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  • 1
    Publication Date: 2015-11-06
    Description: Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent multicenter genetic studies have revealed that mutations in the glucocerebrosidase 1 ( GBA1 ) gene, which are responsible for Gaucher's disease, are strong risk factors for PD and DLB. However, the mechanistic link between the functional loss of glucocerebrosidase (GCase) and the toxicity of αSyn in vivo is not fully understood. In this study, we employed Drosophila models to examine the effect of GCase deficiency on the neurotoxicity of αSyn and its molecular mechanism. Behavioral and histological analyses showed that knockdown of the Drosophila homolog of GBA1 ( dGBA1 ) exacerbates the locomotor dysfunction, loss of dopaminergic neurons and retinal degeneration of αSyn-expressing flies. This phenotypic aggravation was associated with the accumulation of proteinase K (PK)-resistant αSyn, rather than with changes in the total amount of αSyn, raising the possibility that glucosylceramide (GlcCer), a substrate of GCase, accelerates the misfolding of αSyn. Indeed, in vitro experiments revealed that GlcCer directly promotes the conversion of recombinant αSyn into the PK-resistant form, representing a toxic conformational change. Similar to dGBA1 knockdown, knockdown of the Drosophila homolog of β - galactosidase ( β-Gal ) also aggravated locomotor dysfunction of the αSyn flies, and its substrate GM1 ganglioside accelerated the formation of PK-resistant αSyn. Our findings suggest that the functional loss of GCase or β-Gal promotes the toxic conversion of αSyn via aberrant interactions between αSyn and their substrate glycolipids, leading to the aggravation of αSyn-mediated neurodegeneration.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2014-06-10
    Description: We present a systematic study for ionization state of inter-stellar medium in galaxies at z  = 0– with ~140 000 Sloan Digital Sky Survey (SDSS) galaxies and 108 intermediate- to high-redshift galaxies from the literature, using an ionization parameter sensitive line ratio of [O iii ]5007/[O ii ]3727 and photoionization models. We confirm that z  ~ 2–3 galaxies show an [O iii ]/[O ii ] ratio significantly higher than a typical star-forming galaxy of SDSS by a factor of 10, and the photoionization models reveal that these high- z galaxies have an ionization parameter of log ( q ion /cm s –1 ) ~ 7.6–9.0, a factor of ~4–10 higher than local galaxies. For galaxies at any redshift, we identify a correlation between the [O iii ]/[O ii ] ratio and galaxy global properties of star formation rate (SFR), stellar mass ( M * ), and metallicity ( Z ). We extend the fundamental metallicity relation (FMR) and develop the fundamental ionization relation (FIR), a four-dimensional relation of ionization parameter, SFR, M * , and Z . The intermediate- and high- z galaxies up to z ~= 3 follow the FIR defined with the local galaxies, in contrast with the FMR whose possible evolution from z  ~ 2 to 3 is reported. We find that the FMR evolution of z  ~ 2–3 appears, if one omits ionization parameter differences, and that the FMR evolution does not exist for an average metallicity solution of z  ~ 3 galaxies with a high-ionization parameter. Interestingly, all of two local Lyman-continuum emitting galaxies (LyC leakers) have a high [O iii ]/[O ii ] ratio, indicating a positive correlation between [O iii ]/[O ii ] and ionizing photon escape fraction ( f esc ), which is successfully explained by our photoionization models. Because [O iii ]/[O ii ] ratios of z  ~ 2–3 galaxies, especially Lyα emitters (LAEs), are comparable to, or higher than, those of the local LyC leakers, these high- z galaxies are candidates of Lyman-continuum emitting objects. A strong Lyα emission can coexist with a large f esc of 0.8, and the increasing fraction of LAEs towards high- z reconciles the picture of cosmic reionization whose major ionizing sources are faint galaxies having intrinsically bright Lyα emission.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 3
    Publication Date: 2014-06-06
    Description: We present diffuse Lyα haloes (LAHs) identified in the composite Subaru narrow-band images of 100–3600 Lyα emitters (LAEs) at z  = 2.2, 3.1, 3.7, 5.7, and 6.6. First, we carefully examine potential artefacts mimicking LAHs that include a large-scale point-spread function made by instrumental and atmospheric effects. Based on our critical test with composite images of non-LAE samples whose narrow-band-magnitude and source-size distributions are the same as our LAE samples, we confirm that no artefacts can produce a diffuse extended feature similar to our LAHs. After this test, we measure the scalelengths of exponential profile for the LAHs estimated from our z  = 2.2–6.6 LAE samples of L Lyα 2 10 42  erg s –1 . We obtain the scalelengths of ~=5–10 kpc at z  = 2.2–5.7, and find no evolution of scalelengths in this redshift range beyond our measurement uncertainties. Combining this result and the previously known UV-continuum size evolution, we infer that the ratio of LAH to UV-continuum sizes is nearly constant at z  = 2.2–5.7. The scalelength of our z  = 6.6 LAH is larger than 5-10 kpc just beyond the error bar, which is a hint that the scalelengths of LAHs would increase from z  = 5.7 to 6.6. If this increase is confirmed by future large surveys with significant improvements of statistical and systematical errors, this scalelength change at z 6 would be a signature of increasing fraction of neutral hydrogen scattering Lyα photons, due to cosmic reionization.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 4
    Publication Date: 2014-06-14
    Description: We review nano-palpation atomic force microscopy, which offers quantitative mechanical property mapping especially for soft materials. The method measures force–deformation curves on the surfaces of soft materials. The emphasis is placed on how both Hertzian and Derjaguin–Muller–Toporov contact mechanics fail to reproduce the experimental curves and, alternatively, how the Johnson–Kendall–Roberts model does. We also describe the force–volume technique for obtaining a two-dimensional map of mechanical properties, such as the elastic modulus and adhesive energy, based on the above-mentioned analysis. Finally, we conclude with several counterpart measurements, which describe the viscoelastic nature of soft materials, and give examples, including vulcanized isoprene rubber and the current status of ISO standardization.
    Print ISSN: 0022-0744
    Electronic ISSN: 1477-9986
    Topics: Electrical Engineering, Measurement and Control Technology , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-09-04
    Description: Myelin, a multilamellar structure extended from oligodendrocytes or Schwann cells, plays a critical role in maintenance of neuronal function, and damage or loss of myelin causes demyelinating diseases such as multiple sclerosis. For precise alignment of the myelin sheath, there is a requirement for expression of galactosylceramide (GalCer), a major glycosphingolipid in myelin. Synthesis of GalCer is strictly limited in oligodendrocytes in a developmental stage-specific manner. Ceramide galactosyltransferase (CGT), a key enzyme for biosynthesis of GalCer, exhibits restricted expression in oligodendrocytes but the mechanism is poorly understood. Based on our assumption that particular oligodendrocyte-lineage-specific transcription factors regulate CGT expression, we co-expressed a series of candidate transcription factors with the human CGT promoter-driving luciferase expression in oligodendroglioma cells to measure the promoter activity. We found that Nkx2.2 strongly activated the CGT promoter. In addition, we identified a novel repressive DNA element in the first intron of CGT and OLIG2, an oligodendrocyte-specific transcription factor, as a binding protein of this element. Moreover, overexpression of OLIG2 completely canceled the activating effect of Nkx2.2 on CGT promoter activity. Expression of CGT mRNA was also upregulated by Nkx2.2, but this upregulation was cancelled by co-expression of OLIG2 with Nkx2.2. Our study suggests that CGT expression is controlled by balanced expression of the negative modulator OLIG2 and positive regulator Nkx2.2, providing new insights into how expression of GalCer is tightly regulated in cell-type- and stage-specific manners.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2012-04-27
    Description: Thyroid hormone (TH) regulates gene transcription by binding to the thyroid hormone receptor (TR) and plays a critical role in the regulation of development, growth and metabolism. The ligated TR activates many effector genes, which contributes to the orchestrated remodelling of the amphibian metamorphosis. However, the mechanisms regulating TRα protein level remain unknown. We determined the nucleotide sequences of the 5'-untranslated regions (5'-UTRs) in amphibian TRα mRNAs. The TRα 5'-UTR contains evolutionarily conserved regions. We demonstrated that a 161-nt stretch of the Xenopus TRα 5'-UTR strongly represses the translation of the downstream open reading frame in both frog and human cell lines, as well as in a cell-free translation system. An analysis using successive deletions of the TRα 5'-UTR revealed five elements possessing translational repressive activity. We analysed two elements, the 14-nt GC-rich region and the 15-nt upstream open reading frame (uORF), by introducing point mutations. This analysis showed that the GC-rich region, which shares its nucleotide sequence with the Sp1-binding site, requires stringent sequence specificity at a nucleotide level for translational repression to take place, whereas under our study conditions, the uORF does not. This study provides an example of complex translational regulation by multiple elements.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
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  • 7
    Publication Date: 2016-12-10
    Description: We present physical properties of spectroscopically confirmed Lyα emitters (LAEs) with very large rest-frame Lyα equivalent widths EW 0 (Lyα). Although the definition of large EW 0 (Lyα) LAEs is usually difficult due to limited statistical and systematic uncertainties, we identify six LAEs selected from ~3000 LAEs at z ~ 2 with reliable measurements of EW 0 (Lyα) ~= 200–400 Å given by careful continuum determinations with our deep photometric and spectroscopic data. These large EW 0 (Lyα) LAEs do not have signatures of AGN, but notably small stellar masses of M * = 10 7–8 M and high specific star formation rates (star formation rate per unit galaxy stellar mass) of ~100 Gyr –1 . These LAEs are characterized by the median values of L (Lyα) = 3.7 x 10 42  erg s –1 and M UV = –18.0 as well as the blue UV continuum slope of β = –2.5 ± 0.2 and the low dust extinction $E(B-V)_{\rm *} = 0.02^{+0.04}_{-0.02}$ , which indicate a high median Lyα escape fraction of $f_{\rm esc}^{\rm Ly\alpha }=0.68\pm 0.30$ . This large $f_{\rm esc}^{\rm Ly\alpha }$ value is explained by the low H i column density in the interstellar medium which is consistent with full width at half-maximum (FWHM) of the Lyα line, FWHM(Lyα) = 212 ± 32 km s –1 , significantly narrower than those of small EW 0 (Lyα) LAEs. Based on the stellar evolution models, our observational constraints of the large EW 0 (Lyα), the small β, and the rest-frame He ii EW imply that at least a half of our large EW 0 (Lyα) LAEs would have young stellar ages of 20 Myr and very low metallicities of Z 〈 0.02 Z regardless of the star formation history.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 8
    Publication Date: 2016-02-12
    Description: We present statistical properties of diffuse Lyα haloes (LAHs) around high- z star-forming galaxies with large Subaru samples of Lyα emitters (LAEs) at z = 2.2. We make subsamples defined by the physical quantities of LAEs’ central Lyα luminosities, ultraviolet (UV) magnitudes, Lyα equivalent widths, and UV slopes, and investigate LAHs’ radial surface brightness (SB) profiles and scale lengths r n as a function of these physical quantities. We find that there exist prominent LAHs around LAEs with faint Lyα luminosities, bright UV luminosities, and small Lyα equivalent widths in cumulative radial Lyα SB profiles. We confirm this trend with the anticorrelation between r n and Lyα luminosities (equivalent widths) based on the Spearman's rank correlation coefficient that is = –0.9 (–0.7) corresponding to the 96 per cent (93 per cent) confidence level, although the correlation between r n and UV magnitudes is not clearly found in the rank correlation coefficient. Our results suggest that LAEs with properties similar to typical Lyman-break galaxies (with faint Lyα luminosities and small equivalent widths) possess more prominent LAHs. We investigate scenarios for the major physical origins of LAHs with our results. Because we find relatively small Lyα equivalent widths up to 77 Å in LAHs that include LAEs’ central components, these results suggest that the cold stream scenario is not preferred. There remain two possible scenarios of Lyα scattering in circumgalactic medium and satellite galaxies that cannot be tested with our observational data.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 9
    Publication Date: 2015-07-16
    Description: We present Early Science observations with the Large Millimeter Telescope, AzTEC 1.1 mm continuum images and wide bandwidth spectra (73–111 GHz) acquired with the Redshift Search Receiver, towards four bright lensed submillimetre galaxies identified through the Herschel Lensing Survey-snapshot and the Submillimetre Common-User Bolometer Array-2 Cluster Snapshot Survey. This pilot project studies the star formation history and the physical properties of the molecular gas and dust content of the highest redshift galaxies identified through the benefits of gravitational magnification. We robustly detect dust continuum emission for the full sample and CO emission lines for three of the targets. We find that one source shows spectroscopic multiplicity and is a blend of three galaxies at different redshifts ( z  = 2.040, 3.252, and 4.680), reminiscent of previous high-resolution imaging follow-up of unlensed submillimetre galaxies, but with a completely different search method, that confirm recent theoretical predictions of physically unassociated blended galaxies. Identifying the detected lines as 12 CO ( J up  = 2–5) we derive spectroscopic redshifts, molecular gas masses, and dust masses from the continuum emission. The mean H 2 gas mass of the full sample is (2.0 ± 0.2)  x  10 11 M /μ, and the mean dust mass is (2.0 ± 0.2)  x  10 9 M /μ, where μ  2–5 is the expected lens amplification. Using these independent estimations we infer a gas-to-dust ratio of GDR   55–75, in agreement with other measurements of submillimetre galaxies. Our magnified high-luminosity galaxies fall on the same locus as other high-redshift submillimetre galaxies, extending the $L^{\prime }_{\rm CO}$ – L FIR correlation observed for local luminous and ultraluminous infrared galaxies to higher far-infrared and CO luminosities.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 10
    Publication Date: 2015-02-26
    Description: The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the chromosome 9 open-reading frame 72 ( C9orf72 ) gene is the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (c9FTD/ALS). Recently, it was reported that an unconventional mechanism of repeat-associated non-ATG (RAN) translation arises from C9orf72 expansion. Sense and anti-sense transcripts of the expanded C9orf72 repeat, i.e. the dipeptide repeat protein (DRP) of glycine–alanine (poly-GA), glycine–proline (poly-GP), glycine–arginine (poly-GR), proline–arginine (poly-PR) and proline–alanine (poly-PA), are deposited in the brains of patients with c9FTD/ALS. However, the pathological significance of RAN-translated peptides remains unknown. We generated synthetic cDNAs encoding 100 repeats of DRP without a GGGGCC repeat and evaluated the effects of these proteins on cultured cells and cortical neurons in vivo. Our results revealed that the poly-GA protein formed highly aggregated ubiquitin/p62-positive inclusion bodies in neuronal cells. In contrast, the highly basic proteins poly-GR and PR also formed unique ubiquitin/p62-negative cytoplasmic inclusions, which co-localized with the components of RNA granules. The evaluation of cytotoxicity revealed that overexpressed poly-GA, poly-GP and poly-GR increased the substrates of the ubiquitin–proteasome system (UPS), including TDP-43, and enhanced the sensitivity to a proteasome inhibitor, indicating that these DRPs are cytotoxic, possibly via UPS dysfunction. The present data indicate that a gain-of-function mechanism of toxic DRPs possibly contributes to pathogenesis in c9FTD/ALS and that DRPs may serve as novel therapeutic targets in c9FTD/ALS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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