| 1. |
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| 2. |
- 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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| 3. |
- Diez, S., et al.
(författare)
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A double-sided, shield-less stave prototype for the ATLAS Upgrade strip tracker for the High Luminosity LHC
- 2014
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 9, s. P03012-
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Tidskriftsartikel (refereegranskat)abstract
- A detailed description of the integration structures for the barrel region of the silicon strips tracker of the ATLAS Phase-II upgrade for the upgrade of the Large Hadron Collider, the so-called High Luminosity LHC (HL-LHC), is presented. This paper focuses on one of the latest demonstrator prototypes recently assembled, with numerous unique features. It consists of a shortened, shield-less, and double sided stave, with two candidate power distributions implemented. Thermal and electrical performances of the prototype are presented, as well as a description of the assembly procedures and tools.
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| 4. |
- Gonzalez-Sevilla, S., et al.
(författare)
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A double-sided silicon micro-strip Super-Module for the ATLAS Inner Detector upgrade in the High-Luminosity LHC
- 2014
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 9, s. P02003-
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Tidskriftsartikel (refereegranskat)abstract
- The ATLAS experiment is a general purpose detector aiming to fully exploit the discovery potential of the Large Hadron Collider (LHC) at CERN. It is foreseen that after several years of successful data-taking, the LHC physics programme will be extended in the so-called High-Luminosity LHC, where the instantaneous luminosity will be increased up to 5 x 10(34) cm(-2) s(-1). For ATLAS, an upgrade scenario will imply the complete replacement of its internal tracker, as the existing detector will not provide the required performance due to the cumulated radiation damage and the increase in the detector occupancy. The current baseline layout for the new ATLAS tracker is an all-silicon-based detector, with pixel sensors in the inner layers and silicon micro-strip detectors at intermediate and outer radii. The super-module is an integration concept proposed for the strip region of the future ATLAS tracker, where double-sided stereo silicon micro-strip modules are assembled into a low-mass local support structure. An electrical super-module prototype for eight double-sided strip modules has been constructed. The aim is to exercise the multi-module readout chain and to investigate the noise performance of such a system. In this paper, the main components of the current super-module prototype are described and its electrical performance is presented in detail.
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| 5. |
- Harrison, C. J., et al.
(författare)
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An international study of intrachromosomal amplification of chromosome 21 (iAMP21) : cytogenetic characterization and outcome
- 2014
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 28:5, s. 1015-1021
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Tidskriftsartikel (refereegranskat)abstract
- Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.
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| 6. |
- Hayes, A. B., et al.
(författare)
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Coulomb excitation of a Am-242 isomeric target: E2 and E3 strengths, rotational alignment, and collective enhancement
- 2010
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 82:4
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Tidskriftsartikel (refereegranskat)abstract
- A 98% pure Am-242m ( K = 5(-), t(1/2) = 141 years) isomeric target was Coulomb excited with a 170.5-MeV Ar-40 beam. The selectivity of Coulomb excitation, coupled with the sensitivity of Gammasphere plus CHICO, was sufficient to identify 46 new states up to spin 18h in at least four rotational bands; 11 of these new states lie in the isomer band, 13 in a previously unknown yrast K-pi = 6(-) rotational band, and 13 in a band tentatively identified as the predicted yrast K-pi = 5(+) band. The rotational bands based on the K-pi = 5- isomer and the 6(-) bandhead were populated by Coulomb excitation with unexpectedly equal cross sections. The gamma-ray yields are reproduced by Coulomb excitation calculations using a two-particle plus rotor model (PRM), implying nearly complete Delta K = 1 mixing of the two almost-degenerate rotational bands, but recovering the Alaga rule for the unperturbed states. The degeneracy of the 5(-) and 6(-) bands allows for precise determination of the mixing interaction strength V, which approaches the strong-mixing limit; this agrees with the 50% attenuation of the Coriolis matrix element assumed in the model calculations. The fractional admixture of the I-K(pi) = 6(6)(-) state in the nominal 6(5)(-) isomer band state is measured within the PRM as 45.6(-1.1)(+0.3)%. The E2 and M1 strengths coupling the 5(-) and 6(-) bands are enhanced significantly by the mixing, while E1 and E2 couplings to other low-K bands are not measurably enhanced. The yields of the 5(+) band are reproduced by an E3 strength of approximate to 15 W.u., competitive with the interband E2 strength. Alignments of the identified two-particle Nilsson states in Am-242 are compared with the single-particle alignments in Am-241.
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| 7. |
- Carroll, R. J., et al.
(författare)
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Blurring the Boundaries : Decays of Multiparticle Isomers at the Proton Drip Line
- 2014
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 112:9, s. 092501-
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Tidskriftsartikel (refereegranskat)abstract
- A multiparticle spin-trap isomer has been discovered in the proton-unbound nucleus 158 73 Ta 85. The isomer mainly decays by (h) over bar -ray emission with a half-life of 6.1d(1) mu s. Analysis of the gamma-ray data shows that the isomer lies 2668 keV above the known 9(+) state and has a spin 10h higher and negative parity. This 19(-) isomer also has an 8644(11) keV, 1.4(2)% alpha-decay branch that populates the 9(+) state in Lu-154. No proton-decay branch from the isomer was identified, despite the isomer being unbound to proton emission by 3261(14) keV. This remarkable stability against proton emission is compared with theoretical predictions, and the implications for the extent of observable nuclides are considered.
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| 8. |
- Van Deerlin, Vivian M, et al.
(författare)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 9. |
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| 10. |
- Carroll, R. K., et al.
(författare)
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Identification of an intracellular M17 family leucine aminopeptidase that is required for virulence in Staphylococcus aureus
- 2012
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Ingår i: Microbes and Infection. - : Elsevier BV. - 1286-4579. ; 14:11, s. 989-999
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is a highly virulent bacterial pathogen capable of causing a variety of ailments throughout the human body. It is a major public health concern due to the continued emergence of highly pathogenic methicillin resistant strains (MRSA) both within hospitals and in the community. Virulence in S. aureus is mediated by an array of secreted and cell wall associated virulence factors, including toxins, hemolysins and proteases. In this work we identify a (l) under bar eucine (a) under bar mino (p) under bar eptidase (LAP, pepZ) that strongly impacts the pathogenic abilities of S. aureus. Disruption of the pepZ gene in either Newman or USA300 resulted in a dramatic attenuation of virulence in both localized and systemic models of infection. LAP is required for survival inside human macrophages and gene expression analysis shows that pepZ expression is highest in the intracellular environment. We examine the cellular location of LAP and demonstrate that it is localized to the bacterial cytosol. These results identify for the first time an intracellular leucine aminopeptidase that influences disease causation in a Gram-positive bacterium. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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| 11. |
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| 12. |
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| 13. |
- Holmfeldt, Linda, et al.
(författare)
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The genomic landscape of hypodiploid acute lymphoblastic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:3, s. 242-252
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Tidskriftsartikel (refereegranskat)abstract
- The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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| 14. |
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| 15. |
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| 16. |
- Xu, M. H., et al.
(författare)
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Enhancement of ion generation in femtosecond ultraintense laser-foil interactions by defocusing
- 2012
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 100:8
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Tidskriftsartikel (refereegranskat)abstract
- A simple method to enhance ion generation with femtosecond ultraintense lasers is demonstrated experimentally by defocusing laser beams on target surface. When the laser is optimally defocused, we find that the population of medium and low energy protons from ultra-thin foils is increased significantly while the proton cutoff energy is almost unchanged. In this way, the total proton yield can be enhanced by more than 1 order, even though the peak laser intensity drops. The depression of the amplified spontaneous emission (ASE) effect and the population increase of moderate-energy electrons are believed to be the main reasons for the effective enhancement. (C) 2012 American Institute of Physics. [doi:10.1063/1.3688027]
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| 17. |
- Baldwin, Scott A., et al.
(författare)
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Intraclass correlation associated with therapists : estimates and applications in planning psychotherapy research
- 2011
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Ingår i: Cognitive Behaviour Therapy. - : Routledge, Taylor and Francis Group. - 1650-6073 .- 1651-2316. ; 40:1, s. 15-33
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Tidskriftsartikel (refereegranskat)abstract
- It is essential that outcome research permit clear conclusions to be drawn about the efficacy of interventions. The common practice of nesting therapists within conditions can pose important methodological challenges that affect interpretation, particularly if the study is not powered to account for the nested design. An obstacle to the optimal design of these studies is the lack of data about the intraclass correlation coefficient (ICC), which measures the statistical dependencies introduced by nesting. To begin the development of a public database of ICC estimates, the authors investigated ICCs for a variety outcomes reported in 20 psychotherapy outcome studies. The magnitude of the 495 ICC estimates varied widely across measures and studies. The authors provide recommendations regarding how to select and aggregate ICC estimates for power calculations and show how researchers can use ICC estimates to choose the number of patients and therapists that will optimize power. Attention to these recommendations will strengthen the validity of inferences drawn from psychotherapy studies that nest therapists within conditions.
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| 18. |
- Bohman, Tony, et al.
(författare)
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Prognosis of patients with whiplash-associated disorders consulting physiotherapy : development of a predictive model for recovery
- 2012
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Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with whiplash-associated disorders (WAD) have a generally favourable prognosis, yet some develop longstanding pain and disability. Predicting who will recover from WAD shortly after a traffic collision is very challenging for health care providers such as physical therapists. Therefore, we aimed to develop a prediction model for the recovery of WAD in a cohort of patients who consulted physical therapists within six weeks after the injury.METHODS: Our cohort included 680 adult patients with WAD who were injured in Saskatchewan, Canada, between 1997 and 1999. All patients had consulted a physical therapist as a result of the injury. Baseline prognostic factors were collected from an injury questionnaire administered by Saskatchewan Government Insurance. The outcome, global self-perceived recovery, was assessed by telephone interviews six weeks, three and six months later. Twenty-five possible baseline prognostic factors were considered in the analyses. A prediction model was built using Cox regression. The predictive ability of the model was estimated with concordance statistics (c-index). Internal validity was checked using bootstrapping.RESULTS: Our final prediction model included: age, number of days to reporting the collision, neck pain intensity, low back pain intensity, pain other than neck and back pain, headache before collision and recovery expectations. The model had an acceptable level of predictive ability with a c-index of 0.68 (95% CI: 0.65, 0.71). Internal validation showed that our model was robust and had a good fit.CONCLUSIONS: We developed a model predicting recovery from WAD, in a cohort of patients who consulted physical therapists. Our model has adequate predictive ability. However, to be fully incorporated in clinical practice the model needs to be validated in other populations and tested in clinical settings.
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| 19. |
- Brenner, C. M., et al.
(författare)
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Dependence of laser accelerated protons on laser energy following the interaction of defocused, intense laser pulses with ultra-thin targets
- 2011
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Ingår i: Laser and Particle Beams. - 0263-0346. ; 29:3, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- The scaling of the flux and maximum energy of laser-driven sheath-accelerated protons has been investigated as a function of laser pulse energy in the range of 15-380 mJ at intensities of 10(16)-10(18) W/cm(2). The pulse duration and target thickness were fixed at 40 fs and 25 nm, respectively, while the laser focal spot size and drive energy were varied. Our results indicate that while the maximum proton energy is dependent on the laser energy and laser spot diameter, the proton flux is primarily related to the laser pulse energy under the conditions studied here. Our measurements show that increasing the laser energy by an order of magnitude results in a more than 500-fold increase in the observed proton flux. Whereas, an order of magnitude increase in the laser intensity generated by decreasing the laser focal spot size, at constant laser energy, gives rise to less than a tenfold increase in observed proton flux.
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| 20. |
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| 21. |
- Cancelliere, Carol, et al.
(författare)
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Systematic review of return to work after mild traumatic brain injury : results of the international collaboration on mild traumatic brain injury prognosis
- 2014
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Ingår i: Archives of Physical Medicine and Rehabilitation. - : Elsevier. - 0003-9993 .- 1532-821X. ; 95:3, Suppl, s. S201-S209
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Forskningsöversikt (refereegranskat)abstract
- ObjectiveTo synthesize the best available evidence on return to work (RTW) after mild traumatic brain injury (MTBI).Data SourcesMEDLINE and other databases were searched (2001–2012) with terms including “craniocerebral trauma” and “employment.” Reference lists of eligible articles were also searched.Study SelectionControlled trials and cohort and case-control studies were selected according to predefined criteria. Studies had to assess RTW or employment outcomes in at least 30 MTBI cases.Data ExtractionEligible studies were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria. Two reviewers independently reviewed and extracted data from accepted studies into evidence tables.Data SynthesisEvidence was synthesized qualitatively according to modified Scottish Intercollegiate Guidelines Network criteria and prioritized according to design as exploratory or confirmatory. After 77,914 records were screened, 299 articles were found eligible and reviewed; 101 (34%) of these with a low risk of bias were accepted as scientifically admissible, and 4 of these had RTW or employment outcomes. This evidence is preliminary and suggests that most workers RTW within 3 to 6 months after MTBI; MTBI is not a significant risk factor for long-term work disability; and predictors of delayed RTW include a lower level of education (<11y of formal education), nausea or vomiting on hospital admission, extracranial injuries, severe head/bodily pain early after injury, and limited job independence and decision-making latitude.ConclusionsOur findings are based on preliminary evidence with varied patient characteristics and MTBI definitions, thus limiting firm conclusions. More well-designed studies are required to understand RTW and sustained employment after MTBI in the longer term (≥2y post-MTBI).
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| 22. |
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| 23. |
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| 24. |
- Green, J. S., et al.
(författare)
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Enhanced proton flux in the MeV range by defocused laser irradiation
- 2010
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Thin Al foils (50 nm and 6 mu m) were irradiated at intensities of up to 2x10(19) W cm(-2) using high contrast (10(8)) laser pulses. Ion emission from the rear of the targets was measured using a scintillator-based Thomson parabola and beam sampling 'footprint' monitor. The variation of the ion spectra and beam profile with focal spot size was systematically studied. The results show that while the maximum proton energy is achieved around tight focus for both target thicknesses, as the spot size increases the ion flux at lower energies is seen to peak at significantly increased spot sizes. Measurements of the proton footprint, however, show that the off-axis proton flux is highest at tight focus, indicating that a previously identified proton deflection mechanism may alter the on-axis spectrum. One-dimensional particle-in-cell modelling of the experiment supports our hypothesis that the observed change in spectra with focal spot size is due to the competition of two effects: decrease in laser intensity and an increase in proton emission area.
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| 25. |
- Hadinia, B., et al.
(författare)
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IN-BEAM gamma-RAY SPECTROSCOPY ABOVE THE HIGH-SPIN ISOMERIC STATE IN Lu-155
- 2013
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Ingår i: CAPTURE GAMMA-RAY SPECTROSCOPY AND RELATED TOPICS. - : WORLD SCIENTIFIC PUBL CO PTE LTD. ; , s. 139-144
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Konferensbidrag (refereegranskat)abstract
- Excited states in Lu-155 have been studied at the Accelerator Laboratory of the University of Jyvaskyla in Finland. The Lu-155 nuclei were populated using the reaction of Ni-58 on (102)pd at a beam energy of 280 MeV. The nuclei of interest were selected using the RITU gas filled recoil separator and the prompt gamma rays belonging to 155Lu were identified using the recoil-decay tagging technique. The gamma-ray transitions de-exciting the excited states above the high-spin isomeric a-decaying state in Lu-155 have been identified. A gamma-ray coincidence analysis shows that the previously reported level scheme for Lu-155 should be revised.
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| 26. |
- Hung, Ryan, et al.
(författare)
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Systematic Review of the Clinical Course, Natural History, and Prognosis for Pediatric Mild Traumatic Brain Injury : Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis
- 2014
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Ingår i: Archives of Physical Medicine and Rehabilitation. - : Elsevier. - 0003-9993 .- 1532-821X. ; 95:3, Suppl, s. S174-S191
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Forskningsöversikt (refereegranskat)abstract
- ObjectiveTo synthesize the best available evidence on prognosis after pediatric mild traumatic brain injury (MTBI).Data SourcesWe searched MEDLINE, Embase, PsycINFO, CINAHL, and SPORTDiscus (2001–2012), as well as reference lists of eligible articles, and relevant systematic reviews and meta-analyses.Study SelectionControlled trials and cohort and case-control studies were selected according to predefined criteria. Studies had to have a minimum of 30 MTBI pediatric cases. After 77,914 records were screened for the entire review, 299 studies were eligible and assessed for scientific rigor.Data ExtractionEligible studies were critically appraised using the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Two reviewers independently reviewed each study and extracted data from accepted articles into evidence tables.Data SynthesisEvidence from 25 accepted articles was synthesized qualitatively according to SIGN criteria, and prognostic information was prioritized according to design as exploratory or confirmatory. Most studies show that postconcussion symptoms and cognitive deficits resolve over time. Limited evidence suggests that postconcussion symptoms may persist in those with lower cognitive ability and intracranial pathology on neuroimaging. Preliminary evidence suggests that the risk of epilepsy is increased for up to 10 years after MTBI; however, there is insufficient high-quality evidence at this time to support this link.ConclusionsCommon post-MTBI symptoms and deficits in children are not specific to MTBI and appear to resolve with time; however, limited evidence suggests that children with intracranial pathology on imaging may experience persisting symptoms or deficits. Well-designed, long-term studies are needed to confirm these findings.
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| 27. |
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| 28. |
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| 29. |
- Stanton, G. R., et al.
(författare)
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Chelation-Controlled Addition of Organozincs to alpha-Chloro Aldimines
- 2012
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134:42, s. 17599-17604
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Tidskriftsartikel (refereegranskat)abstract
- Nucleophilic additions to alpha-chiral alpha-halo carbonyl derivatives are well-known to generate Cornforth-Evans products via a nonchelation pathway. What was unprecedented before this report is C-X bonds reversing the diastereoselectivity through coordination to metals during C-C bond-forming reactions (chelation control). Herein we describe chelation control involving C-X bonds in highly diastereoselective additions of organozinc reagents to a variety of alpha-chloro aldimines. The unique ability of alkylzinc halide Lewis acids to coordinate to the Cl, N, and O of alpha-chloro sulfonyl imine substrates is supported by computational studies.
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| 30. |
- Ahola-Erkkilä, Sofia, et al.
(författare)
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Ketogenic diet slows down mitochondrial myopathy progression in mice
- 2010
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Ingår i: Human Molecular Genetics. - : Elsevier. - 0964-6906 .- 1460-2083. ; 19:10, s. 1974-1984
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Coury, M., et al.
(författare)
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Influence of laser irradiated spot size on energetic electron injection and proton acceleration in foil targets
- 2012
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 100:7
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Tidskriftsartikel (refereegranskat)abstract
- The influence of irradiated spot size on laser energy coupling to electrons, and subsequently to protons, in the interaction of intense laser pulses with foil targets is investigated experimentally. Proton acceleration is characterized for laser intensities ranging from 2 x 10(18) - 6 x 10(20) W/cm(2), by (1) variation of the laser energy for a fixed irradiated spot size, and (2) by variation of the spot size for a fixed energy. At a given laser pulse intensity, the maximum proton energy is higher under defocus illumination compared to tight focus and the results are explained in terms of geometrical changes to the hot electron injection. (C) 2012 American Institute of Physics. [doi:10.1063/1.3685615]
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| 35. |
- Coury, M., et al.
(författare)
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Injection and transport properties of fast electrons in ultraintense laser-solid interactions
- 2013
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Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 20:4
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Tidskriftsartikel (refereegranskat)abstract
- Fast electron injection and transport in solid foils irradiated by sub-picosecond-duration laser pulses with peak intensity equal to 4 x 10(20)W/cm(2) is investigated experimentally and via 3D simulations. The simulations are performed using a hybrid-particle-in-cell (PIC) code for a range of fast electron beam injection conditions, with and without inclusion of self-generated resistive magnetic fields. The resulting fast electron beam transport properties are used in rear-surface plasma expansion calculations to compare with measurements of proton acceleration, as a function of target thickness. An injection half-angle of similar to 50 degrees - 70 degrees is inferred, which is significantly larger than that derived from previous experiments under similar conditions. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4799726]
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| 36. |
- Gray, R. J., et al.
(författare)
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Laser pulse propagation and enhanced energy coupling to fast electrons in dense plasma gradients
- 2014
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Laser energy absorption to fast electrons during the interaction of an ultra-intense (10(20) Wcm(-2)), picosecond laser pulse with a solid is investigated, experimentally and numerically, as a function of the plasma density scale length at the irradiated surface. It is shown that there is an optimum density gradient for efficient energy coupling to electrons and that this arises due to strong self-focusing and channeling driving energy absorption over an extended length in the preformed plasma. At longer density gradients the laser filaments, resulting in significantly lower overall energy coupling. As the scale length is further increased, a transition to a second laser energy absorption process is observed experimentally via multiple diagnostics. The results demonstrate that it is possible to significantly enhance laser energy absorption and coupling to fast electrons by dynamically controlling the plasma density gradient.
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| 37. |
- Lemmen, P., et al.
(författare)
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Development of an advanced frontal dummy thorax demonstrator
- 2012
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Ingår i: 2012 IRCOBI Conference Proceedings - International Research Council on the Biomechanics of Injury, Dublin:12 September through14 September 2012. ; :IRC-12-87, s. 828-842
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Konferensbidrag (refereegranskat)
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| 38. |
- MacLellan, D. A., et al.
(författare)
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Annular Fast Electron Transport in Silicon Arising from Low-Temperature Resistivity
- 2013
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Ingår i: Physical Review Letters. - 1079-7114. ; 111:9
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Tidskriftsartikel (refereegranskat)abstract
- Fast electron transport in Si, driven by ultraintense laser pulses, is investigated experimentally and via 3D hybrid particle-in-cell simulations. A transition from a Gaussian-like to an annular fast electron beam profile is demonstrated and explained by resistively generated magnetic fields. The results highlight the potential to completely transform the beam transport pattern by tailoring the resistivity-temperature profile at temperatures as low as a few eV.
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| 39. |
- MacLellan, D A, et al.
(författare)
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Tunable mega-ampere electron current propagation in solids by dynamic control of lattice melt.
- 2014
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Ingår i: Physical Review Letters. - 1079-7114. ; 113:18
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Tidskriftsartikel (refereegranskat)abstract
- The influence of lattice-melt-induced resistivity gradients on the transport of mega-ampere currents of fast electrons in solids is investigated numerically and experimentally using laser-accelerated protons to induce isochoric heating. Tailoring the heating profile enables the resistive magnetic fields which strongly influence the current propagation to be manipulated. This tunable laser-driven process enables important fast electron beam properties, including the beam divergence, profile, and symmetry to be actively tailored, and without recourse to complex target manufacture.
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| 40. |
- Mahaffey, Kenneth W., et al.
(författare)
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Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
- 2011
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 124:5, s. 544-554
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Tidskriftsartikel (refereegranskat)abstract
- Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P = 0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results-Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose >= 300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. Conclusions-The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin.
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| 41. |
- Martin, Nadine, et al.
(författare)
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Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK⁴a regulation.
- 2013
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 32:7
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Tidskriftsartikel (refereegranskat)abstract
- The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.
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| 42. |
- McKenna, P., et al.
(författare)
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Effect of Lattice Structure on Energetic Electron Transport in Solids Irradiated by Ultraintense Laser Pulses
- 2011
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Ingår i: Physical Review Letters. - 1079-7114. ; 106:18
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Tidskriftsartikel (refereegranskat)abstract
- The effect of lattice structure on the transport of energetic (MeV) electrons in solids irradiated by ultraintense laser pulses is investigated using various allotropes of carbon. We observe smooth electron transport in diamond, whereas beam filamentation is observed with less ordered forms of carbon. The highly ordered lattice structure of diamond is shown to result in a transient state of warm dense carbon with metalliclike conductivity, at temperatures of the order of 1-100 eV, leading to suppression of electron beam filamentation.
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| 43. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 44. |
- Ploussard, Guillaume, et al.
(författare)
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The Contemporary Concept of Significant Versus Insignificant Prostate Cancer
- 2011
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 60:2, s. 291-303
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Forskningsöversikt (refereegranskat)abstract
- Context: The notion of insignificant prostate cancer (Ins-PCa) has progressively emerged in the past two decades. The clinical relevance of such a definition was based on the fact that low-grade, small-volume, and organ-confined prostate cancer (PCa) may be indolent and unlikely to progress to biologic significance in the absence of treatment. Objective: To review the definition of Ins-PCa, its incidence, and the clinical impact of Ins-PCa on the contemporary management of PCa. Evidence acquisition: A review of the literature was performed using the Medline, Scopus, and Web of Science databases with no restriction on language up to September 2010. The literature search used the following terms: insignificant, indolent, minute, microfocal, minimal, low volume, low risk, and prostate cancer. Evidence synthesis: The most commonly used criteria to define Ins-PCa are based on the pathologic assessment of the radical prostatectomy specimen: (1) Gleason score <= 6 without Gleason pattern 4 or 5, (2) organ-confined disease, and (3) tumour volume < 0.5 cm(3). Several preoperative criteria and prognostication tools for predicting Ins-PCa have been suggested. Nomograms are best placed to estimate the risk of progression on an individualised basis, but a substantial proportion of men with a high probability of harbouring Ins-PCa are at risk for pathologic understaging and/or undergrading. Thus, there is an ongoing need for identifying novel and more accurate predictors of Ins-PCa to improve the distinction between insignificant versus significant disease and thus to promote the adequate management of PCa patients at low risk for progression. Conclusions: The exciting challenge of obtaining the pretreatment diagnostic tools that can really distinguish insignificant from significant PCa should be one of the main objectives of urologists in the following years to decrease the risk of overtreatment of Ins-PCa. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.
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| 45. |
- Tammiste, A, et al.
(författare)
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Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression
- 2013
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Ingår i: Journal of psychopharmacology (Oxford, England). - : SAGE Publications. - 1461-7285 .- 0269-8811. ; 27:10, s. 915-920
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Tidskriftsartikel (refereegranskat)abstract
- Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram ( n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets ( p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome.
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| 46. |
- Tomaz, Tiago, et al.
(författare)
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Mitochondrial malate dehydrogenase lowers leaf respiration and alters photorespiration and plant growth in Arabidopsis.
- 2010
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Ingår i: Plant Physiology. - : American Society of Plant Biologists. - 0032-0889 .- 1532-2548. ; 154:3, s. 1143-1157
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Tidskriftsartikel (refereegranskat)abstract
- Malate dehydrogenase (MDH) catalyzes a reversible NAD(+)-dependent-dehydrogenase reaction involved in central metabolism and redox homeostasis between organelle compartments. To explore the role of mitochondrial MDH (mMDH) in Arabidopsis (Arabidopsis thaliana), knockout single and double mutants for the highly expressed mMDH1 and lower expressed mMDH2 isoforms were constructed and analyzed. A mmdh1mmdh2 mutant has no detectable mMDH activity but is viable, albeit small and slow growing. Quantitative proteome analysis of mitochondria shows changes in other mitochondrial NAD-linked dehydrogenases, indicating a reorganization of such enzymes in the mitochondrial matrix. The slow-growing mmdh1mmdh2 mutant has elevated leaf respiration rate in the dark and light, without loss of photosynthetic capacity, suggesting that mMDH normally uses NADH to reduce oxaloacetate to malate, which is then exported to the cytosol, rather than to drive mitochondrial respiration. Increased respiratory rate in leaves can account in part for the low net CO(2) assimilation and slow growth rate of mmdh1mmdh2. Loss of mMDH also affects photorespiration, as evidenced by a lower postillumination burst, alterations in CO(2) assimilation/intercellular CO(2) curves at low CO(2), and the light-dependent elevated concentration of photorespiratory metabolites. Complementation of mmdh1mmdh2 with an mMDH cDNA recovered mMDH activity, suppressed respiratory rate, ameliorated changes to photorespiration, and increased plant growth. A previously established inverse correlation between mMDH and ascorbate content in tomato (Solanum lycopersicum) has been consolidated in Arabidopsis and may potentially be linked to decreased galactonolactone dehydrogenase content in mitochondria in the mutant. Overall, a central yet complex role for mMDH emerges in the partitioning of carbon and energy in leaves, providing new directions for bioengineering of plant growth rate and a new insight into the molecular mechanisms linking respiration and photosynthesis in plants.
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| 47. |
- Tyynismaa, Henna, et al.
(författare)
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Mitochondrial myopathy induces a starvation-like response
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 19:20, s. 3948-3958
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.
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| 48. |
- Uddling, Johan, 1972, et al.
(författare)
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Stomatal uptake of O3 in aspen and aspen-birch forests under free-air CO2 and O3 enrichment
- 2010
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Ingår i: Environmental Pollution. - 0269-7491. ; 158:6, s. 2023-2031
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Tidskriftsartikel (refereegranskat)abstract
- Rising atmospheric carbon dioxide (CO2) may alleviate the toxicological impacts of concurrently rising tropospheric ozone (O3) during the present century if higher CO2 is accompanied by lower stomatal conductance (gs), as assumed by many models. We investigated how elevated concentrations of CO2 and O3, alone and in combination, affected the accumulated stomatal flux of O3 (AFst) by canopies and sun leaves in closed aspen and aspen-birch forests in the free-air CO2–O3 enrichment experiment near Rhinelander, Wisconsin. Stomatal conductance for O3 was derived from sap flux data and AFst was estimated either neglecting or accounting for the potential influence of non-stomatal leaf surface O3 deposition. Leaf-level AFst (AFstl) was not reduced by elevated CO2. Instead, there was a significant CO2 × O3 interaction on AFstl, as a consequence of lower values of gs in control plots and the combination treatment than in the two single-gas treatments. In addition, aspen leaves had higher AFstl than birch leaves, and estimates of AFstl were not very sensitive to non-stomatal leaf surface O3 deposition. Our results suggest that model projections of large CO2-induced reductions in gs alleviating the adverse effect of rising tropospheric O3 may not be reasonable for northern hardwood forests.
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| 49. |
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| 50. |
- Yuan, X. H., et al.
(författare)
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Effects of target pre-heating and expansion on terahertz radiation production from intense laser-solid interactions
- 2014
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Ingår i: High Power Laser Science and Engineering. - : Cambridge University Press (CUP). - 2095-4719 .- 2052-3289. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- The first experimental measurements of intense laser-driven terahertz (THz) radiation from a solid target which is preheated by an intense pulse of laser-accelerated protons is reported. The total energy of the THz radiation is found to decrease by approximately a factor of 2 compared to a cold target reference. This is attributed to an increase in the scale length of the preformed plasma, driven by proton heating, at the front surface of the target, where the THz radiation is generated. The results show the importance of controlling the preplasma scale length for THz production.
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