| 1. |
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| 2. |
- Gorlova, Olga, et al.
(författare)
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Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (IcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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| 3. |
- Nordin, E. Z., et al.
(författare)
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Secondary organic aerosol formation from idling gasoline passenger vehicle emissions investigated in a smog chamber
- 2013
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 13:12, s. 6101-6116
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Tidskriftsartikel (refereegranskat)abstract
- Gasoline vehicles have recently been pointed out as potentially the main source of anthropogenic secondary organic aerosol (SOA) in megacities. However, there is a lack of laboratory studies to systematically investigate SOA formation in real-world exhaust. In this study, SOA formation from pure aromatic precursors, idling and cold start gasoline exhaust from three passenger vehicles (EURO2-EURO4) were investigated with photo-oxidation experiments in a 6 m(3) smog chamber. The experiments were carried out down to atmospherically relevant organic aerosol mass concentrations. The characterization instruments included a high-resolution aerosol mass spectrometer and a proton transfer mass spectrometer. It was found that gasoline exhaust readily forms SOA with a signature aerosol mass spectrum similar to the oxidized organic aerosol that commonly dominates the organic aerosol mass spectra downwind of urban areas. After a cumulative OH exposure of similar to 5 x 10(6) cm(-3) h, the formed SOA was 1-2 orders of magnitude higher than the primary OA emissions. The SOA mass spectrum from a relevant mixture of traditional light aromatic precursors gave f(43) (mass fraction at m/z = 43), approximately two times higher than to the gasoline SOA. However O:C and H:C ratios were similar for the two cases. Classical C-6-C-9 light aromatic precursors were responsible for up to 60% of the formed SOA, which is significantly higher than for diesel exhaust. Important candidates for additional precursors are higher-order aromatic compounds such as C-10 and C-11 light aromatics, naphthalene and methyl-naphthalenes. We conclude that approaches using only light aromatic precursors give an incomplete picture of the magnitude of SOA formation and the SOA composition from gasoline exhaust.
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| 4. |
- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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| 5. |
- Stenler, S., et al.
(författare)
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Micro-minicircle gene therapy : Implications of size on fermentation, complexation, shearing resistance, and expression
- 2014
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Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 3, s. e140-
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Tidskriftsartikel (refereegranskat)abstract
- The minicircle (MC), composed of eukaryotic sequences only, is an interesting approach to increase the safety and efficiency of plasmid-based vectors for gene therapy. In this paper, we investigate micro-MC (miMC) vectors encoding small regulatory RNA. We use a construct encoding a splice-correcting U7 small nuclear RNA, which results in a vector of 650 base pairs (bp), as compared to a conventional 3600 bp plasmid carrying the same expression cassette. Furthermore, we construct miMCs of varying sizes carrying different number of these cassettes. This allows us to evaluate how size influences production, supercoiling, stability and efficiency of the vector. We characterize coiling morphology by atomic force microscopy and measure the resistance to shearing forces caused by an injector device, the Biojector. We compare the behavior of miMCs and plasmids in vitro using lipofection and electroporation, as well as in vivo in mice. We here show that when the size of the miMC is reduced, the formation of dimers and trimers increases. There seems to be a lower size limit for efficient expression. We demonstrate that miMCs are more robust than plasmids when exposed to shearing forces, and that they show extended expression in vivo.
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| 6. |
- Ketelhuth, D. F., et al.
(författare)
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Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses
- 2011
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Ingår i: Circulation. - Stockholm : Karolinska Institutet, Dept of Medicine, Solna. - 1524-4539 .- 0009-7322. ; 124:22
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subendothelial deposited low-density lipoprotein particles are a known inflammatory factor in atherosclerosis. However, the causal components derived from low-density lipoprotein are still poorly defined. Apolipoprotein B100 (ApoB100) is the unexchangeable protein component of low-density lipoprotein, and the progression of atherosclerosis is associated with immune responses to ApoB100-derived peptides. In this study, we analyzed the proinflammatory activity of ApoB100 peptides in atherosclerosis. METHODS AND RESULTS: By screening a peptide library of ApoB100, we identified a distinct native peptide referred to as ApoB100 danger-associated signal 1 (ApoBDS-1), which shows sequence-specific bioactivity in stimulation of interleukin-8, CCL2, and interleukin-6. ApoBDS-1 activates mitogen-activated protein kinase and calcium signaling, thereby effecting the expression of interleukin-8 in innate immune cells. Ex vivo stimulation of carotid plaques with ApoBDS-1 enhances interleukin-8 and prostaglandin E release. Furthermore, we demonstrated that ApoBDS-1-positive peptide fragments are present in atherosclerotic lesions using immunoassays and that low-molecular-weight fractions isolated from plaque show ApoBDS-1 activity inducing interleukin-8 production. CONCLUSIONS: Our data show that ApoBDS-1 is a previously unrecognized peptide with robust proinflammatory activity, contributing to the disease-promoting effects of low-density lipoprotein in the pathogenesis of atherosclerosis.
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| 7. |
- Mousavi, Arash, et al.
(författare)
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A method for Human Resource Risk Management in Mobile Workforce Brokering Systems
- 2011
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Ingår i: American Journal of Applied Sciences. - : Science Publications. - 1546-9239 .- 1554-3641. ; 8:12, s. 1287-1294
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Tidskriftsartikel (refereegranskat)abstract
- Problem statement: Human Resource Risk Management is one of the crucial issues in Mobile Workforce Management Systems (MWM) in general, and in Mobile Workforce Brokering Systems (MWBS) in Particular. It is important because, if not properly managed, it will cause reduction in accuracy of the automated MWBS, which in turn necessitates more human involvement in the task allocation process. Thus, no reliable planning and scheduling schema can be made or achieved. Approach: However, a proven approach to tackle this problem is via contingency planning. In this study, we examined a specific type of HR risk called Unexpected Absence of mobile workforces in the context of an ontology-driven and multiagent-based MWBS. Our contingency plan that mainly consists of a statistical method is incorporated into the body of a coordination medium represented in OWL ontology format. Results: The proposed statistical method evaluates the past history and the current claims of an MW in order to find out a realistic plan for the next period of the system's run. Conclusion: Finally, via a case study we have illustrated that this method increases the accuracy and reliability of a periodical plan, made for MWBS in its initialization phase.
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| 8. |
- Mousavi, Arash, et al.
(författare)
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An ontology driven, procedural reasoning system-like agent model, for multi-agent based mobile workforce brokering systems
- 2010
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Ingår i: Journal of Computer Science. - 0973-2926. ; 6:5, s. 557-565
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Tidskriftsartikel (refereegranskat)abstract
- Problem statement: It has been proven that Believe, Desire, Intention (BDI) agent architecture, performs suitably in dynamic and unpredictable environments. Although BDI architecture has been formulated rigorously, implementing BDI architecture is not as straightforward as it has been promised. Nevertheless, the preeminent implementation of BDI architecture is Procedural Reasoning System (PRS) and Jadex is a Java-based platform that successfully applies PRS BDI architecture to implement BDI agents. However, Jadex utilizes XML format to represent plans, beliefs and goals which are the core of the PRS BDI agents. Although XML is a suitable format for exchanging data, it does not add any semantic to the data that it represents. Approach: In contrast, in our proposed Ontology driven PRS like model (O-PRS), we used Ontology with OWL format to represent Believes, Plans and Events. Our Ontology had been designed particularly for implementing BDI agents which are used in Mobile Workforce Brokering Systems (MWBS), a multi-agent system that automated the process of allocating tasks to Mobile Workforces. Results: This research was an endeavor to equip the PRS model with Ontology and semantic knowledge representation and reasoning capability. In this study firstly, our proposed model was formulated, then the model was been examined using a simulation tool (MWBS-SIM) which simulated MWBS in its Initialization phase. We used JADE to implement the Agents, Protégé OWL to create the Ontology and Jena as a semantic web platform by means of which MWBS is able to connect to the Ontology and apply the O-PRS model. Conclusion: The result of our simulation showed that O-PRS is a feasible approach. Furthermore, Ontology provided better means for knowledge sharing and navigation therefore, multi-agent systems constructed using O-PRS, were more generic and more adaptable in comparison with those that use XML.
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| 9. |
- Mousavi, Arash, et al.
(författare)
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Ontology-driven coordination model for multiagent-based mobile workforce brokering systems
- 2012
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Ingår i: Applied intelligence (Boston). - : Springer Science and Business Media LLC. - 0924-669X .- 1573-7497. ; 36:4, s. 768-787
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Tidskriftsartikel (refereegranskat)abstract
- Coordination has been recognized by many researchers as the most important feature of multi-agent systems. Coordination is defined as managing interdependencies amongst activities (Malone and Crowston in ACM Comput. Surv. 26(1):87-119, 1994). The traditional approach of implementing a coordination mechanism is to hard-wire it into a coordination system at design time. However, in dynamic and open environments, many attributes of the system cannot be accurately identified at the design time. Therefore, dynamic coordination, capable of coordinating activities at run-time, has emerged. On the other hand, a successful dynamic coordination model for multi-agent systems requires knowledge sharing as well as common vocabulary. Therefore, an ontological approach is an appropriate way in proposing dynamic coordination models for multi-agent systems. In this paper, an Ontology-Driven Dynamic Coordination Model (O-DC) for Multiagent-Based Mobile Workforce Brokering Systems (MWBS) (Mousavi et al. in Int. J. Comput. Sci. 6:(5):557-565, 2010; Mousavi et al. in Proceedings of 4th IEEE international symposium on information technology, ITSim'10, Kuala Lumpur, Malaysia, 15-17 June 2010, vol. 3, pp. 1416-1421, 2010; Mousavi and Nordin in Proceedings of the IEEE international conference on electrical engineering and informatics, Bandung, Indonesia, 17-19 June 2007, pp. 294-297, 2007) is proposed and formulated. Subsequently, the applicability of O-DC is examined via simulation based on a real-world scenario
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| 10. |
- Mousavi, Arash, et al.
(författare)
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Providing fairness to mobile workforces in an automated task allocation process : A semantic multi-agent approach
- 2012
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Ingår i: American Journal of Applied Sciences. - : Science Publications. - 1546-9239 .- 1554-3641. ; 9:7, s. 1055-1062
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Tidskriftsartikel (refereegranskat)abstract
- Problem statement: Mobile Workforces (MW) unlike computational resources of an automated system are active but not passive entities. Therefore, an automated resource allocation system that deals with MWs should assign tasks to them fairly and in a comparatively equal manner. An unfair task allocation in a group will cause dissatisfaction, which in turn demotivates MWs who are supposed to work as a team. Approach: In an automated Mobile Workforce Brokering System (MWBS) tasks are automatically assigned to MWs at Run-Time phase of the system's run. However, the environmental risks specifically risk of disconnection disrupts the task allocation process. Disconnection causes unfair task allocation when an MW must carry the next upcoming task according to a rotator work schedule, but he is disconnected. In this situation another MW has to perform the task in order to satisfy a pre-planned daily workload. Results: In this study we explore through the Run-Time phase of MWBS and explain how its underpinning ontology-driven coordination model tackles the risk of disconnection and improves the fairness in the task allocation process. Conclusion: Moreover, fairness rates in task allocation processes are compared between an existing system and MWBS and improvement in fairness rate is shown and analyzed for 4 consecutive periods (months) of the system's run
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| 11. |
- Nordin, E. Z., et al.
(författare)
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Secondary organic aerosol formation from gasoline passenger vehicle emissions investigated in a smog chamber
- 2012
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Ingår i: Atmospheric Chemistry and Physics Discussions. - : Copernicus Publications. - 1680-7367 .- 1680-7375. ; 12:12, s. 31725-31765
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Tidskriftsartikel (refereegranskat)abstract
- Gasoline vehicles have elevated emissions of volatile organic compounds during cold starts and idling and have recently been pointed out as potentially the main source of anthropogenic secondary organic aerosol (SOA) in megacities. However, there is a lack of laboratory studies to systematically investigate SOA formation in real-world exhaust. In this study, SOA formation from pure aromatic precursors, idling and cold start gasoline exhaust from one Euro II, one Euro III and one Euro IV passenger vehicles were investigated using photo-oxidation experiments in a 6 m3 smog chamber. The experiments were carried out at atmospherically relevant organic aerosol mass concentrations. The characterization methods included a high resolution aerosol mass spectrometer and a proton transfer mass spectrometer. It was found that gasoline exhaust readily forms SOA with a signature aerosol mass spectrum similar to the oxidized organic aerosol that commonly dominates the organic aerosol mass spectra downwind urban areas. After 4 h aging the formed SOA was 1–2 orders of magnitude higher than the Primary OA emissions. The SOA mass spectrum from a relevant mixture of traditional light aromatic precursors gave f43 (mass fraction at m/z = 4 3) approximately two times higher than to the gasoline SOA. However O : C and H : C ratios were similar for the two cases. Classical C6–C9 light aromatic precursors were responsible for up to 60% of the formed SOA, which is significantly higher than for diesel exhaust. Important candidates for additional precursors are higher order aromatic compounds such as C10, C11 light aromatics, naphthalene and methyl-naphthalenes.
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