| 1. |
- Abdallah, J., et al.
(författare)
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Study of leading hadrons in gluon and quark fragmentation
- 2006
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 643:3-4, s. 147-157
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Tidskriftsartikel (refereegranskat)abstract
- The study of quark jets in e(+)e(-) reactions at LEP has demonstrated that the hadronisation process is reproduced well by the Lund string model. However. our understanding of gluon fragmentation is less complete. In this study enriched quark and gluon jet samples of different purities are selected in three-jet events from hadronic decays of the Z collected by the DELPHI experiment in the LEP runs during 1994 and 1995. The leading systems of the two kinds of jets are defined by requiring a rapidity gap and their sum of charges is studied. An excess of leading systems with total charge zero is found for gluon jets in all cases, when compared to Monte Carlo simulations with JETSET (with and without Bose-Einstein correlations included) and ARIADNE. The corresponding leading systems of quark jets do not exhibit such an excess. The influence of the gap size and of the gluon purity on the effect is studied and a concentration of the excess of neutral leading systems at low invariant masses (less than or similar to 2 GeV/c(2)) is observed, indicating that gluon jets might have an additional hitherto undetected fragmentation mode via a two-gluon system. This could be an indication of a possible production of gluonic states as predicted by QCD.
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| 2. |
- Abdallah, J., et al.
(författare)
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A measurement of the tau hadronic branching ratios
- 2006
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 46:1, s. 1-26
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Tidskriftsartikel (refereegranskat)abstract
- The exclusive and semi-exclusive branching ratios of the tau lepton hadronic decay modes (h(-)upsilon(tau), h(-)pi(0)upsilon(tau), h(-)pi(0)pi(0)upsilon(tau), h(-) >= 2 pi(0)nu(tau), 2h(-)h(+)upsilon(tau), 2h(-)h(+)>= 2 pi(0)upsilon(tau), 3h(-)2h(+)upsilon(tau) and 3h(-)2h(+) >= 1 pi(0)upsilon(tau)) were measured with data from the DELPHI detector at LEP.
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| 3. |
- Abdallah, J., et al.
(författare)
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A study of the b-quark fragmentation function with the DELPHI detector at LEP I and an averaged distribution obtained at the Z Pole
- 2011
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 71:2, s. 1557-
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Tidskriftsartikel (refereegranskat)abstract
- The nature of b-quark jet hadronisation has been investigated using data taken at the Z peak by the DELPHI detector at LEP. Two complementary methods are used to reconstruct the energy of weakly decaying b-hadrons, E-B(weak). The average value of x(B)(weak) = E-B(weak)/E-beam is measured to be 0.699 +/- 0.011. The resulting x(B)(weak) distribution is then analysed in the framework of two choices for the perturbative contribution (parton shower and Next to Leading Log QCD calculation) in order to extract measurements of the non-perturbative contribution to be used in studies of b-hadron production in other experimental environments than LEP. In the parton shower framework, data favour the Lund model ansatz and corresponding values of its parameters have been determined within PYTHIA 6.156 from DELPHI data: a = 1.84(-0.21)(+0.23) and b = 0.642(-0.063)(+0.073) GeV-2, with a correlation factor rho = 92.2%. Combining the data on the b-quark fragmentation distributions with those obtained at the Z peak by ALEPH, OPAL and SLD, the average value of x(B)(weak) is found to be 0.7092 +/- 0.0025 and the non-perturbative fragmentation component is extracted. Using the combined distribution, a better determination of the Lund parameters is also obtained: a = 1.48(-0.10)(+0.11) and b = 0.509(-0.023)(+0.024) GeV-2, with a correlation factor rho = 92.6%.
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| 4. |
- Abdallah, J., et al.
(författare)
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Investigation of colour reconnection in WW events with the DELPHI detector at LEP-2
- 2007
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 51:2, s. 249-269
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Tidskriftsartikel (refereegranskat)abstract
- In the reaction e(+)e(-) -> WW -> (q(1) (q) over bar (2))(q(3)(q) over bar (4)) the usual hadronization models treat the colour singlets q(1)(q) over bar (2) and q(3)(q) over bar (4) coming from two W bosons independently. However, since the. nal state partons may coexist in space and time, cross-talk between the two evolving hadronic systems may be possible during fragmentation through soft gluon exchange. This e. ect is known as colour reconnection. In this article the results of the investigation of colour reconnection e. ects in fully hadronic decays of W pairs in DELPHI at LEP are presented. Two complementary analyses were performed, studying the particle. ow between jets and W mass estimators, with negligible correlation between them, and the results were combined and compared to models. In the framework of the SK-I model, the value for its. parameter most compatible with the data was found to be: (SK)-S-kappa-I = 2.2(-1.3) (+2.5) corresponding to the probability of reconnection P-reco to be in the range 0.31 < P-reco < 0.68 at 68% confidence level with its best value at 0.52.
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| 5. |
- Abdallah, J., et al.
(författare)
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Masses, lifetimes and production rates of Xi(-) and Xi(+) at LEP 1
- 2006
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 639:3-4, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of the Xi(-) and (Xi) over bar (+) masses, mass differences, lifetimes and lifetime differences are presented. The (Xi) over bar (+) sample used is much larger than those used previously for such measurements. In addition, the S production rates in Z -> b (b) over bar and Z -> q (q) over bar events are compared and the position xi* of the maximum of the distribution in Z -> q (q) over bar events is measured.
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| 6. |
- Abdallah, J., et al.
(författare)
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Measurement of the electron structure function F-2(e) at LEP energies
- 2014
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 737, s. 39-47
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Tidskriftsartikel (refereegranskat)abstract
- The hadronic part of the electron structure function F-2(e) has been measured for the first time, using e(+)e(-) data collected by the DELPHI experiment at LEP, at centre-of-mass energies of root s = 91.2-209.5 GeV. The data analysis is simpler than that of the measurement of the photon structure function. The electron structure function F-2(e) data are compared to predictions of phenomenological models based on the photon structure function. It is shown that the contribution of large target photon virtualities is significant. The data presented can serve as a cross-check of the photon structure function F-2(gamma) analyses and help in refining existing parameterisations.
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| 7. |
- Abdallah, J., et al.
(författare)
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Search for a fourth generation b '-quark at LEP-II at root s=196-209GeV
- 2007
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 50:3, s. 507-518
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Tidskriftsartikel (refereegranskat)abstract
- A search for the pair production of fourth generation b'-quarks was performed using data taken by the DELPHI detector at LEP-II. The analysed data were collected at centre-of-mass energies ranging from 196 to 209 GeV, corresponding to an integrated luminosity of 420 pb(-1). No evidence for a signal was found. Upper limits on BR(b'-> bZ) and BR(b'-> bZ) were obtained for b' masses ranging from 96 to 103 GeV/c(2) stop. These limits, together with the theoretical branching ratios predicted by a sequential four generations model, were used to constrain the value of R-CKM=vertical bar V-cb(') /V-tb'V-tb vertical bar there V-cb', V-tb' and V-tb are elements of the extended CKM matrix.
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| 8. |
- Abdallah, J., et al.
(författare)
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Search for excited leptons in e(+)e(-) collisions at root s=189-209 GeV
- 2006
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 46:2, s. 277-293
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Tidskriftsartikel (refereegranskat)abstract
- A search for excited lepton production in e(+)e(-) collisions was performed using the data collected by the DELPHI detector at LEP at centre-of-mass energies ranging from 189 GeV to 209 GeV, corresponding to an integrated luminosity of approximately 600 pb(-1). No evidence for excited lepton production was found. In searches for pair-produced excited leptons, lower mass limits were established in the range 94-103 GeV/c(2), depending on the channel and model assumptions. In searches for singly-produced excited leptons, upper limits on the parameter f/Lambda were established as a function of the mass.
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| 9. |
- Abdallah, J., et al.
(författare)
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Search for pentaquarks in the hadronic decays of the Z boson with the DELPHI detector at LEP
- 2007
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 653:2-4, s. 151-160
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Tidskriftsartikel (refereegranskat)abstract
- The quark model does not exclude states composed of more than three quarks, like pentaquark systems. Controversial evidence for such states has been published in the last years, in particular: for a strange pentaquark Theta(1540)(+); for a double-strange state, the Xi(1862)(--), subsequently called Phi(1860)--; and for a charmed state, the Theta(c)(3100)(0). If confirmed, a full pentaquark family might exist; such pentaquark states could be produced in e(+)e(-) annihilations near the Z energy. In this Letter a search for pentaquarks is described using the DELPHI detector at LEP, characterized by powerful particle identification sub-systems crucial in the separation of the signal from the background for these states. At 95% CL, upper limits are set on the production rates N of such particles and their charge-conjugate state per Z decay: N-Theta+ x Br(Theta(+) -> pK(S)(0)) < 5.1 x 10(-4), N Theta++ < 1.6 x 10(-3), N Phi(1860)-- x Br((P(1860)-- -> Xi(-)pi(-)) < 2.9 x 10(-4), N-Theta c(3100)0 x Br(Theta(c)(3100)(0) -> D*(+)p) < 8.8 x 10(-4).
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| 10. |
- Abdallah, J., et al.
(författare)
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Search for single top quark production via contact interactions at LEP2
- 2011
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 71:2, s. 1555-
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Tidskriftsartikel (refereegranskat)abstract
- Single top quark production via four-fermion contact interactions associated to flavour-changing neutral currents was searched for in data taken by the DELPHI detector at LEP2. The data were accumulated at centre-of-mass energies ranging from 189 to 209 GeV, with an integrated luminosity of 598.1 pb(-1). No evidence for a signal was found. Limits on the energy scale Lambda, were set for scalar-, vector- and tensor-like coupling scenarios.
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| 11. |
- Abdallah, J., et al.
(författare)
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Study of triple-gauge-boson couplings ZZZ, ZZ gamma and Z gamma gamma at LEP
- 2007
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 51:3, s. 525-542
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Tidskriftsartikel (refereegranskat)abstract
- Neutral triple-gauge-boson couplings ZZZ, ZZγ and Zγγ have been studied with the DELPHI detector using data at energies between 183 and 208 GeV. Limits are derived on these couplings from an analysis of the reactions e+e-→Zγ, using data from the final states γff̄, with f=q or ν, from e+e-→ZZ, using data from the four-fermion final states qq̄qq̄, qq̄μ+μ-, qq̄e+e-, qq̄νν̄, μ+μ-νν̄ and e+e-νν̄, and from e+e-→Zγ*, in which the final state γ is off mass-shell, using data from the four-fermion final states qq̄e+e- and qq̄μ+μ-. No evidence for the presence of such couplings is observed, in agreement with the predictions of the Standard Model.
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| 12. |
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| 13. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 14. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 15. |
- Uusitupa, M., et al.
(författare)
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Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome : a randomized study (SYSDIET)
- 2013
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 274:1, s. 52-66
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Tidskriftsartikel (refereegranskat)abstract
- Background Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. Methods We conducted a randomized dietary study lasting for 18-24weeks in individuals with features of metabolic syndrome (mean age 55years, BMI 31.6kgm-2, 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. Results Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmolL-1 95% CI -0.35; -0.01, P=0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P=0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P=0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37ngL-1, P= 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P=0.049) and magnesium (mg, -0.23, -0.41; -0.05, P=0.012) were associated with IL-1 Ra. Conclusions Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.
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| 16. |
- Edberg, Niklas J. T., et al.
(författare)
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Spatial distribution of low-energy plasma around comet 67P/CG from Rosetta measurements
- 2015
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 42:11, s. 4263-4269
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Tidskriftsartikel (refereegranskat)abstract
- We use measurements from the Rosetta plasma consortium Langmuir probe and mutual impedance probe to study the spatial distribution of low-energy plasma in the near-nucleus coma of comet 67P/Churyumov-Gerasimenko. The spatial distribution is highly structured with the highest density in the summer hemisphere and above the region connecting the two main lobes of the comet, i.e., the neck region. There is a clear correlation with the neutral density and the plasma to neutral density ratio is found to be approximate to 1-210(-6), at a cometocentric distance of 10km and at 3.1AU from the Sun. A clear 6.2h modulation of the plasma is seen as the neck is exposed twice per rotation. The electron density of the collisionless plasma within 260km from the nucleus falls off with radial distance as approximate to 1/r. The spatial structure indicates that local ionization of neutral gas is the dominant source of low-energy plasma around the comet.
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| 17. |
- Galand, M., et al.
(författare)
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Ionospheric plasma of comet 67P probed by Rosetta at 3 au from the Sun
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 462, s. S331-S351
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Tidskriftsartikel (refereegranskat)abstract
- We propose to identify the main sources of ionization of the plasma in the coma of comet 67P/Churyumov-Gerasimenko at different locations in the coma and to quantify their relative importance, for the first time, for close cometocentric distances (< 20 km) and large heliocentric distances (> 3 au). The ionospheric model proposed is used as an organizing element of a multi-instrument data set from the Rosetta Plasma Consortium (RPC) plasma and particle sensors, from the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis and from the Microwave Instrument on the Rosetta Orbiter, all on board the ESA/Rosetta spacecraft. The calculated ionospheric density driven by Rosetta observations is compared to the RPC-Langmuir Probe and RPC-Mutual Impedance Probe electron density. The main cometary plasma sources identified are photoionization of solar extreme ultraviolet (EUV) radiation and energetic electron-impact ionization. Over the northern, summer hemisphere, the solar EUV radiation is found to drive the electron density - with occasional periods when energetic electrons are also significant. Over the southern, winter hemisphere, photoionization alone cannot explain the observed electron density, which reaches sometimes higher values than over the summer hemisphere; electron-impact ionization has to be taken into account. The bulk of the electron population is warm with temperature of the order of 7-10 eV. For increased neutral densities, we show evidence of partial energy degradation of the hot electron energy tail and cooling of the full electron population.
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| 18. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 19. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 20. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 21. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 22. |
- Edberg, Niklas J. T., et al.
(författare)
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CME impact on comet 67P/Churyumov-Gerasimenko
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 462, s. S45-S56
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Tidskriftsartikel (refereegranskat)abstract
- We present Rosetta observations from comet 67P/Churyumov-Gerasimenko during the impact of a coronal mass ejection (CME). The CME impacted on 2015 Oct 5-6, when Rosetta was about 800 km from the comet nucleus, and 1.4 au from the Sun. Upon impact, the plasma environment is compressed to the level that solar wind ions, not seen a few days earlier when at 1500 km, now reach Rosetta. In response to the compression, the flux of suprathermal electrons increases by a factor of 5-10 and the background magnetic field strength increases by a factor of similar to 2.5. The plasma density increases by a factor of 10 and reaches 600 cm(-3), due to increased particle impact ionization, charge exchange and the adiabatic compression of the plasma environment. We also observe unprecedentedly large magnetic field spikes at 800 km, reaching above 200 nT, which are interpreted as magnetic flux ropes. We suggest that these could possibly be formed by magnetic reconnection processes in the coma as the magnetic field across the CME changes polarity, or as a consequence of strong shears causing Kelvin-Helmholtz instabilities in the plasma flow. Due to the limited orbit of Rosetta, we are not able to observe if a tail disconnection occurs during the CME impact, which could be expected based on previous remote observations of other CME-comet interactions.
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| 23. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 24. |
- Nilsson, Magnus, et al.
(författare)
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Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed : The Study Protocol for the Randomized Controlled NEEDS Trial
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC.Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up.
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| 25. |
- Turcot, Valerie, et al.
(författare)
-
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 26. |
- Albert, J., et al.
(författare)
-
Risk of HIV transmission from patients on antiretroviral therapy: A position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy
- 2014
-
Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 46:10, s. 673-677
-
Tidskriftsartikel (refereegranskat)abstract
- The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.
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| 27. |
- Blanco, A., et al.
(författare)
-
Performance of timing resistive plate chambers with relativistic neutrons from 300 to 1500 MeV
- 2015
-
Ingår i: Journal of Instrumentation. - : IOP Publishing. - 1748-0221. ; 10:2
-
Tidskriftsartikel (refereegranskat)abstract
- A prototype composed of four resistive plate chamber layers has been exposed to quasi-monoenergetic neutrons produced from a deuteron beam of varying energy (300 to 1500 AMeV) in experiment S406 at GSI, Darmstad, Germany. Each layer, with an active area of about 2000 × 500 mm2, is made of modules containing the active gaps, all in multigap construction. Each gap is defined by 0.3 mm nylon mono-filaments positioned between 2.85 mm thick float glass electrodes. The modules are operated in avalanche mode with a non-flammable gas mixture composed of 90% C2H2F4 and 10% SF6. The signals are readout by a pick-up electrode formed by 15 copper strips (per layer), spaced at a pitch of 30 mm, connected at both sides to timing front end electronics. Measurements of the time of flight jitter of neutrons, in the mentioned energy range, point to a contribution of the resistive plate chamber in the order of 150 ps, independent of the neutron energy.
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| 28. |
- Edberg, Niklas J. T., et al.
(författare)
-
Solar wind interaction with comet 67P : Impacts of corotating interaction regions
- 2016
-
Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 121:2, s. 949-965
-
Tidskriftsartikel (refereegranskat)abstract
- We present observations from the Rosetta Plasma Consortium of the effects of stormy solar wind on comet 67P/Churyumov-Gerasimenko. Four corotating interaction regions (CIRs), where the first event has possibly merged with a coronal mass ejection, are traced from Earth via Mars (using Mars Express and Mars Atmosphere and Volatile EvolutioN mission) to comet 67P from October to December 2014. When the comet is 3.1-2.7AU from the Sun and the neutral outgassing rate approximate to 10(25)-10(26)s(-1), the CIRs significantly influence the cometary plasma environment at altitudes down to 10-30km. The ionospheric low-energy (approximate to 5eV) plasma density increases significantly in all events, by a factor of >2 in events 1 and 2 but less in events 3 and 4. The spacecraft potential drops below -20V upon impact when the flux of electrons increases. The increased density is likely caused by compression of the plasma environment, increased particle impact ionization, and possibly charge exchange processes and acceleration of mass-loaded plasma back to the comet ionosphere. During all events, the fluxes of suprathermal (approximate to 10-100eV) electrons increase significantly, suggesting that the heating mechanism of these electrons is coupled to the solar wind energy input. At impact the magnetic field strength in the coma increases by a factor of 2-5 as more interplanetary magnetic field piles up around the comet. During two CIR impact events, we observe possible plasma boundaries forming, or moving past Rosetta, as the strong solar wind compresses the cometary plasma environment. We also discuss the possibility of seeing some signatures of the ionospheric response to tail disconnection events.
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| 29. |
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| 30. |
- Heritier, K. L., et al.
(författare)
-
Plasma source and loss at comet 67P during the Rosetta mission
- 2018
-
Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 618
-
Tidskriftsartikel (refereegranskat)abstract
- Context. The Rosetta spacecraft provided us with a unique opportunity to study comet 67P/Churyumov-Gerasimenko (67P) from a close perspective and over a 2-yr time period. Comet 67P is a weakly active comet. It was therefore unexpected to find an active and dynamic ionosphere where the cometary ions were largely dominant over the solar wind ions, even at large heliocentric distances. Aims. Our goal is to understand the different drivers of the cometary ionosphere and assess their variability over time and over the different conditions encountered by the comet during the Rosetta mission. Methods. We used a multi-instrument data-based ionospheric model to compute the total ion number density at the position of Rosetta. In-situ measurements from the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) and the Rosetta Plasma Consortium (RPC)-Ion and Electron Sensor (IES), together with the RPC-LAngmuir Probe instrument (LAP) were used to compute the local ion total number density. The results are compared to the electron densities measured by RPC-Mutual Impedance Probe (MIP) and RPC-LAP. Results. We were able to disentangle the physical processes responsible for the formation of the cometary ions throughout the 2-yr escort phase and we evaluated their respective magnitudes. The main processes are photo-ionization and electron-impact ionization. The latter is a significant source of ionization at large heliocentric distance (>2 au) and was predominant during the last 4 months of the mission. The ionosphere was occasionally subject to singular solar events, temporarily increasing the ambient energetic electron population. Solar photons were the main ionizer near perihelion at 1.3 au from the Sun, during summer 2015.
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| 31. |
- Huang, Miller, et al.
(författare)
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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
- 2019
-
Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:3, s. 433-
-
Tidskriftsartikel (refereegranskat)abstract
- Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predis- posed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
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| 32. |
- Johansson, Fredrik K., et al.
(författare)
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Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging
- 2004
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:31, s. 11334-11337
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by blast searches of mouse genome databases. A number of candidate brain tumor loci (Btls) were identified. Several of these Btls correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other Btls harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors.
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| 33. |
- Lango Allen, Hana, et al.
(författare)
-
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
-
Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 34. |
- Machado, J., et al.
(författare)
-
Performance of timing Resistive Plate Chambers with protons from 200 to 800 MeV
- 2015
-
Ingår i: Journal of Instrumentation. - 1748-0221. ; 10:1, s. C01043-
-
Tidskriftsartikel (refereegranskat)abstract
- A prototype composed of four resistive plate chamber layers has been exposed to quasi-monoenergetic protons produced from a deuteron beam of varying energy (200 to 800 AMeV) in experiment S406 at GSI, Darmstadt, Germany. The aim of the experiment is to characterize the response of the prototype to protons in this energy range, which deposit from 1.75 to 6 times more energy than minimum ionizing particles. Each layer, with an active area of about 2000 × 500 mm 2 , is made of modules containing the active gaps, all in multigap construction. Each gap is defined by 0.3 mm nylon mono-filaments positioned between 2.85 mm thick float glass electrodes. The modules are operated in avalanche mode with a non-flammable gas mixture composed of 90% C 2 H 2 F 4 and 10% SF 6 . The signals are readout by a pick-up electrode formed by 15 copper strips (per layer), spaced at a pitch of 30 mm, connected at both sides to timing front end electronics. Results show an uniform efficiency close to 100% along with a timing resolution of around 60 ps on the entire 2000 × 500 mm 2 area.
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| 35. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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| 36. |
- Roy, Ananya, et al.
(författare)
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Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential
- 2017
-
Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer. We applied patient-derived BM cell models to the study of BM cell-MC interactions. BM cells when cocultured with MCs demonstrate enhanced growth and self-renewal capacity. Gene set enrichment analyses indicate increased expression of signal transduction and transmembrane proteins related genes in the cocultured BM cells. MCs exert their effect by release of mediators such as IL-8, IL-10, matrix metalloprotease 2, and vascular endothelial growth factor, thereby permitting metastasis. In conclusion, we provide evidence for a role of MCs in BM. Our findings indicate MCs' capability of modulating gene expression in BM cells and suggest that MCs can serve as a new target for drug development against metastases in the brain.
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| 37. |
- Singleton, Rosie K., et al.
(författare)
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Risk prediction for renal cell Carcinoma : Results from the European Prospective Investigation into Cancer and nutrition (EPIC) prospective cohort study
- 2021
-
Ingår i: Cancer Epidemiology Biomarkers and Prevention. - : AACR. - 1055-9965 .- 1538-7755. ; 30:3, s. 507-512
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679–0.721]). Our model had slightly improved discrimination (0.714 [0.694–0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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| 38. |
- Strandberg, E., et al.
(författare)
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Effects of heavy-load resistance training during (neo-)adjuvant chemotherapy on muscle cellular outcomes in women with breast cancer
- 2021
-
Ingår i: Medicine. - : Ovid Technologies (Wolters Kluwer Health). - 0025-7974 .- 1536-5964. ; 100:10
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: (Neo-)adjuvant chemotherapy for breast cancer has a deleterious impact on muscle tissue resulting in reduced cardiorespiratory fitness, skeletal muscle mass and function. Physical exercise during treatment may counteract some of these negative effects. However, the effects of resistance training (RT) alone have never been explored. The present study aims to investigate if heavy-load RT during (neo-)adjuvant chemotherapy counteracts deleterious effects on skeletal muscle in women diagnosed with breast cancer. We hypothesize that (neo-)adjuvant treatment with chemotherapy will reduce muscle fiber size, impair mitochondrial function, and increase indicators of cellular stress and that RT during treatment will counteract these negative effects. We also hypothesize that RT during (neo-)adjuvant chemotherapy will increase muscle and blood levels of potential antitumor myokines and reduce treatment-related side effects on muscle strength and cardiorespiratory fitness. Methods: Fifty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to either randomized to either intervention group or to control group. The intervention group will perform supervised heavy-load RT twice a week over the course of chemotherapy (approximately 16-weeks) whereas the control group will be encouraged to continue with their usual activities. Muscle biopsies from m. vastus lateralis will be collected before the first cycle of chemotherapy (T0), after chemotherapy (T1), and 6 months later (T2) for assessment of muscle cellular outcomes. The primary outcome for this study is muscle fiber size. Secondary outcomes are: regulators of muscle fiber size and function, indicators of cellular stress and mitochondrial function, myokines with potential antitumor effects, muscle strength, and cardiorespiratory fitness. Ethics and dissemination: Ethical approval has been obtained from the Regional Ethical Review Board in Uppsala, Sweden (Dnr:2016/230/2). Results will be disseminated through presentations at scientific meetings, publications in peer-reviewed journals, social media, and patient organizations.
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| 39. |
- Susanto, Evelyn, et al.
(författare)
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Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells
- 2020
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:33, s. 20127-20138
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using In-duced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carry-ing a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en-hanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we dem-onstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
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| 40. |
- Weishaupt, Holger, et al.
(författare)
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Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes
- 2019
-
Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811. ; 35:18, s. 3357-3364
-
Tidskriftsartikel (refereegranskat)abstract
- Motivation: Medulloblastoma (MB) is a brain cancer predominantly arising in children. Roughly 70% of patients are cured today, but survivors often suffer from severe sequelae. MB has been extensively studied by molecular profiling, but often in small and scattered cohorts. To improve cure rates and reduce treatment side effects, accurate integration of such data to increase analytical power will be important, if not essential.Results: We have integrated 23 transcription datasets, spanning 1350 MB and 291 normal brain samples. To remove batch effects, we combined the Removal of Unwanted Variation (RUV) method with a novel pipeline for determining empirical negative control genes and a panel of metrics to evaluate normalization performance. The documented approach enabled the removal of a majority of batch effects, producing a large-scale, integrative dataset of MB and cerebellar expression data. The proposed strategy will be broadly applicable for accurate integration of data and incorporation of normal reference samples for studies of various diseases. We hope that the integrated dataset will improve current research in the field of MB by allowing more large-scale gene expression analyses.
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| 41. |
- Xiong, Anqi, 1986-, et al.
(författare)
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Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression
- 2020
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:6
-
Tidskriftsartikel (refereegranskat)abstract
- Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development,NRBP2is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation.
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| 42. |
- Ölvander, J., et al.
(författare)
-
Preface
- 2018
-
Ingår i: Proceedings of NordDesign. - Linköping : Design Research Society. - 9789176851852
-
Konferensbidrag (populärvet., debatt m.m.)
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| 43. |
- Abramowicz, Marek A, 1945, et al.
(författare)
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No Observational Constraints from Hypothetical Collisions of Hypothetical Dark Halo Primordial Black Holes with Galactic Objects
- 2009
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 705:1, s. 659-669
-
Tidskriftsartikel (refereegranskat)abstract
- It was suggested by several authors that hypothetical primordial black holes (PBHs) may contribute to the dark matter (DM) in our Galaxy. There are strong constraints based on the Hawking evaporation that practically exclude PBHs with masses m pbh ~ 1015to1016 g and smaller as significant contributors to the Galactic DM. Similarly, PBHs with masses greater than about 1026 g are practically excluded by the gravitational lensing observation. The mass range between 1016 g
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| 44. |
- Alsterholm, Mikael, 1977, et al.
(författare)
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Establishment and utility of SwedAD : a nationwide Swedish registry for patients with atopic dermatitis receiving systemic pharmacotherapy
- 2023
-
Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 103
-
Tidskriftsartikel (refereegranskat)abstract
- SwedAD, a Swedish nationwide registry for patients with atopic dermatitis receiving systemic pharmacotherapy, was launched on 1 September 2019. We describe here the establishment of a user-friendly registry to the benefit of patients with atopic dermatitis. By 5 November 2022, 38 clinics had recorded 931 treatment episodes in 850 patients with an approximate national coverage rate of 40%. Characteristics at enrolment included median Eczema Area and Severity Index (EASI) 10.2 (interquartile range 4.0, 19.4), Patient-Oriented Eczema Measure (POEM) 18.0 (10.0, 24.0), Dermatology Life Quality Index (DLQI) 11.0 (5.0, 19.0) and Peak Itch Numerical Rating Scale-11 (NRS-11) 6.0 (3.0, 8.0). At 3 months, median EASI was 3.2 (1.0, 7.3) and POEM, DLQI, and NRS-11 were improved. Regional coverage varied, reflecting the distribution of dermatologists, the ratio of public to private healthcare, and difficulties in recruiting certain clinics. This study highlights the importance of a nationwide registry when managing systemic pharmacotherapy of atopic dermatitis.
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| 45. |
- Amundadottir, Laufey T., et al.
(författare)
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A common variant associated with prostate cancer in European and African populations
- 2006
-
Ingår i: Nature Genetics. - DeCODE Genet, IS-101 Reykjavik, Iceland. Univ Iceland, Landspitali Hosp, Dept Pathol, IS-101 Reykjavik, Iceland. Univ Iceland, Landspitali Hosp, Dept Urol, IS-101 Reykjavik, Iceland. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 38:6, s. 652-658
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Tidskriftsartikel (refereegranskat)abstract
- With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
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| 46. |
- Backman, Filip, 1991-, et al.
(författare)
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The development of the NNBAR experiment
- 2022
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Ingår i: Journal of Instrumentation. - : Institute of Physics (IOP). - 1748-0221. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- The NNBAR experiment for the European Spallation Source will search for free neutrons converting to antineutrons with a sensitivity improvement of three orders of magnitude compared to the last such search. This paper describes progress towards a conceptual design report for NNBAR. The design of a moderator, neutron reflector, beamline, shielding and annihilation detector is reported. The simulations used form part of a model which will be used for optimisation of the experiment design and quantification of its sensitivity.
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| 47. |
- Cancer, Matko, et al.
(författare)
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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
- 2019
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.
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| 48. |
- Čančer, Matko, et al.
(författare)
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Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
- 2019
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Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:6, s. 855-870
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.
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| 49. |
- Carlström, Karl E., et al.
(författare)
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Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate
- 2020
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Ingår i: NEUROTHERAPEUTICS. - : SPRINGER. - 1933-7213 .- 1878-7479. ; 17, s. 1142-1152
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Tidskriftsartikel (refereegranskat)abstract
- The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NF kappa B, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.
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| 50. |
- Chorell, Erik, et al.
(författare)
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Design and Synthesis of Fluorescent Pilicides and Curlicides : Bioactive Tools to Study Bacterial Virulence Mechanisms
- 2012
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Ingår i: Chemistry - A European Journal. - Berlin : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 18:15, s. 4522-4532
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.
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