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| 2. |
- Covacu, Ruxandra, et al.
(författare)
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Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis
- 2006
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 178, s. 268-268
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.
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| 3. |
- Johansson, Leif B.G.
(författare)
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Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Luminescent conjugated polymers (LCPs) and luminescent conjugated oligothiophenes (LCOs) can be used as molecular probes to study diseases associated with protein aggregation. The conventionally used dyes to study and detect protein aggregates, denoted amyloid, have been Congo red (CR) and Thioflavin T (ThT). In contrast to these amyloid ligands, LCOs offer the possibility to detect aggregated proteinaceous species occurring at earlier stages of amyloid formation as well as to distinguish different morphotypes of protein aggregates. The interaction between the LCOs and the protein deposits can be studied by fluorescence spectroscopy and microscopy both in vitro and ex vivo. In this thesis we report the development of multimodal asymmetric LCOs that can be utilized with two novel techniques, Surface Plasmon Resonance (SPR) and Positron Emission Tomography (PET), to study the interaction between LCO and amyloid fibrils in real time. With SPR, we have been able to determine binding affinities between LCO and amyloid, and with PET we have shown that radiolabelled LCOs can be used as a non-invasive method to study amyloid deposits in vivo. In addition, by alteration of the backbone (change of thiophene units), and of adding different side chains functionalities, we have shown that the properties of the amyloid ligands have a huge impact of the binding to different stages or forms of protein aggregates. By making asymmetrical LCOs, which can be attached to a surface, we also foresee a methodology that will offer the possibility to create a sensitive and selective detection method, and maybe lead to a lab-on-a-chip-application.
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| 4. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 6. |
- Lundin-Ström, Kristina B., et al.
(författare)
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Parental origin of monosomy 7 in acute leukaemia
- 2021
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Ingår i: British Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0007-1048 .- 1365-2141. ; 192:5, s. e132-e135
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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| 7. |
- Salomonsson, A., et al.
(författare)
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A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer
- 2018
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 13:10, s. S431-S432
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes.Method: Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients' medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4].Result: In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented.Conclusion: SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.
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| 10. |
- Zou, Zhenhua, 1984-
(författare)
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Real-time communication in wireless lossy networks
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The last decades’ tremendous advances in wireless communications havebeen driven mainly by personal communications. Radio resource allocationmechanisms for optimizing key metrics, such as average throughput and delay,are by now rather well-developed. However, with the increased interest inwireless machine-to-machine communication, new challenges emerge, such asmulti-hop connectivity, lossy and bursty links, battery-powered nodes, andchanging/unknown link parameters, among others. With these challenges inmind, this thesis studies real-time communication in wireless lossy networks,and how the resulting networking primitive can be used to design networkedcontrol systems with optimal closed-loop performance.First, we study optimal forwarding of deadline-constrained traffic overmulti-hop networks with losses on links described by finite-state Markovchains. We consider two problems: maximizing the probability that packetsare delivered within specified deadlines; and minimizing the expected energycost with a guaranteed probability of on-time delivery. Both problems fallinto the category of Markov Decision Processes and can be studied in a generaldynamic programming framework. Particular instances with Bernoulliand Gilbert-Elliot loss models, which admit insight and efficient computations,are discussed. Moreover, a number of extensions and variations ofthe deadline-constrained forwarding problem are investigated. These extensionsinclude systems with unknown channel states and unknown link lossmodels, scenarios with multiple concurrent flows, and solutions adapted toopportunistic routing and the recent WirelessHART standard.Second, we show how the solution for the deadline-constrained forwardingproblem can be used in the optimal co-design of networked control systems.Specifically, we consider the joint design of packet forwarding policies andcontrollers for wireless control loops where sensor data are sent to the controllerover an unreliable and energy-constrained multi-hop wireless network.For fixed sampling rate of the sensor, the co-design problem separates into twowell-defined and independent subproblems: transmission scheduling for maximizingthe deadline-constrained reliability and optimal control under packetloss. We develop optimal and implementable solutions for these subproblemsand show that the optimally co-designed system can be efficiently found.Finally, we study online shortest-path routing problems in which link delaysare time-varying and modeled by random processes with initially unknownparameters. The optimal path can only be estimated by routing packetsthrough the network and observing the realized delays. The aim is to finda routing policy that minimizes the regret (the cumulative delay difference)between the path chosen by the policy and the unknown optimal path. Weformulate the problem as a combinatorial bandit optimization problem andconsider several scenarios. For each scenario, we derive the tight asymptoticlower bound on the regret that has to be satisfied by any online routing policy.These bounds help us to understand the performance improvements wecan expect when (i) taking routing decisions at each hop rather than at thesource only, and (ii) observing per-link costs rather than aggregate path costs.Efficient algorithms are proposed and evaluated against the state-of-the-art.
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