| 1. |
- Roeder, Sebastian S., et al.
(författare)
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Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry
- 2023
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Ingår i: Frontiers in Neuroscience. - 1662-4548. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.
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| 2. |
- Akiyama, Eiji, et al.
(författare)
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SPIRAL STRUCTURE AND DIFFERENTIAL DUST SIZE DISTRIBUTION IN THE LkH alpha 330 DISK
- 2016
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 152:6
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Tidskriftsartikel (refereegranskat)abstract
- Dust trapping accelerates the coagulation of dust particles, and, thus, it represents an initial step toward the formation of planetesimals. We report H-band (1.6 mu m) linear polarimetric observations and 0.87 mm interferometric continuum observations toward a transitional disk around LkH alpha 330. As a. result, a pair of spiral arms were detected in the H-band emission, and an asymmetric (potentially arm-like) structure was detected in the 0.87 mm continuum emission. We discuss the origin of the spiral arm and the asymmetric structure. and suggest that a massive unseen planet is the most plausible explanation. The possibility of dust trapping and grain growth causing the asymmetric structure was also investigated through the opacity index (beta) by plotting the observed spectral energy distribution slope between 0.87 mm from our Submillimeter Array observation and 1.3 mm from literature. The results imply that grains are indistinguishable from interstellar medium-like dust in the east side (beta = 2.0 +/- 0.5) but are much smaller in the west side beta = 0.7(-0.4)(+0.5), indicating differential dust size distribution between the two sides of the disk. Combining the results of near-infrared and submillimeter observations, we conjecture that the spiral arms exist at the upper surface and an asymmetric structure resides in the disk interior. Future observations at centimeter wavelengths and differential polarization imaging in other bands (Y-K) with extreme AO imagers are required to understand how large dust grains form and to further explore the dust distribution in the disk.
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| 3. |
- Albèr, Cathrine, et al.
(författare)
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Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy
- 2013
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Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier. - 0005-2736 .- 1879-2642 .- 0006-3002. ; 1828:11, s. 2470-2478
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Tidskriftsartikel (refereegranskat)abstract
- The rather thin outermost layer of the mammalian skin, stratum corneum (SC), is a complex biomembrane which separates the water rich inside of the body from the dry outside. The skin surface can be exposed to rather extreme variations in ambient conditions (e.g. water activity, temperature and pH), with potential effects on the barrier function. Increased understanding of how the barrier is affected by such changes is highly relevant for regulation of transdermal uptake of exogenous chemicals. In the present study we investigate the effect of hydration and the use of a well-known humectant, urea, on skin barrier ultrastructure by means of confocal Raman microspectroscopy. We also perform dynamic vapor sorption (DVS) microbalance measurements to examine the water uptake capacity of SC pretreated with urea. Based on novel Raman images, constructed from 2D spectral maps, we can distinguish large water inclusions within the skin membrane exceeding the size of fully hydrated corneocytes. We show that these inclusions contain water with spectral properties similar to that of bulk water. The results furthermore show that the ambient water activity has an important impact on the formation of these water inclusions as well as on the hydration profile across the membrane. Urea significantly increases the water uptake when present in skin, as compared to skin without urea, and it promotes formation of larger water inclusions in the tissue. The results confirm that urea can be used as a humectant to increase skin hydration.
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| 4. |
- Boot, James, et al.
(författare)
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Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.
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| 5. |
- Constantinou, Myrianni, et al.
(författare)
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Lineage specification in glioblastoma is regulated by METTL7B
- 2024
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 43:6
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.
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| 6. |
- de Leon, Jerome, et al.
(författare)
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NEAR-IR HIGH-RESOLUTION IMAGING POLARIMETRY OF THE SU Aur DISK : CLUES FOR TIDAL TAILS?
- 2015
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 806:1
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Tidskriftsartikel (refereegranskat)abstract
- We present new high-resolution (similar to 0.09) H-band imaging observations of the circumstellar disk around the T Tauri star SU Aur. Our observations with Subaru-HiCIAO have revealed the presence of scattered light as close as 0.15 (similar to 20 AU) to the star. Within our image, we identify bright emission associated with a disk with a minimum radius of similar to 90 AU, an inclination of similar to 35 degrees from the plane of the sky, and an approximate PA of 15 degrees for the major axis. We find a brightness asymmetry between the northern and southern sides of the disk due to a non-axisymmetric disk structure. We also identify a pair of asymmetric tail structures extending east and west from the disk. The western tail extends at least 2.5 (350 AU) from the star, and is probably associated with a reflection nebula previously observed at optical and near-IR wavelengths. The eastern tail extends at least 1. (140 AU) at the present signal-to-noise. These tails are likely due to an encounter with an unseen brown dwarf, but our results do not exclude the explanation that these tails are outflow cavities or jets.
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| 7. |
- Follette, Katherine B., et al.
(författare)
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SEEDS ADAPTIVE OPTICS IMAGING OF THE ASYMMETRIC TRANSITION DISK OPH IRS 48 IN SCATTERED LIGHT
- 2015
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 798:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the first resolved near-infrared imagery of the transition disk Oph IRS 48 (WLY 2-48), which was recently observed with ALMA to have a strongly asymmetric submillimeter flux distribution. H-band polarized intensity images show a similar to 60 AU radius scattered light cavity with two pronounced arcs of emission, one from northeast to southeast and one smaller, fainter, and more distant arc in the northwest. K-band scattered light imagery reveals a similar morphology, but with a clear third arc along the southwestern rim of the disk cavity. This arc meets the northwestern arc at nearly a right angle, revealing the presence of a spiral arm or local surface brightness deficit in the disk, and explaining the east-west brightness asymmetry in the H-band data. We also present 0.8-5.4 mu m IRTF SpeX spectra of this object, which allow us to constrain the spectral class to A0 +/- 1 and measure a low mass accretion rate of 10(-8.5) M-circle dot yr(-1), both consistent with previous estimates. We investigate a variety of reddening laws in order to fit the multiwavelength spectral energy distribution of Oph IRS 48 and find a best fit consistent with a younger, higher luminosity star than previous estimates.
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| 8. |
- Keck, Michaela Kristina, et al.
(författare)
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Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
- 2023
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 145:1, s. 49-69
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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| 9. |
- Kooistra, Robin, et al.
(författare)
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Radial decoupling of small and large dust grains in the transitional disk RX J1615.3-3255
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 597
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Tidskriftsartikel (refereegranskat)abstract
- We present H-band (1.6 mu m) scattered light observations of the transitional disk RX J1615.3-3255, located in the similar to 1 Myr old Lupus association. From a polarized intensity image, taken with the HiCIAO instrument of the Subaru Telescope, we deduce the position angle and the inclination angle of the disk. The disk is found to extend out to 68 +/- 12 AU in scattered light and no clear structure is observed. Our inner working angle of 24 AU does not allow us to detect a central decrease in intensity similar to that seen at 30 AU in the 880 mu m continuum observations. We compare the observations with multiple disk models based on the spectral energy distribution (SED) and submm interferometry and find that an inner rim of the outer disk at 30 AU containing small silicate grains produces a polarized intensity signal which is an order of magnitude larger than observed. We show that a model in which the small dust grains extend smoothly into the cavity found for large grains is closer to the actual H-band observations. A comparison of models with di ff erent dust size distributions suggests that the dust in the disk might have undergone significant processing compared to the interstellar medium.
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| 10. |
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