| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 10. |
- Birznieks, Ingvars, et al.
(författare)
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Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type
- 2019
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Ingår i: eLIFE. - Cambridge, United Kingdom : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies amp;lt; 60 Hz) and vibratory hum (frequencies amp;gt; 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.
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| 11. |
- Chiang, Nan, et al.
(författare)
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Infection regulates pro-resolving mediators that lower antibiotic requirements
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 484, s. 524-528
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Tidskriftsartikel (refereegranskat)abstract
- Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (105colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12h were at significantly greater levels than in exudates from higher titre E. coli (107c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (Ri). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 107c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance. © 2012 Macmillan Publishers Limited. All rights reserved.
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- Deen, Pascale, et al.
(författare)
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A design study of VOR: A versatile optimal resolution chopper spectrometer for the ESS
- 2015
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Ingår i: QENS/WINS 2014 - 11th International Conference on Quasielastic Neutron Scattering and 6th International Workshopon Inelastic Neutron Spectrometers. - : EDP Sciences. - 2101-6275 .- 2100-014X. ; 83, s. 03002-03002
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Konferensbidrag (refereegranskat)abstract
- VOR, the versatile optimal resolution chopper spectrometer, is designed to probe dynamic phenomena that are currently inaccessible for inelastic neutron scattering due to flux limitations. VOR is a short instrument by the standards of the European Spallation Source (ESS), 30.2m moderator to sample, and provides instantaneous access to a broad dynamic range, 1-120 meV within each ESS period. The short instrument length combined with the long ESS pulse width enables a quadratic flux increase, even at longer wavelengths, by relaxing energy resolution from Delta E/E = 1% up to Delta E/E = 7%. This is impossible both on a long chopper spectrometer at the ESS and with instruments at short pulsed sources. In comparison to current day chopper spectrometers, VOR can offer an order of magnitude improvement in flux for equivalent energy resolutions, Delta E/E = 1-3%. Further relaxing the energy resolution enables VOR to gain an extra order of magnitude in flux. In addition, VOR has been optimised for repetition rate multiplication (RRM) and is therefore able to measure, in a single ESS period, 6-14 incident wavelengths, across a wavelength band of 9 angstrom with a novel chopper configuration that transmits all incident wavelengths with equivalent counting statistics. The characteristics of VOR make it a unique instrument with capabilities to access small, limited-lifetime samples and transient phenomena with inelastic neutron scattering.
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- Vickery, A., et al.
(författare)
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Choppers to optimise the repetition rate multiplication technique on a direct geometry neutron chopper spectrometer
- 2014
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 1089-7623 .- 0034-6748. ; 85:11
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Tidskriftsartikel (refereegranskat)abstract
- In recent years the use of repetition rate multiplication (RRM) on direct geometry neutron spectrometers has been established and is the common mode of operation on a growing number of instruments. However, the chopper configurations are not ideally optimised for RRM with a resultant 100 fold flux difference across a broad wavelength band. This paper presents chopper configurations that will produce a relative constant (RC) energy resolution and a relative variable (RV) energy resolution for optimised use of RRM. The RC configuration provides an almost uniform Delta E/E for all incident wavelengths and enables an efficient use of time as the entire dynamic range is probed with equivalent statistics, ideal for single shot measurements of transient phenomena. The RV energy configuration provides an almost uniform opening time at the sample for all incident wavelengths with three orders of magnitude in time resolution probed for a single European Spallation Source (ESS) period, which is ideal to probe complex relaxational behaviour. These two chopper configurations have been simulated for the Versatile Optimal Resolution direct geometry spectrometer, VOR, that will be built at ESS. (c) 2014 AIP Publishing LLC.
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