relatively stable percepts were felt that may be used to deliver graded sensory feedback. This opens up opportunities for signaling feedback during movements (e.g., for precision grip), but also for conveying more complex cutaneous sensations. such as texture. NEW & NOTEWORTHY We demonstrate the long-term stability and generation of sensations from electrical peripheral nerve stimulation in an amputee. through an osseointegrated implant. We find that perceived tactilelike sensations could be generated for over 2 yr. in the missing hand. This is useful for prosthetic development and the implementation of feedback in artificial body parts.
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| 6. |
- Ackerley, Rochelle, 1980, et al.
(författare)
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Differential effects of radiant and mechanically applied thermal stimuli on human C-tactile afferent firing patterns.
- 2018
-
Ingår i: Journal of neurophysiology. - : American Physiological Society. - 1522-1598 .- 0022-3077. ; 120:4, s. 1885-1892
-
Tidskriftsartikel (refereegranskat)abstract
- C-tactile (CT) afferents respond to gentle tactile stimulation, but only a handful of studies in humans and animals have investigated whether their firing is modified by temperature. We describe the effects of radiant thermal stimuli, and of stationary and very slowly moving mechanothermal stimuli, on CT afferent responses. We find that CT afferents are primarily mechanoreceptors, as they fired little during radiant thermal stimuli, but they exhibited different patterns of firing during combined mechano-cool stimulation compared with warming. CTs fired optimally to gentle, very slowly moving, or stationary mechanothermal stimuli delivered at neutral temperature (~32°C, normal skin temperature), but they responded with fewer spikes (median 67% decrease) and at significantly lower rates (47% decrease) during warm (~42°C) tactile stimuli. During cool tactile stimuli (~18°C), their mean instantaneous firing frequency significantly decreased by 35%, but they often fired a barrage of afterdischarge spikes at a low frequency (~5 Hz) that outlasted the mechanical stimulus. These effects were observed under a variety of stimulus conditions, including during stationary and slowly moving touch (0.1 cm/s), and we complemented these tactile approaches using a combined electrical-thermal stimulation experiment where we found a suppression of spiking during warming. Overall, CT afferents are exquisitely sensitive to tactile events, and we show that their firing is modulated with touch temperatures above and below neutral skin temperature. Warm touch consistently decreased their propensity to fire, whereas cool touch produced lower firing rates but afterdischarge spiking. NEW & NOTEWORTHY C-tactile (CT) afferents are thought to underpin pleasant touch, and previous work has shown that they respond optimally to a slow caress delivered at typical (neutral) skin temperature. Here, we show that, although CTs are primarily mechanoreceptive afferents, they are modified by temperature: warm touch decreases their firing, whereas cool touch produces lower firing rates but long-lasting spiking, frequently seen as afterdischarges. This has implications for the encoding of affective sensory events in human skin.
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| 7. |
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| 8. |
- Ackerley, Rochelle, 1980, et al.
(författare)
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Human C-tactile afferents are tuned to the temperature of a skin-stroking caress
- 2014
-
Ingår i: Journal of Neuroscience. - 0270-6474. ; 34:8, s. 2879-2883
-
Tidskriftsartikel (refereegranskat)abstract
- Human C-tactile (CT) afferents respond vigorously to gentle skin stroking and have gained attention for their importance in social touch. Pharmacogenetic activation of the mouse CT equivalent has positively reinforcing, anxiolytic effects, suggesting a role in grooming and affiliative behavior. We recorded from single CT axons in human participants, using the technique of microneurography, and stimulated a unit's receptive field using a novel, computer-controlled moving probe, which stroked the skin of the forearm over five velocities (0.3, 1, 3, 10, and 30 cm s-1) at three temperatures (cool, 18°C; neutral, 32°C; warm, 42°C). We show that CTs are unique among mechanoreceptive afferents: they discharged preferentially to slowly moving stimuli at a neutral (typical skin) temperature, rather than at the cooler or warmer stimulus temperatures. In contrast, myelinated hair mechanoreceptive afferents proportionally increased their firing frequency with stroking velocity and showed no temperature modulation. Furthermore, the CT firing frequency correlated with hedonic ratings to the same mechano-thermal stimulus only at the neutral stimulus temperature, where the stimuli were felt as pleasant at higher firing rates. We conclude that CT afferents are tuned to respond to tactile stimuli with the specific characteristics of a gentle caress delivered at typical skin temperature. This provides a peripheral mechanism for signaling pleasant skin-to-skin contact in humans, which promotes interpersonal touch and affiliative behavior. © 2014 the authors.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Backlund, Johan, 1973
(författare)
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Multifunctional Waveguide Grating Couplers for Integrated Optics
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes a novel waveguide component in integrated optics called a multifunctional grating coupler. It couples light in or out of optical waveguides and provides additional optical functions such as beam splitting, arbitrary focusing, polarization sensing, and wavelength separation (wavelength division demultiplexing). The couplers are quasi-periodic grating structures etched into the surface of an optical waveguide and thus they can be conveniently integrated monolithically with other components such as lasers, detectors, or switches. Multifunctional grating couplers might be used in optical fiber communication to couple light into waveguide detectors or to couple light from an in-plane waveguide laser out into air and focus it into optical fibers. The multifunctionality reduces the need for additional optical components, both integrated and external. Therefore, optical systems using the grating couplers are potentially robust, small-size, and simple to align and package. This thesis presents a new design algorithm for multifunctional waveguide grating couplers. A grating for outcoupling is demonstrated for focusing into a three-dimensional image above the waveguide. The emphasis, however, is on incoupling. Different optical functions are demonstrated, as incoupling and focusing into any arbitrary positions within the waveguide. Furthermore, it is shown that different polarization states (TE- and TM-polarization) can be separated in the waveguide (polarization sensor) or combined to obtain polarization insensitive grating couplers. It is also possible to separate different wavelengths incident on the coupler, thus obtaining wavelength division demultiplexing or wavelength encoding. The performance of the grating couplers was evaluated by numerical simulations and tested experimentally in InP-based waveguides for approximately 1550nm wavelength. The results were in good agreement with the simulations.
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| 13. |
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| 14. |
- Backlund, Lars G., et al.
(författare)
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Improving Fast and Frugal Modeling in Relation to Regression Analysis : Test of 3 Models for Medical Decision Making
- 2009
-
Ingår i: Medical decision making. - : Sage Publications. - 0272-989X .- 1552-681X. ; 29:1, s. 140-148
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Tidskriftsartikel (refereegranskat)abstract
- Background. A matching heuristic (MH) model of decision makinghas been evaluated previously in a series of studies on medicaldecision making. The authors' purpose is to evaluate an extendedMH model that considers the prevalence of cue values. Methods.Data from 2 previous studies were reanalyzed, one on judgmentsregarding drug treatment of hyperlipidemia and the other ondiagnosing heart failure. The original MH model and the extendedMH model were compared with logistic regression (LR) in termsof fit to actual judgments, number of cues, and the extent towhich the cues were consistent with clinical guidelines. Results. There was a slightly better fit with LR compared with MH. Theextended MH model gave a significantly better fit than the originalMH model in the drug treatment task. In the diagnostic task,the number of cues was significantly lower in the MH modelscompared to LR, whereas in the therapeutic task, LR could beless or more frugal than the matching heuristic models dependingon the significance level chosen for inclusion of cues. Forthe original MH model, but not for the extended MH model orLR, the most important cues in the drug treatment task wereoften used in a direction contrary to treatment guidelines.Conclusions. The extended MH model represents an improvementin that prevalence of cue values is adequately taken into account,which in turn may result in better fit and in better agreementwith medical guidelines in the evaluation of cues.
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| 15. |
- Backlund, Sandra
(författare)
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Efficient improvement of energy efficiency in small and medium- sized Swedish firms
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This is a dissertation about efficient implementation of energy efficiency measures in small and medium-sized Swedish firms. The aim is to investigate the potential for economically efficient implementation of energy efficiency improvement measures in small and medium-sized firms. The thesis contains five papers that analyse different aspects that have been put forth in policy documents and academic debate as methods to improve energy efficiency in non-energy intensive sectors.By reading policy documents, interviewing representatives of small and medium- sized firms and energy auditors as well as analysing data from the Swedish energy audit program, different aspects of energy management practices, energy services and energy audits are considered. The thesis is the product of an interdisciplinary context but economic theory is at the foundation of the analysis and has helped formulate questions and hypotheses that have been tested and explored with the data.The results show that while the potential for improving energy efficiency in the small and medium- sized sector in Sweden is large there are challenges to realizing it in each individual firm. There is potential for improving energy efficiency in the sector and not just for investments in new technology but also for adjusting existing machinery and changing behaviour, but costs for investigating the potential and implementing the measures are large relative to the improvement potential in each company. Energy management practices in this sector are lacking and energy services will only be demanded if reduction in production cost is estimated larger than transaction costs of the service. The Swedish energy audit program has led to the implementation of energy efficiency improvements in the participating firms but compared to other policy instruments it has been a less cost-efficient way to improve energy efficiency in Sweden.
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| 16. |
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| 17. |
- Backlund, Sara, et al.
(författare)
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STATIC! The Aesthetics of Energy in Everyday Things
- 2007. - 1
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Ingår i: Proceedings of Design Research Society Wonderground International Conference 2006.
-
Konferensbidrag (refereegranskat)abstract
- Abstract: Static! is a project investigating interaction and product design as a way of increasing our awareness of how energy is used in everyday life. Revisiting the design of everyday things with focus on issues related to energy use, we have developed a palette of design examples in the form of prototypes, conceptual design proposals and use scenarios, to be used as a basis for communication and discussion with users and designers. With respect to design research and practice, the aim has been to develop a more profound understanding of energy as material in design, including its expressive and aesthetic potential, thus locating issues related to energy use at the centre of the design process.
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| 18. |
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| 19. |
- Berg Marklund, Björn, et al.
(författare)
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A Game-Based Approach to Support Social Presence and Awareness in Distributed Project-Based Learning
- 2014
-
Ingår i: International Journal of Games Based Learning. - : IGI Global. - 2155-6849 .- 2155-6857. ; 4:1, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- An important factor for success in project-based learning (PBL) is that the involved project groups establish an atmosphere of social interaction in their working environment. In PBL-scenarios situated in distributed environments, most of a group's work-processes are mediated through the use of production-focused tools that are unconcerned with the important informal and social aspects of a project. On the other hand, there are plenty of tools and platforms that focus on doing the opposite and mainly support informal bonding (e.g., Facebook), but these types of environments can be obtrusive and contain distractions that can be detrimental to a group's productivity and are thus often excluded from working environments. The aim of this paper is to examine how a game-based multi-user environment (MUVE) can be designed to support project-based learning by bridging the gap between productivity-focused and social software. To explore this, the authors developed a game-based MUVE which was evaluated in a PBL-scenario. The result of the study revealed several crucial design elements that are needed to make such a MUVE work effectively, and that the acceptance towards game-based MUVEs is high, even with a rudimentary execution.
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| 20. |
- Frederick, Raphael, et al.
(författare)
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Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:14, s. 6489-6501
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Tidskriftsartikel (refereegranskat)abstract
- To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel beta-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel beta-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active beta-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.
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| 21. |
- Haag, Sabrina, et al.
(författare)
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Positional Identification of RT1-B (HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:6, s. 2539-2550
-
Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.
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| 22. |
- Hallberg, Josef, et al.
(författare)
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Creating dynamic groups using context-awareness
- 2007
-
Ingår i: Proceedings of the 6th International Conference on Mobile and Ubiquitous Multimedia. - Red Hook, NY : Curran Associates, Inc.. - 9781595939166 ; , s. 42-49
-
Konferensbidrag (refereegranskat)abstract
- This article presents the conceptual communication model of dynamic groups, that dynamically utilizes three traditional communication metaphors through the use of context-based information. Dynamic groups makes creation, management and usage of groups easy. It enables social network structures to be maintained in both virtual and face-to-face settings as well as in the combination thereof. This article defines the dynamic management of advanced contact lists which can include presence and status information, a/synchronous multimedia communication tools, and methods for structuring social networks. It also contains an initial evaluation and a proposed architecture for technical realisation.
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| 23. |
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| 24. |
- Henz Ryen, Astrid
(författare)
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Bisabolane sesquiterpenes from the leaves of Lindera benzoin reduce prostaglandin E2 formation in A549 cells
-
Ingår i: Phytochemistry Letters. - 1874-3900 .- 1876-7486.
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Phytochemical investigation of leaves from the American shrub Lindera benzoin (L.) Blume (Lauraceae) resulted in the isolation of one pure compound (1) and a diastereomeric mixture of (2 and 3). The structures of these new bisabolane sesquiterpenes were elucidated via MS and extensive NMR measurements and identified as 6-(2-hydroxy-6-methylhept-5-en-2-yl)-3-(hydroxymethyl)-4-oxocyclohex-2-en-1-yl acetate (1) and 3-(hydroxymethyl)-6-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-4-oxocyclohex-2-en-1-yl acetate (2 and 3). The compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, 1-3 reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner.
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| 25. |
- Henz Ryen, Astrid, et al.
(författare)
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Bisabolane sesquiterpenes from the leaves of Lindera benzoin reduce prostaglandin E2 formation in A549 cells
- 2020
-
Ingår i: Phytochemistry Letters. - : ELSEVIER. - 1874-3900 .- 1876-7486. ; 38, s. 6-11
-
Tidskriftsartikel (refereegranskat)abstract
- Phytochemical investigation of leaves from the American shrub Lindera benzoin (L.) Blume (Lauraceae) resulted in the isolation of one pure compound 1 and a diastereomeric mixture of 2 and 3. The structures of these new bisabolane sesquiterpenes were elucidated via MS and extensive NMR measurements and identified as 6-(2hydroxy-6-methylhept-5-en-2-yl)-3-(hydroxymethyl)-4-oxocyclohex-2-en-1-yl acetate (1) and 3-(hydroxymethyl)-6-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-4-oxocyclohex-2-en-1-yl acetate (2 and 3). The compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, 1-3 reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner.
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| 26. |
- Högberg, Johan, 1973-
(författare)
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Gameful experiences : The not so painful road to gainful behavior
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this work is to investigate the experiences that users make when using gamified services and the effect that such experiences have on the targeted behavioral outcomes. Considerable attention is dedicated to the gameful experience, since this experience is necessary for gamification to affect the target behavior. Moreover, the effectiveness of gamification at triggering different motivational mechanisms and the role of engagement is investigated.This dissertation contains three papers. Paper 1 uses a mixed-methods approach to develop a model and a measure of the gameful experience. Paper 2 uses a field experimental approach to investigate the effect of gamification on a decision to use offers in a store, and the role of engagement for this effect to occur. Finally, Paper 3 uses a field experiment to investigate the contribution of gamification to value creation in stores and how such value creation relates to brand engagement.The first main finding is a model of the gameful experience that includes the dimensions of accomplishment, challenge, competition, guided, immersion, playfulness, and social experience, and the instrument for measuring this experience. The second main finding is that challenge-based gamification can induce positive affect, which can influence evaluative judgments (thus utilizing the affective quality of System 1 to change the target behavior) and, ultimately, brand engagement. However, such challenge-based gamification does not seem to be effective when aiming to affect the biased System 1 through effort justification. The third main finding is the results that indicate that a user needs to be engaged in order for a gamified service to work properly.
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| 27. |
- Jönsson, Emma H., et al.
(författare)
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The relation between human hair follicle density and touch perception
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Unmyelinated low threshold C-tactile fibers moderate pleasant aspects of touch. These fibers respond optimally to stroking stimulation of the skin with slow velocities (1-10 cm/s). Low threshold mechanoreceptors are arranged around hair follicles in rodent skin. If valid also in humans, hair follicle density (HFD) may relate to the perceived pleasantness of stroking tactile stimulation. We conducted two studies that examined the relation between HFD and affective touch perception in humans. In total, 138 healthy volunteers were stroked on the forearm and rated the pleasantness and intensity. Stimulation was performed by a robotic tactile stimulator delivering C-tactile optimal (1, 3, 10 cm/s) and non-optimal (0.1, 0.3, 30 cm/s) stroking velocities. Additionally, a measure of discriminative touch was applied in study 2. HFD of the same forearm was determined using the Cyanoacrylate Skin Stripping Method (CSSM), which we validated in a pretest. Women had higher HFD than men, which was explained by body size and weight. Furthermore, women rated affective touch stimuli as more pleasant and had higher tactile acuity. Depilation did not affect touch perception. A weak relationship was found between the C-tactile specific aspects of affective touch perception and HFD, and the hypothesis of HFD relating to pleasant aspects of stroking only received weak support.
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| 28. |
- Lanner, Daniel, et al.
(författare)
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Evaluation of finite element human body models in lateral padded pendulum impacts to the shoulder
- 2010
-
Ingår i: International Journal of Crashworthiness. - : Informa UK Limited. - 1358-8265 .- 1754-2111. ; 15:2, s. 125-142
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Tidskriftsartikel (refereegranskat)abstract
- Lateral impacts are of great concern for occupant safety. In order to design side protective systems, it is of importance that the timing of the body and the head should be well predicted. Today, experimental and numerical Anthropometric Test Devices (ATDs) are used as human substitutes to predict the human kinematics. As a complement to the ATDs, numerical Human Body Models (HBMs) are used as research tools. The objective of this study is to compare the loading and kinematics of the shoulder complex in three different HBMs with published biological experiments. This study also compares the models with each other and with two numerical ATDs. The results indicate that no HBM can be used for detailed prediction of the kinematics of the human shoulder complex. However, in the presented statistical analysis, all HBMs show a better overall correlation to experiments compared to the numerical ATDs.
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| 29. |
- Larsson, Josefin, et al.
(författare)
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ChemGPS-NP : tuned for navigation in biologically relevant chemical space
- 2007
-
Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 70:5, s. 789-794
-
Tidskriftsartikel (refereegranskat)abstract
- Natural compounds are evolutionary selected and prevalidated by Nature, displaying a unique chemical diversity and a corresponding diversity of biological activities. These features make them highly interesting for studies of chemical biology, and in the pharmaceutical industry for development of new leads. Of utmost importance, for the discovery of new biologically active compounds, is the identification and charting of the corresponding biologically relevant chemical space. The primary key to this is the coverage of the natural products' chemical space. Here we introduce ChemGPS-NP, a new tool tuned for handling the chemical diversity encountered in natural products research, in contrast to previous tools focused on the much more restricted drug-like chemical space. The aim is to provide a framework for making compound classification and comparison more efficient and stringent, to identify volumes of chemical space related to particular biological activities, and to track changes in chemical properties due to, for example, evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be discovered, making selection more efficient and increasing the probability of hit generation when screening natural compounds and analogues.
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| 30. |
- Larsson, Josefin, et al.
(författare)
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Expanding the ChemGPS chemical space with natural products
- 2005
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Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 68:7, s. 985-991
-
Tidskriftsartikel (refereegranskat)abstract
- Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
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| 31. |
- Löken, Line Sofie, 1977, et al.
(författare)
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A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine
- 2022
-
Ingår i: Journal of Neurophysiology. - : AMER PHYSIOLOGICAL SOC. - 0022-3077 .- 1522-1598. ; 127:2, s. 463-473
-
Tidskriftsartikel (refereegranskat)abstract
- Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of soda) affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch. NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.
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| 32. |
- Oddo, Calogero Maria, 1983, et al.
(författare)
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A mechatronic platform for human touch studies
- 2011
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Ingår i: Mechatronics. - : Elsevier BV. - 0957-4158. ; 21:3, s. 604-613
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Tidskriftsartikel (refereegranskat)abstract
- The development of a mechatronic tactile stimulation platform for touch studies is presented. The platform was developed for stimulation of the fingertip using textured surfaces, providing repeatable tangential sliding motion of stimuli with controlled indentation force. Particular requirements were addressed to make the platform suitable for neurophysiological studies in humans with particular reference to electrophysiological measurements, but allowing a variety of other studies too, such as psychophysical, tri-bological and artificial touch ones. The design of the mechatronic tactile stimulator is detailed, as well as the performance in tracking reference trajectories. Using microneurography, we recorded from human tactile afferents and validated the platform compatibility with the exacting demands of electrophysiological methods, comprising the absence of spurious vibrations and the lack of relevant electromagnetic interference.
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| 33. |
- Oddo, Calogero Maria, 1983, et al.
(författare)
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Roughness Encoding in Human and Biomimetic Artificial Touch: Spatiotemporal Frequency Modulation and Structural Anisotropy of Fingerprints
- 2011
-
Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 11:6, s. 5596-5615
-
Tidskriftsartikel (refereegranskat)abstract
- The influence of fingerprints and their curvature in tactile sensing performance is investigated by comparative analysis of different design parameters in a biomimetic artificial fingertip, having straight or curved fingerprints. The strength in the encoding of the principal spatial period of ridged tactile stimuli (gratings) is evaluated by indenting and sliding the surfaces at controlled normal contact force and tangential sliding velocity, as a function of fingertip rotation along the indentation axis. Curved fingerprints guaranteed higher directional isotropy than straight fingerprints in the encoding of the principal frequency resulting from the ratio between the sliding velocity and the spatial periodicity of the grating. In parallel, human microneurography experiments were performed and a selection of results is included in this work in order to support the significance of the biorobotic study with the artificial tactile system.
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| 34. |
- Park, Sungkyu, et al.
(författare)
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Cyclotide Evolution : Insights from the Analyses of Their Precursor Sequences, Structures and Distribution in Violets (Viola)
- 2017
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Ingår i: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Cyclotides are a family of plant proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. By disrupting cell membranes, the cyclotides function as host defense peptides by exhibiting insecticidal, anthelmintic, antifouling, and molluscicidal activities. In this work, we provide the first insight into the evolution of this family of plant proteins by studying the Violaceae, in particular species of the genus Viola. We discovered 157 novel precursor sequences by the transcriptomic analysis of six Viola species: V. albida var. takahashii, V. mandshurica, V. orientalis, V. verecunda, V. acuminata, and V. canadensis. By combining these precursor sequences with the phylogenetic classification of Viola, we infer the distribution of cyclotides across 63% of the species in the genus (i.e., ~380 species). Using full precursor sequences from transcriptomes, we show an evolutionary link to the structural diversity of the cyclotides, and further classify the cyclotides by sequence signatures from the non-cyclotide domain. Also, transcriptomes were compared to cyclotide expression on a peptide level determined using liquid chromatography-mass spectrometry. Furthermore, the novel cyclotides discovered were associated with the emergence of new biological functions.
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| 35. |
- Park, Sungkyu, et al.
(författare)
-
Insights into cyclotide evolution from transcriptomic analyses and studies on their distribution in violets
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we explore cyclotide evolution by sequencing and analyzing the transcriptomes of Viola albida var. takahashii, V. mandshurica, V. orientalis, V. verecunda and V. acuminata, in combination with reported precursor sequences. The distribution of the cyclotide precursors in the genus Viola was analyzed in relation to the infrageneric phylogeny, providing insights into the overall distribution of cyclotides within the genus. The structures and activities of predicted cyclotides are linked to the evolution of their precursors and the associated selective pressures. Furthermore, sequence variations between related precursors were generalized to deduce evolutionary trends, and to shed light on the evolution into novel mature cyclotides with the emergence of new functions.
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| 36. |
- Rosén, Josefin, 1978-
(författare)
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ChemGPS-NP and the Exploration of Biologically Relevant Chemical Space
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chemical space is basically infinite, and comprises all molecules that could possibly exist. Intelligent ways to efficiently navigate through chemical space and to select promising compounds in drug discovery are important tasks, and the focus of this thesis. In this work a new model for chemical space navigation, ChemGPS-NP, was developed. This model is based on a methodology where a global chemical space map is defined through principal component analysis of physico-chemical properties of a reference set of compounds. Through interpolation from the reference set, positions of novel compounds can be defined on this map and interpreted as chemical properties. ChemGPS-NP was demonstrated to be able to chart the entire biologically relevant chemical space, including both drug-like and natural compounds. This is an important improvement considering the present interest in natural products (NPs) in the pharmaceutical industry, as well as the track record of NPs to serve as basis for more than 50% of all marketed drugs. ChemGPS-NP proved able to handle and process large data sets, to aid in efficient selection of test objects, and to extract useful information from the results of high-throughput screening campaigns. Using ChemGPS-NP, it was shown that NPs occupy unique regions of chemical property space in comparison to drug-like compounds, and a number of features distinguishing NPs from medicinal chemistry compounds were identified. ChemGPS-NP was also shown to be able to reliably predict mode of action of anticancer agents based on chemical structure, a finding that has potential to improve cancer research efficiency. Applying a property based similarity search based on calculated eight dimensional Euclidean distances from ChemGPS-NP rendered a tool to identify NP inspired potential leads for drug discovery. Furthermore, ChemGPS-NPWeb, an online version of ChemGPS-NP, was developed, which provides scientists with open access to the tool via http://chemgps.bmc.uu.se/.
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| 37. |
- Rosén, Josefin, 1978-, et al.
(författare)
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ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action
- 2009
-
Ingår i: QSAR & combinatorial science (Print). - : Wiley. - 1611-020X .- 1611-0218. ; 28:4, s. 436-446
-
Tidskriftsartikel (refereegranskat)abstract
- A combined graph describing the growth inhibition values from a number of human cancer cell lines represents an activity profile for a compound. The fact that compounds with similar activity profiles often show similar mode of action (MOA) has frequently been used in prediction of MOA. Obtaining the profiles is demanding with respect to both time and resources. Therefore, as a work and time efficient alternative, we explore the central premise of medicinal chemistry that structurally similar molecules often have similar biological activity. In this study we investigate correlations between chemical structure and MOA, and subsequently use this as a complementing basis for prediction. The correlations between MOA and activity profile on one hand and between MOA and chemical structure on the other were analyzed for anticancer agents, classified with regard to MOA, using principal component analysis (PCA), chemographic mapping with ChemGPS-NP, and orthogonal partial least squares discriminant analysis (OPLS-DA). The compounds clustered according to MOA both based on chemical structures and activity profiles. The subsequent validation with external test sets showed that initial PCA scores prediction or chemographic mapping followed by OPLS-DA could be used for prediction of MOA as well as identification of novel MOAs in a highly accurate way. An efficient and straight forward procedure for prediction of MOA of anticancer agents is suggested. With today’s resistance problems in cancer therapy, there is a need for new anticancer agents and mechanisms. We believe that the fast initial virtual guidance this procedure implies, especially the novel step using ChemGPS-NP, could be of general use in early stages of cancer research.
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| 38. |
- Rosén, Josefin, 1978-, et al.
(författare)
-
ChemGPS-NPweb : chemical space navigation online
- 2009
-
Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 23:4, s. 253-259
-
Tidskriftsartikel (refereegranskat)abstract
- Internet has become a central source for information, tools, and services facilitating the work for medicinal chemists and drug discoverers worldwide. In this paper we introduce a web-based public tool, ChemGPS-NPWeb (http://chemgps.bmc.uu.se), for comprehensive chemical space navigation and exploration in terms of global mapping onto a consistent, eight dimensional map over structure derived physico-chemical characteristics. ChemGPS-NPWeb can assist in compound selection and prioritization; property description and interpretation; cluster analysis and neighbourhood mapping; as well as comparison and characterization of large compound datasets. By using ChemGPS-NPWeb, researchers can analyze and compare chemical libraries in a consistent manner. In this study it is demonstrated how ChemGPS-NPWeb can assist in interpreting results from two large datasets tested for activity in biological assays for pyruvate kinase and Bcl-2 family related protein interactions, respectively. Furthermore, a more than 30-year-old suggestion of “chemical similarity” between the natural pigments betalains and muscaflavins is tested.
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| 39. |
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| 40. |
- Rosén, Josefin, 1978-, et al.
(författare)
-
Novel chemical space exploration via natural products
- 2009
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:7, s. 1953-1962
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Tidskriftsartikel (refereegranskat)abstract
- Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties.
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| 41. |
- Skånér, Ylva, et al.
(författare)
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General practitioners’ reasoning when considering the diagnosis heart failure : A think-aloud study.
- 2005
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Ingår i: BMC Family Practice. - : Springer Science and Business Media LLC. - 1471-2296. ; 6:4
-
Tidskriftsartikel (refereegranskat)abstract
- Diagnosing chronic heart failure is difficult, especially in mild cases or early in the course of the disease, and guidelines are not easily implemented in everyday practice. The aim of this study was to investigate general practitioners' diagnostic reasoning about patients with suspected chronic heart failure in comparison with recommendations in European guidelines. The think-aloud technique was used. Fifteen general practitioners reasoned about six case vignettes, representing authentic patients with suspected chronic heart failure. Information about each case was added successively in five steps. The general practitioners said their thoughts aloud while reasoning about the probability of the patient having chronic heart failure, and tried to decide about the diagnosis. Arguments for and against chronic heart failure were analysed and compared to recommendations in guidelines. Information about ejection fraction was the most frequent diagnostic argument, followed by information about cardiac enlargement or pulmonary congestion on chest X-ray. However, in a third of the judgement situations, no information about echocardiography was utilized in the general practitioners' diagnostic reasoning. Only three of the 15 doctors used information about a normal electrocardiography as an argument against chronic heart failure. Information about other cardio-vascular diseases was frequently used as a diagnostic argument. It was concluded that the clinical information was not utilized to the extent recommended in guidelines. Some implications of our study are that 1) general practitioners need more information about how to utilize echocardiography when diagnosing chronic heart failure, 2) guidelines ought to give more importance to information about other cardio-vascular diseases in the diagnostic reasoning, and 3) guidelines ought to treat the topic of diastolic heart failure in a clearer way.
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| 42. |
- Strandberg, Johan, et al.
(författare)
-
Fuels as contaminants in water : Chemical content, odour thresholds, ecotoxicological data and evaporation of VOC:s to air
- 2024
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Oil spills, the most frequent environmental incidents in Sweden, have decreased in recent years but still pose risks to drinking water and aquatic ecosystems, with about 600 cases registered annually by the Swedish Fire Protection Association. Yet, detailed information about modern fuels and their environmental and human health impacts remains scarce. Hence, this study focuses on enhancing the understanding of the environmental impact of common fuels.This study collected thirty fuel samples of different types: petrol, diesel, fuel oil, and marine gas oil. A selected number of substances in the fuels and the water-soluble phase were analysed using GC-MS. A crucial step in the analytical method in this project, since the focus was on the effect on sub-surface aquatic life and drinking water production, was to form a stable water-accommodated fraction (WAF) where non-dissolved fuel elements were separated from the water. Since odour properties were of interest, the mixing was extensive, with limited space allowed for gases, meaning that more volatile organic carbons (VOC:s) would be in solution.The chemical analysis focused on identifying and quantifying 50 substances, including aromatic hydrocarbons, aliphatic hydrocarbons, ethers, and esters, plus 17 polycyclic aromatic hydrocarbons (PAH:s) for eight of the samples. These substances were chosen for their significance in interpreting results related to odour and to illustrate the proportion of light and heavy substances in the fuels. Twelve of the thirty fuel samples were selected for odour threshold testing, where a dilution series from the WAF was used to evaluate the intensity of odours at different concentrations. Six samples were chosen for ecotoxicological assessments on crustaceans, algae, and bacteria, offering a comprehensive understanding of the ecotoxicity of the fuel-water mixtures. Four samples were used in tailor-made evaporation experiments to study how volatile fuel components evaporate from the water surface under different temperatures and ethanol concentrations. For odour, three fuels were notably distinguished, namely the fuels containing higher concentrations of ether: 98 Octane petrol and E85 fuel. While there was significant variability in odour thresholds among different panel members, the concentration of MTBE (Methyl Tertiary-Butyl Ether) in the fuel-water mixtures was generally identified as a precise predictor of odour.Conversely, the lack of ether in diesel fuels made them significantly less prone to cause odour in the WAF. Generally, petrol-specific substances dissolve more readily in water than those in diesel, which only marginally ended up in the water-accommodated fraction. However, ethanol in petrol and RME (rapeseed methyl ester) in diesel favoured the dissolution of hydrocarbons into water. For ether, which is of utmost importance for odour, a strong correlation was observed between the concentration of ether in water and its content in the fuel. Therefore, it is possible to predict the ether concentration in the WAF solely from ether concentration in the fuel, meaning that ethanol did not significantly increase ether solubility. In the case of a fuel spill into surface water, volatile substances like ether or toluene evaporate into the air, reducing the water concentration. The experimental conditions in this study do not reflect actual real-world conditions. The evaporation experiments showed that the evaporation of ether can be predicted based on the WAF ether concentration, water temperature, and ethanol content. It was found that cold water (5 °C) conditions reduce the evaporation rate of ether to almost negligible levels. The ecotoxicological tests showed reproduction inhibitions in crustaceans across all fuel samples. However, the inhibiting effect from HVO (hydrogenated vegetable oil) was only marginally greater than that of the control. Fuel oil and some petrol fuels had detrimental effects on the algae growth, while diesel did not. The decrease of luminescence of bacteria, an indicator of toxicity, exhibited a similar trend; petrol fuels inhibited luminescence more than diesel. None of the fuels disturbed activated sludge to the extent that respiration was inhibited at toxic levels.This shows that an active sludge is more robust than single organisms, probably due to the diverse bacteria flora. For a drinking water producer, fuels containing water-soluble ethers, such as E85 and 98 Octane petrol, are the most prominent risk. If a spill occurs in the drinking water supply, the production disturbance likelihood depends on the dilution prerequisites below the odour threshold of 1.5-4 µg/L. The study also shows that modern diesel has become an issue of marginal concern for surface water-based raw water sources due to very low solubility and regulations that have reduced the amounts of toxic substances in the products. For freshwater ecosystems, water-soluble petrol-associated substances and hydrophobic toxic substances in fuel oil or EU diesel have the most severe effects during a spill. However, MK1 and HVO diesel only marginally affected the test organisms compared to the control, which represents unaffected organisms.
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| 43. |
- Strawbridge, Rona J., et al.
(författare)
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Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
-
Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
-
Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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| 44. |
- Vancheri, Federico, et al.
(författare)
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General practitioners’ coronary risk assessments and lipid-lowering treatment decisions in primary prevention : Comparison between two European areas with different cardiovascular risk levels
- 2008
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Ingår i: Primary Health Care Research and Development. - : Cambridge University Press. - 1463-4236 .- 1477-1128. ; 9:4, s. 248-256
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate whether general practitioners (GPs) in countries with different levels of cardiovascular risk would make different risk estimates and choices about lipid-lowering treatment when assessing the same patients. Background: Primary prevention of coronary heart disease should be based on the quantitative assessment of an individual’s absolute risk. Risk-scoring charts have been developed, but in clinical practice risk estimates are often made on a subjective basis. Methods: Mail survey: Nine written case simulations of four cases rated by the Framingham equations as high risk, and five rated as low-risk were mailed to 90 randomly selected GPs in Stockholm, as a high-risk area, and 90 in Sicily as a low-risk area. GPs were asked to estimate the 10-year coronary risk and to decide whether to start a lipid-lowering drug treatment. Findings: Overall risk estimate was lower in Stockholm than in Sicily for both high-risk cases (median 20.8; interquartile range (IQR) 13.5–30.0 versus 29.1; IQR 21.8–30.6; P = 0.033) and low-risk cases (6.4; IQR 2.2–9.6 versus 8.5; IQR 6.0–14.5; P = 0.006). Swedish GPs were less likely than Sicilian GPs to choose to treat when their estimate of risk was above the recommended cut-off limit for treatment, both for the entire group (means of GPs’ decision proportions: 0.64 (0.45) and 0.92 (0.24), respectively, P = 0.001) and for high-risk cases (0.65 (0.45) and 0.93 (0.23), P = 0.001). Conclusions: The cardiovascular risk level in the general population influences GPs’ evaluations of risk and subsequent decisions to start treatment. GPs’ risk estimates seem to be inversely related to the general population risk level, and may lead to inappropriate over- or under-treatment of patients.
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| 45. |
- Wannberg, Johan, et al.
(författare)
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A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
- 2018
-
Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 28:3, s. 519-522
-
Tidskriftsartikel (refereegranskat)abstract
- A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.
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| 46. |
- Wasling, Helena Backlund, 1972, et al.
(författare)
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Cortical processing of lateral skin stretch stimulation in humans.
- 2008
-
Ingår i: Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. - : Springer Science and Business Media LLC. - 1432-1106. ; 190:2, s. 117-24
-
Tidskriftsartikel (refereegranskat)abstract
- Direction discrimination of a moving tactile stimulus requires intact dorsal columns and provides a sensitive clinical test of somatosensory dysfunction. Cortical mechanisms are poorly understood. We have applied tangential skin pulls to the right lower leg during functional magnetic resonance imaging. Healthy subjects judged the direction of the skin pulls (task experiment, n = 7) or received skin pulls passively (no task experiment, n = 8). Second somatosensory cortex (S2) was activated in the task as well as no task experiment, and there was no significant difference in cortical activation between the two experiments. Within S2 nearly all subjects had prominent activations in the caudal and superficial part, i.e., in the opercular parietal (OP) area 1. S1 was activated in only one of the subjects. Thus, S2 and especially OP 1 seems to be important for processing of lateral skin stretch stimulation. The finding suggests that a lesion of this area might cause a disturbance in tactile direction discrimination which should be relevant for clinical testing.
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| 47. |
- Watkins, Roger H., 1988, et al.
(författare)
-
Evidence for sparse C-tactile afferent innervation of glabrous human hand skin
- 2021
-
Ingår i: Journal of neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 125:1, s. 232-237
-
Tidskriftsartikel (refereegranskat)abstract
- C-tactile (CT) afferents were long-believed to be lacking in humans, but these were subsequently shown to densely innervate the face and arm skin, and to a lesser extent the leg. Their firing frequency to stroking touch at different velocities has been correlated with ratings of tactile pleasantness. CT afferents were thought to be absent in human glabrous skin; however, tactile pleasantness can be perceived across the whole body, including glabrous hand skin. We used microneurography to investigate mechanoreceptive afferents in the glabrous skin of the human hand, during median and radial nerve recordings. We describe CTs found in the glabrous skin, with characteristics comparable with those in hairy arm skin, and detail recordings from three such afferents. CTs were infrequently encountered in the glabrous skin and we estimate that the ratio of recorded CTs relative to myelinated mechanoreceptors (1:80) corresponds to an absolute innervation density of around seven times lower than in hairy skin. This sparse innervation sheds light on discrepancies between psychophysical findings of touch perception on glabrous skin and hairy skin, although the role of these CT afferents in the glabrous skin remains subject to future work. NEW & NOTEWORTHY Human touch is encoded by low-threshold mechanoreceptors, including myelinated A beta afferents and unmyelinated C-tactile (CT) afferents. CTs are abundant in hairy skin and are thought to code gentle, stroking touch that signals positive affective interactions. CTs have never been described in human glabrous skin, yet we show evidence of their existence on the hand, albeit at a relatively low density. Glabrous skin CTs may provide modulatory reinforcement of gentle tactile interactions during touch using the hands.
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| 48. |
- Watkins, Roger H., 1988, et al.
(författare)
-
Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing
- 2017
-
Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 117:4, s. 1608-1614
-
Tidskriftsartikel (refereegranskat)abstract
- C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological "signatures" (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information. NEW & NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch.
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| 49. |
- Watkins, R. H., et al.
(författare)
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Slowly-adapting type II afferents contribute to conscious touch sensation in humans: Evidence from single unit intraneural microstimulation
- 2022
-
Ingår i: Journal of Physiology-London. - : Wiley. - 0022-3751 .- 1469-7793. ; 600:12, s. 2939-2952
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Tidskriftsartikel (refereegranskat)abstract
- Slowly-adapting type II (SA-II, Ruffini) mechanoreceptive afferents respond well to pressure and stretch, and are regularly encountered in human microneurography studies. Despite an understanding of SA-II response properties, their role in touch perception remains unclear. Specific roles of different myelinated A beta mechanoreceptive afferents in tactile perception have been revealed using single unit intraneural microstimulation (INMS), via microneurography, recording from and then electrically stimulating individual afferents. This method directly links single afferent artificial activation to perception, where INMS produces specific 'quantal' touch percepts associated with different mechanoreceptive afferent types. However, SA-II afferent stimulation has been ambiguous, producing inconsistent, vague sensations, or no clear percept. We physiologically characterized hundreds of individual A beta mechanoreceptive afferents in the glabrous hand skin and examined the subsequent percepts evoked by trains of low amplitude INMS current pulses (<10 mu A). We present 18 SA-II afferents where INMS resulted in a clear, electrically evoked sensation of large (similar to 36 mm(2)) diffuse pressure, which was projected precisely to their physiologically-defined receptive field in the skin. This sensation was felt as natural, distinctive from other afferents, and showed no indications of multi-afferent stimulation. Stimulus frequency modulated sensation intensity and even brief stimuli (4 pulses, 60 ms) were perceived. These results suggest that SA-II afferents contribute to perceived tactile sensations, can signal this rapidly and precisely, and are relevant and important for computational models of touch sensation and artificial prosthetic feedback. Key points Slowly adapting type II mechanoreceptors (SA-IIs) are primary sensory neurons in humans that respond to pressure and stretch applied to the skin. To date, no specific conscious correlate of touch has been linked to SA-II activation. Using microneurography and intraneural microstimulation to stimulate single sensory neurons in human subjects, we find a specific sensation linked to the activation of single SA-II afferents. This sensation of touch was reported as gentle pressure and subjects could detect this with a high degree of accuracy. Methods of artificial tactile sensory feedback and computational models of touch should include SA-IIs as meaningful contributors to the conscious sensation of touch.
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