| 1. |
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| 2. |
- Puckett, A. J. R., et al.
(author)
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Final analysis of proton form factor ratio data at Q(2)=4.0, 4.8, and 5.6 GeV2
- 2012
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In: Physical Review C (Nuclear Physics). - 0556-2813. ; 85:4
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Journal article (peer-reviewed)abstract
- Precise measurements of the proton electromagnetic form factor ratio R = mu(p)G(E)(p)/G(M)(p) using the polarization transfer method at Jefferson Lab have revolutionized the understanding of nucleon structure by revealing the strong decrease of R with momentum transfer Q(2) for Q(2) greater than or similar to 1 GeV2, in strong disagreement with previous extractions of R from cross-section measurements. In particular, the polarization transfer results have exposed the limits of applicability of the one-photon-exchange approximation and highlighted the role of quark orbital angular momentum in the nucleon structure. The GEp-II experiment in Jefferson Lab's Hall A measured R at four Q(2) values in the range 3.5 GeV2 <= Q(2) <= 5.6 GeV2. A possible discrepancy between the originally published GEp-II results and more recent measurements at higher Q(2) motivated a new analysis of the GEp-II data. This article presents the final results of the GEp-II experiment, including details of the new analysis, an expanded description of the apparatus, and an overview of theoretical progress since the original publication. The key result of the final analysis is a systematic increase in the results for R, improving the consistency of the polarization transfer data in the high-Q(2) region. This increase is the result of an improved selection of elastic events which largely removes the systematic effect of the inelastic contamination, underestimated by the original analysis.
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| 3. |
- Wijesooriya, K, et al.
(author)
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Polarization measurements in high-energy deuteron photodisintegration
- 2001
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In: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 86:14, s. 2975-2979
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Journal article (peer-reviewed)abstract
- We present measurements of the recoil proton polarization for the d(γ⃗,p⃗)n reaction at θc.m. = 90° for photon energies up to 2.4 GeV. These are the first data in this reaction for polarization transfer with circularly polarized photons. The induced polarization py vanishes above 1 GeV, contrary to meson-baryon model expectations, in which resonances lead to large polarizations. However, the polarization transfer Cx does not vanish above 1 GeV, inconsistent with hadron helicity conservation. Thus, we show that the scaling behavior observed in the d(γ,p)ncross sections is not a result of perturbative QCD. These data should provide important tests of new nonperturbative calculations in the intermediate energy regime.
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| 4. |
- Kelly, J. J., et al.
(author)
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Recoil polarization measurements for neutral pion electroproduction at Q(2)=1(GeV/c)(2) near the Delta resonance
- 2007
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In: Physical Review C (Nuclear Physics). - 0556-2813. ; 75:2
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Journal article (peer-reviewed)abstract
- We measured angular distributions of differential cross section, beam analyzing power, and recoil polarization for neutral pion electroproduction at Q(2)=1.0 (GeV/c)(2) in 10 bins of 1.17 <= W <= 1.35 GeV across the Delta resonance. A total of 16 independent response functions were extracted, of which 12 were observed for the first time. Comparisons with recent model calculations show that response functions governed by real parts of interference products are determined relatively well near the physical mass, W=M-Delta approximate to 1.232 GeV, but the variation among models is large for response functions governed by imaginary parts, and for both types of response functions, the variation increases rapidly with W > M-Delta. We performed a multipole analysis that adjusts suitable subsets of center dot(pi)<= 2 amplitudes with higher partial waves constrained by baseline models. This analysis provides both real and imaginary parts. The fitted multipole amplitudes are nearly model independent-there is very little sensitivity to the choice of baseline model or truncation scheme. By contrast, truncation errors in the traditional Legendre analysis of N ->Delta quadrupole ratios are not negligible. Parabolic fits to the W dependence around M-Delta for the multiple analysis gives values for Re(S1+/M1+)=(-6.61 +/- 0.18)% and Re(E1+/M1+)=(-2.87 +/- 0.19)% for the p pi(0) channel at W=1.232 GeV and Q(2)=1.0 (GeV/c)(2) that are distinctly larger than those from the Legendre analysis of the same data. Similarly, the multipole analysis gives Re(S0+/M1+)=(+7.1 +/- 0.8)% at W=1.232 GeV, consistent with recent models, while the traditional Legendre analysis gives the opposite sign because its truncation errors are quite severe.
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| 5. |
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| 6. |
- Zhu, L Y, et al.
(author)
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Cross section measurements of charged pion photoproduction in hydrogen and deuterium from 1.1 to 5.5 GeV
- 2005
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 71:4
-
Journal article (peer-reviewed)abstract
- The differential cross sections for the gamma n ->pi(-)p and the gamma p ->pi(+)n processes were measured at Jefferson Lab. The photon energies ranged from 1.1 to 5.5 GeV, corresponding to center-of-mass energies from 1.7 to 3.4 GeV. The pion center-of-mass angles varied from 50(degrees) to 110(degrees). The pi(-) and pi(+) photoproduction data both exhibit a global scaling behavior at high energies and high transverse momenta, consistent with the constituent counting rule prediction and the existing pi(+) data. The data suggest possible substructure of the scaling behavior, which might be oscillations around the scaling value. The data show an enhancement in the scaled cross section at center-of-mass energy near 2.2 GeV. The differential cross section ratios [d sigma/dt(gamma n ->pi(-)p)/d sigma/dt(gamma p ->pi(+)n)] at high energies and high transverse momenta can be described by calculations based on one-hard-gluon-exchange diagrams.
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| 7. |
- Alcorn, J, et al.
(author)
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Basic instrumentation for Hall A at Jefferson Lab
- 2004
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In: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 522:3, s. 294-346
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Journal article (peer-reviewed)abstract
- The instrumentation in Hall A at the Thomas Jefferson National Accelerator Facility was designed to study electro-and photo-induced reactions at very high luminosity and good momentum and angular resolution for at least one of the reaction products. The central components of Hall A are two identical high resolution spectrometers, which allow the vertical drift chambers in the focal plane to provide a momentum resolution of better than 2 x 10(-4). A variety of Cherenkov counters, scintillators and lead-glass calorimeters provide excellent particle identification. The facility has been operated successfully at a luminosity well in excess of 10(38) CM-2 s(-1). The research program is aimed at a variety of subjects, including nucleon structure functions, nucleon form factors and properties of the nuclear medium. (C) 2003 Elsevier B.V. All rights reserved.
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| 8. |
- Schulte, EC, et al.
(author)
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High energy angular distribution measurements of the exclusive deuteron photodisintegration reaction
- 2002
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In: Physical Review C (Nuclear Physics). - : American Physical Society. - 0556-2813 .- 1089-490X. ; 66:4
-
Journal article (peer-reviewed)abstract
- The first complete measurements of the angular distributions of the two-body deuteron photodisintegration differential cross section at photon energies above 1.6 GeV were performed at the Thomas Jefferson National Accelerator Facility. The results show a persistent forward-backward asymmetry up to E-gamma=2.4 GeV, the highest-energy measured in this experiment. The Hard Rescattering and the Quark-Gluon string models are in fair agreement with the results.
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| 9. |
- Gayou, O, et al.
(author)
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Measurement of G(Ep)/G(Mp) in (e)over-right-arrowp -> e(p)over-right-arrow to Q(2)=5.6 GeV2
- 2002
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In: Physical Review Letters. - 1079-7114. ; 88:9
-
Journal article (peer-reviewed)abstract
- The ratio of the electric and magnetic form factors of the proton G(Ep)/G(Mp), which is an image of its charge and magnetization distributions, was measured at the Thomas Jefferson National Accelerator Facility (JLab) using the recoil polarization technique. The ratio of the form factors is directly proportional to the ratio of the transverse to longitudinal components of the polarization of the recoil proton in the elastic (e) over right arrowp --> e (p) over right arrow reaction. The new data presented span the range 3.5 < Q(2) < 5.6 GeV2 and are well described by a linear Q(2) fit. Also, the ratio rootQ(2) F-2p/F-1p reaches a constant value above Q(2) = 2 GeV2.
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| 10. |
- Strauch, S, et al.
(author)
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Polarization transfer in the He-4((e)over-right-arrow,e '(p)over-right-arrow)H-3 reaction up to Q(2)=2.6 (GeV/c)(2)
- 2003
-
In: Physical Review Letters. - 1079-7114. ; 91:5: 052301
-
Journal article (peer-reviewed)abstract
- We have measured the proton recoil polarization in the He-4((e) over right arrow ,e(')(p) over right arrow)H-4 reaction at Q(2)=0.5, 1.0, 1.6, and 2.6 (GeV/c)(2). The measured ratio of polarization transfer coefficients differs from a fully relativistic calculation, favoring the inclusion of a medium modification of the proton form factors predicted by a quark-meson coupling model. In addition, the measured induced polarizations agree reasonably well with the fully relativistic calculation indicating that the treatment of final-state interactions is under control.
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| 11. |
- Dutta, D, et al.
(author)
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Nuclear transparency with the gamma n ->pi(-)p process in He-4
- 2003
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 68:2: 021001
-
Journal article (peer-reviewed)abstract
- We have measured the nuclear transparency of the fundamental process gamman-->pi(-)p in He-4. These measurements were performed at Jefferson Lab in the photon energy range of 1.6-4.5 GeV and at theta(cm)(pi)=70degrees and 90degrees. These measurements are the first of their kind in the study of nuclear transparency in photoreactions. They also provide a benchmark test of Glauber calculations based on traditional models of nuclear physics. The transparency results suggest deviations from the traditional nuclear physics picture. The momentum transfer dependence of the measured nuclear transparency is consistent with Glauber calculations that include the quantum chromodynamics phenomenon of color transparency.
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| 12. |
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| 13. |
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| 14. |
- Meier, H. E. M., et al.
(author)
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modeling the combined impact of changing climate and changing nutrient loads on the baltic sea environment in an ensemble of transient simulations for 1961 2099
- 2012
-
In: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 39:9-10, s. 2421-2441
-
Journal article (peer-reviewed)abstract
- The combined future impacts of climate change and industrial and agricultural practices in the Baltic Sea catchment on the Baltic Sea ecosystem were assessed. For this purpose 16 transient simulations for 1961-2099 using a coupled physical-biogeochemical model of the Baltic Sea were performed. Four climate scenarios were combined with four nutrient load scenarios ranging from a pessimistic business-as-usual to a more optimistic case following the Baltic Sea Action Plan (BSAP). Annual and seasonal mean changes of climate parameters and ecological quality indicators describing the environmental status of the Baltic Sea like bottom oxygen, nutrient and phytoplankton concentrations and Secchi depths were studied. Assuming present-day nutrient concentrations in the rivers, nutrient loads from land increase during the twenty first century in all investigated scenario simulations due to increased volume flows caused by increased net precipitation in the Baltic catchment area. In addition, remineralization rates increase due to increased water temperatures causing enhanced nutrient flows from the sediments. Cause-and-effect studies suggest that both processes may play an important role for the biogeochemistry of eutrophicated seas in future climate partly counteracting nutrient load reduction efforts like the BSAP.
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| 15. |
- Rvachev, MM, et al.
(author)
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Quasielastic He-3(e,e(')p)H-2 reaction at Q(2)=1.5 GeV2 for recoil momenta up to 1 GeV/c
- 2005
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In: Physical Review Letters. - 1079-7114. ; 94:19
-
Journal article (peer-reviewed)abstract
- We have studied the quasielastic He-3(e,e(')p)H-2 reaction in perpendicular coplanar kinematics, with the energy and the momentum transferred by the electron fixed at 840 MeV and 1502 MeV/c, respectively. The He-3(e,e(')p)H-2 cross section was measured for missing momenta up to 1000 MeV/c, while the A(TL) asymmetry was extracted for missing momenta up to 660 MeV/c. For missing momenta up to 150 MeV/c, the cross section is described by variational calculations using modern He-3 wave functions. For missing momenta from 150 to 750 MeV/c, strong final-state interaction effects are observed. Near 1000 MeV/c, the experimental cross section is more than an order of magnitude larger than predicted by available theories. The A(TL) asymmetry displays characteristic features of broken factorization with a structure that is similar to that generated by available models.
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| 16. |
- Wallgard, Elisabet, et al.
(author)
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Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development
- 2012
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In: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 241:4, s. 770-786
-
Journal article (peer-reviewed)abstract
- Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains.Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas.Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.
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| 17. |
- Wijesooriya, K, et al.
(author)
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Polarization measurements in neutral pion photoproduction
- 2002
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 66:3
-
Journal article (peer-reviewed)abstract
- We present measurements of the recoil proton polarization for the H-1((γ) over right arrow,(p) over right arrow)pi(0) reaction for theta(c.m.)(pi) = 60degrees-135degrees and for photon energies up to 4.1 GeV. These are the first data in this reaction for polarization transfer with circularly polarized photons. Various theoretical models are compared with the results. No evidence for hadron helicity conservation is observed. Models that employ factorization are not favored. It appears from the strong angular dependence of the induced polarization at photon energies of 2.5 and 3.1 GeV that a relatively high spin resonance or background amplitude might exist in this energy region.
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| 18. |
- Zhu, LY, et al.
(author)
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Cross-section measurement of charged-pion photoproduction from hydrogen and deuterium
- 2003
-
In: Physical Review Letters. - 1079-7114. ; 91:2: 022003
-
Journal article (peer-reviewed)abstract
- We have measured the differential cross section for the gamman-->pi(-)p and gammap-->pi(+)n reactions at theta(c.m.)=90degrees in the photon energy range from 1.1 to 5.5 GeV at Jefferson Lab (JLab). The data at E(gamma)greater than or similar to3.3 GeV exhibit a global scaling behavior for both pi(-) and pi(+) photoproduction, consistent with the constituent counting rule and the existing pi(+) photoproduction data. Possible oscillations around the scaling value are suggested by these new data. The data show enhancement in the scaled cross section at a center-of-mass energy near 2.2 GeV. The cross section ratio of exclusive pi(-) to pi(+) photoproduction at high energy is consistent with the prediction based on one-hard-gluon-exchange diagrams.
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| 19. |
- Dai, F., et al.
(author)
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The Discovery and Mass Measurement of a New Ultra-short-period Planet: K2-131
- 2017
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In: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 154:6, s. 226-
-
Journal article (peer-reviewed)abstract
- We report the discovery of a new ultra-short-period planet and summarize the properties of all such planets for which the mass and radius have been measured. The new planet, EPIC 228732031b, was discovered in K2 Campaign 10. It has a radius of 1.81-0.12+0.16 R_Earth and orbits a G dwarf with a period of 8.9 hr. Radial velocities obtained with Magellan/PFS and TNG/HARPS-N show evidence for stellar activity along with orbital motion. We determined the planetary mass using two different methods: (1) the “floating chunk offset” method, based only on changes in velocity observed on the same night; and (2) a Gaussian process regression based on both the radial velocity and photometric time series. The results are consistent and lead to a mass measurement of 6.5+/- 1.6 M_Earth and a mean density of 6.0-2.7+3.0 g cm‑3.
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| 20. |
- Dieterich, Lothar C., et al.
(author)
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alpha B-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-kappa B-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin
- 2013
-
In: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 16:4, s. 975-983
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Journal article (peer-reviewed)abstract
- alpha B-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of alpha B-crystallin in regulating vascular function, through enhancing tumor necrosis factor alpha (TNF-alpha) induced expression of endothelial adhesion molecules involved in leukocyte recruitment. Ectopic expression of alpha B-crystallin in endothelial cells increases the level of E-selectin expression in response to TNF-alpha, and enhances leukocyte-endothelial interaction in vitro. Conversely, TNF-alpha-induced expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin is markedly inhibited in endothelial cells isolated from alpha B-crystallin-deficient mice. This is associated with elevated levels of I kappa B in alpha B-crystallin deficient cells and incomplete degradation upon TNF-alpha stimulation. Consistent with this, endothelial adhesion molecule expression is reduced in inflamed vessels of alpha B-crystallin deficient mice, and leukocyte rolling velocity is increased. Our data identify alpha B-crystallin as a new regulator of leukocyte recruitment, by enhancing pro-inflammatory nuclear factor kappa B-signaling and endothelial adhesion molecule expression during endothelial activation.
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| 21. |
- Dieterich, L. C., et al.
(author)
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alphaB-Crystallin regulates expansion of CD11b(+)Gr-1(+) immature myeloid cells during tumor progression
- 2013
-
In: The FASEB Journal. - : FASEB. - 0892-6638 .- 1530-6860. ; 27:1, s. 151-62
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Journal article (peer-reviewed)abstract
- The molecular chaperone alphaB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis. alphaB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether alphaB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45(+) leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in alphaB-crystallin-deficient mice. Notably, alphaB-crystallin is prominently expressed in CD11b(+) Gr-1(+) immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low alphaB-crystallin expression. alphaB-Crystallin deficiency results in a 3-fold higher accumulation of CD11b(+) Gr-1(+) IMCs in tumors and a significant rise in CD11b(+) Gr-1(+) IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b(+) Gr-1(+) IMCs in chronically inflamed livers in alphaB-crystallin-deficient mice. The effect of alphaB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b(+) Gr-1(+) IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b(+) Gr-1(+) cells, we provide evidence that alphaB-crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of alphaB-crystallin in limiting expansion of CD11b(+) Gr-1(+) IMCs in diverse pathological conditions.
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| 22. |
- Dieterich, Lothar C., et al.
(author)
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Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
- 2012
-
In: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 228:3, s. 378-390
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Journal article (peer-reviewed)abstract
- Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.
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| 23. |
- Dimberg, Anna, et al.
(author)
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alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
- 2008
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:4, s. 2015-2023
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Journal article (peer-reviewed)abstract
- Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators.
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| 24. |
- Eriksson, Emma, et al.
(author)
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Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment
- 2017
-
In: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 24:2, s. 92-103
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Journal article (peer-reviewed)abstract
- CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.
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| 25. |
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| 26. |
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| 27. |
- Freischmidt, Axel, et al.
(author)
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Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers
- 2014
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:11, s. 2938-2950
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Journal article (peer-reviewed)abstract
- Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.
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| 28. |
- Gröger, M., et al.
(author)
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Summer hydrographic changes in the Baltic Sea, Kattegat and Skagerrak projected in an ensemble of climate scenarios downscaled with a coupled regional ocean–sea ice–atmosphere model
- 2019
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In: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 53, s. 5945-5966
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Journal article (peer-reviewed)abstract
- © 2019, The Author(s). This model study investigates summer hydrographic changes in response to climate projections following the CMIP5 RCP8.5 scenario. We use the high resolution regional coupled ocean–sea ice–atmospheremodel RCA4–NEMO to downscale an ensemble of five global climate projections with a main focus on the Baltic Sea and neighboring shelf basins to the west. We find consistently across the ensemble a northward shift in the mean summer position of the westerlies at the end of the twenty-first century compared to the twentieth century. Associated with this is an anomalous precipitation pattern marked by increased rainfall over northern Europe and dryer conditions over the continental central part. In response to these large-scale atmospheric changes, a strong freshening mainly resulting from a higher net precipitation over the year combined with higher annual mean runoff is registered for the Baltic Sea and adjacent seas. The strongest freshening takes place in the southern Skagerrak region where stronger winds enhance the cyclonic circulation and by this, recirculation of fresher waters from the Baltic Sea strengthens. In the Baltic Sea freshening leads to a reduction in basin averaged salinities between 0.6 and 2.3gkg−1 throughout the ensemble. Likewise, the sea surface temperature response in the Baltic Sea varies between + 2.5 and + 4.7K depending on the applied global model scenario. The climate induced changes in atmospheric forcing have further consequences for the large-scale circulation in the Baltic Sea. All ensemble members indicate a strengthening of the zonal, wind driven near surface overturning circulation in the southwestern Baltic Sea towards the end of the twenty-first century whereas the more thermohaline driven overturning at depth is reduced by ~ 25%. In the Baltic Proper, the meridional overturning shows no clear climate change signal. However, three out of five ensemble members indicate at least a northward expansion of the main overturning cell. In the Bothnian Sea, all ensemble members show a significant weakening of the meridional overturning. The entire ensemble consistently indicates a basin-wide intensification of the pycnocline (9–35%) for the Baltic Sea and a shallowing of the pycnocline depth in most regions as well. In the Baltic Sea, which is dominated by mesohaline conditions under the historical period, the changes in salinity at the end of the twenty-first century have turned wide areas to be dominated by oligohaline conditions as a result of climate change. Potential consequences for biogeochemical conditions and implications for biodiversity are discussed.
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| 29. |
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| 30. |
- Hosseinzadeh, Ava, et al.
(author)
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Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
- 2019
-
In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 10
-
Journal article (peer-reviewed)abstract
- Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.
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| 31. |
- Huang, Hua, et al.
(author)
-
VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
- 2015
-
In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:1, s. 227-238
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Journal article (peer-reviewed)abstract
- Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.
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| 32. |
- Klein, S, et al.
(author)
-
DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C
- 2016
-
In: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 129:13, s. 2573-2585
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Journal article (peer-reviewed)abstract
- Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors (TF) upregulated in human lymphatic endothelial cells (LEC) within the first 30 to 80 min after VEGFR-3 activation. Expression of these TFs must be regulated by additional, pre-existing TFs, which are rapidly activated by VEGFR-3 signaling. Using TF activity analysis, we identified the homeobox TF HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early TFs, including NR4A1. Gain- and loss of function studies revealed that HOXD10 is involved in LEC migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and e-NOS, and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells and in the control of lymphangiogenesis and permeability.
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| 33. |
- Liljenfeldt, Lina, et al.
(author)
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CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes
- 2014
-
In: Cancer Gene Therapy. - : Springer Science and Business Media LLC. - 0929-1903 .- 1476-5500. ; 21:3, s. 95-102
-
Journal article (peer-reviewed)abstract
- CD40 ligand (CD40L) is a potent stimulator of tumor immunity via its activation of dendritic cells, which in turn initiate T-cell activation. However, T cells are inhibited by suppressive myeloid cells, which constitute an important part of immune evasion. We hypothesized that CD40L may revert the function of suppressive myeloid cells to generate a T-cell stimulatory environment, and this was investigated in the murine bladder cancer model MB49/C57BL/6. Upon intratumoral adenoviral CD40L (AdCD40L) gene therapy, the infiltration of CD11b(+)Gr-1(+) cells was significantly reduced, whereas activated T cells were increased. In vitro, CD40L-expressing MB49 cells tilted the myeloid subpopulations in favor of granulocytic CD11b(+)Gr-1(high) myeloid cells instead of monocytic CD11b(+)Gr-1(int/low) myeloid cells. Further, the level of macrophages in splenocyte co-cultures with MB49 cells was evaluated. In cultures with MB49 cells expressing CD40L, the overall level of macrophages was reduced and the remaining cells were differentiated into M1-like cells. Hence, these data support that CD40L tilts myeloid immune cell populations in favor of anti-tumor immunity (M1) instead of immunosuppression (CD11b(+)Gr-1(int/low) and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue.
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| 34. |
- Meier, H. E. Markus, et al.
(author)
-
Assessment of Eutrophication Abatement Scenarios for the Baltic Sea by Multi-Model Ensemble Simulations
- 2018
-
In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 5
-
Journal article (peer-reviewed)abstract
- To assess the impact of the implementation of the Baltic Sea Action Plan (BSAP) on the future environmental status of the Baltic Sea, available uncoordinated multi-model ensemble simulations for the Baltic Sea region for the twenty-first century were analyzed. The scenario simulations were driven by regionalized global general circulation model (GCM) data using several regional climate system models and forced by various future greenhouse gas emission and air- and river-borne nutrient load scenarios following either reference conditions or the BSAP. To estimate uncertainties in projections, the largest ever multi-model ensemble for the Baltic Sea comprising 58 transient simulations for the twenty-first century was assessed. Data from already existing simulations from different projects including regionalized GCM simulations of the third and fourth assessment reports of the Intergovernmental Panel on Climate Change based on the corresponding Coupled Model Intercomparison Projects, CMIP3 and CMIP5, were collected.Various strategies to weigh the ensemble members were tested and the results for ensemble mean changes between future and present climates are shown to be robust with respect to the chosen metric. Although (1) the model simulations during the historical period are of different quality and (2) the assumptions on nutrient load levels during present and future periods differ between models considerably, the ensemble mean changes in biogeochemical variables in the Baltic proper with respect to nutrient load reductions are similar between the entire ensemble and a subset consisting only of the most reliable simulations.Despite the large spread in projections, the implementation of the BSAP will lead to a significant improvement of the environmental status of the Baltic Sea according to both weighted and unweighted ensembles. The results emphasize the need for investigating ensembles with many members and rigorous assessments of models’ performance.
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| 35. |
- Meier, H. E. Markus, et al.
(author)
-
Assessment of Uncertainties in Scenario Simulations of Biogeochemical Cycles in the Baltic Sea
- 2019
-
In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 6
-
Research review (peer-reviewed)abstract
- Following earlier regional assessment studies, such as the Assessment of Climate Change for the Baltic Sea Basin and the North Sea Region Climate Change Assessment, knowledge acquired from available literature about future scenario simulations of biogeochemical cycles in the Baltic Sea and their uncertainties is assessed. The identification and reduction of uncertainties of scenario simulations are issues for marine management. For instance, it is important to know whether nutrient load abatement will meet its objectives of restored water quality status in future climate or whether additional measures are required. However, uncertainties are large and their sources need to be understood to draw conclusions about the effectiveness of measures. The assessment of sources of uncertainties in projections of biogeochemical cycles based on authors' own expert judgment suggests that the biggest uncertainties are caused by (1) unknown current and future bioavailable nutrient loads from land and atmosphere, (2) the experimental setup (including the spin up strategy), (3) differences between the projections of global and regional climate models, in particular, with respect to the global mean sea level rise and regional water cycle, (4) differing model-specific responses of the simulated biogeochemical cycles to long-term changes in external nutrient loads and climate of the Baltic Sea region, and (5) unknown future greenhouse gas emissions. Regular assessments of the models' skill (or quality compared to observations) for the Baltic Sea region and the spread in scenario simulations (differences among projected changes) as well as improvement of dynamical downscaling methods are recommended.
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| 36. |
- Meier, H. E. Markus, et al.
(author)
-
Impact of Climate Change on Ecological Quality Indicators and Biogeochemical Fluxes in the Baltic Sea : A Multi-Model Ensemble Study
- 2012
-
In: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 41:6, s. 558-573
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Journal article (peer-reviewed)abstract
- Multi-model ensemble simulations using three coupled physical-biogeochemical models were performed to calculate the combined impact of projected future climate change and plausible nutrient load changes on biogeochemical cycles in the Baltic Sea. Climate projections for 1961-2099 were combined with four nutrient load scenarios ranging from a pessimistic business-as-usual to a more optimistic case following the Helsinki Commission's (HELCOM) Baltic Sea Action Plan (BSAP). The model results suggest that in a future climate, water quality, characterized by ecological quality indicators like winter nutrient, summer bottom oxygen, and annual mean phytoplankton concentrations as well as annual mean Secchi depth (water transparency), will be deteriorated compared to present conditions. In case of nutrient load reductions required by the BSAP, water quality is only slightly improved. Based on the analysis of biogeochemical fluxes, we find that in warmer and more anoxic waters, internal feedbacks could be reinforced. Increased phosphorus fluxes out of the sediments, reduced denitrification efficiency and increased nitrogen fixation may partly counteract nutrient load abatement strategies.
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| 37. |
- Mourier, A, et al.
(author)
-
Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels
- 2015
-
In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 208:4, s. 429-442
-
Journal article (peer-reviewed)abstract
- Mitochondria form a dynamic network within the cell as a result of balanced fusion and fission. Despite the established role of mitofusins (MFN1 and MFN2) in mitochondrial fusion, only MFN2 has been associated with metabolic and neurodegenerative diseases, which suggests that MFN2 is needed to maintain mitochondrial energy metabolism. The molecular basis for the mitochondrial dysfunction encountered in the absence of MFN2 is not understood. Here we show that loss of MFN2 leads to impaired mitochondrial respiration and reduced ATP production, and that this defective oxidative phosphorylation process unexpectedly originates from a depletion of the mitochondrial coenzyme Q pool. Our study unravels an unexpected and novel role for MFN2 in maintenance of the terpenoid biosynthesis pathway, which is necessary for mitochondrial coenzyme Q biosynthesis. The reduced respiratory chain function in cells lacking MFN2 can be partially rescued by coenzyme Q10 supplementation, which suggests a possible therapeutic strategy for patients with diseases caused by mutations in the Mfn2 gene.
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| 38. |
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| 39. |
- Schimanke, S., et al.
(author)
-
An algorithm based on sea-level pressure fluctuations to identify major Baltic inflow events
- 2014
-
In: Tellus. Series A, Dynamic meteorology and oceanography. - : Stockholm University Press. - 0280-6495 .- 1600-0870. ; 66, s. 23452-
-
Journal article (peer-reviewed)abstract
- Major Baltic inflows are an important process to sustain the sensitive steady state of the Baltic Sea. We introduce an algorithm to identify atmospheric variability favourable for major Baltic inflows. The algorithm is based on sea-level pressure (SLP) fields as the only parameter. Characteristic SLP pattern fluctuations include a precursory phase of 30 days and 10 days of inflow period. The algorithm identifies successfully the majority of observed major Baltic inflows between 1961 and 2010. In addition, the algorithm finds some occurrences which cannot be related to observed inflows. In these cases with favourable atmospheric conditions, inflows were precluded by contemporaneously existing saline water masses or strong freshwater supply. Moreover, the algorithm clearly identifies the stagnation periods as a lack of SLP variability favourable for MBIs. This indicates that the lack of inflows is mainly a consequence of missing atmospheric forcing during this period. The only striking inflow which is not identified by the algorithm is the event in January 2003. We demonstrate that this is due to the special evolution of SLP fields which are not comparable with any other event. Finally, the algorithm is applied to an ensemble of scenario simulations. The result indicates that the number of atmospheric events favourable for major Baltic inflows increases slightly in all scenarios.
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| 40. |
- Vromman, Marieke, et al.
(author)
-
Large-scale benchmarking of circRNA detection tools reveals large differences in sensitivity but not in precision
- 2023
-
In: Nature Methods. - 1548-7091 .- 1548-7105. ; 20:8, s. 1159-1169
-
Journal article (peer-reviewed)abstract
- The detection of circular RNA molecules (circRNAs) is typically based on short-read RNA sequencing data processed using computational tools. Numerous such tools have been developed, but a systematic comparison with orthogonal validation is missing. Here, we set up a circRNA detection tool benchmarking study, in which 16 tools detected more than 315,000 unique circRNAs in three deeply sequenced human cell types. Next, 1,516 predicted circRNAs were validated using three orthogonal methods. Generally, tool-specific precision is high and similar (median of 98.8%, 96.3% and 95.5% for qPCR, RNase R and amplicon sequencing, respectively) whereas the sensitivity and number of predicted circRNAs (ranging from 1,372 to 58,032) are the most significant differentiators. Of note, precision values are lower when evaluating low-abundance circRNAs. We also show that the tools can be used complementarily to increase detection sensitivity. Finally, we offer recommendations for future circRNA detection and validation. This study describes benchmarking and validation of computational tools for detecting circRNAs, finding most to be highly precise with variations in sensitivity and total detection. The study also finds over 315,000 putative human circRNAs.
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| 41. |
- Wahlstrom, I., et al.
(author)
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Projected climate change impact on a coastal sea-As significant as all current pressures combined
- 2022
-
In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 28:17, s. 5310-5319
-
Journal article (peer-reviewed)abstract
- Climate change influences the ocean's physical and biogeochemical conditions, causing additional pressures on marine environments and ecosystems, now and in the future. Such changes occur in environments that already today suffer under pressures from, for example, eutrophication, pollution, shipping, and more. We demonstrate how to implement climate change into regional marine spatial planning by introducing data of future temperature, salinity, and sea ice cover from regional ocean climate model projections to an existing cumulative impact model. This makes it possible to assess climate change impact in relation to pre-existing cumulative impact from current human activities. Results indicate that end-of-century projected climate change alone is a threat of the same magnitude as the combination of all current pressures to the marine environment. These findings give marine planners and policymakers forewarning on how future climate change may impact marine ecosystems, across space, emission scenarios, and in relation to other pressures.
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| 42. |
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