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  • 1
    Publication Date: 2016-05-12
    Description: We report on the results of a search for radio transients between 115 and 190 MHz with the LOw-Frequency ARray (LOFAR). Four fields have been monitored with cadences between 15 min and several months. A total of 151 images were obtained, giving a total survey area of 2275 deg 2 . We analysed our data using standard LOFAR tools and searched for radio transients using the LOFAR Transients Pipeline. No credible radio transient candidate has been detected; however, we are able to set upper limits on the surface density of radio transient sources at low radio frequencies. We also show that low-frequency radio surveys are more sensitive to steep-spectrum coherent transient sources than GHz radio surveys. We used two new statistical methods to determine the upper limits on the transient surface density. One is free of assumptions on the flux distribution of the sources, while the other assumes a power-law distribution in flux and sets more stringent constraints on the transient surface density. Both of these methods provide better constraints than the approach used in previous works. The best value for the upper limit we can set for the transient surface density, using the method assuming a power-law flux distribution, is 1.3  x  10 –3  deg –2 for transients brighter than 0.3 Jy with a time-scale of 15 min, at a frequency of 150 MHz. We also calculated for the first time upper limits for the transient surface density for transients of different time-scales. We find that the results can differ by orders of magnitude from previously reported, simplified estimates.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 2
    Publication Date: 2015-01-20
    Description: Changes in exon–intron structures and splicing patterns represent an important mechanism for the evolution of gene functions and species-specific regulatory networks. Although exon creation is widespread during primate and human evolution and has been studied extensively, much less is known about the scope and potential impact of human-specific exon loss events. Historically, transcriptome data and exon annotations are significantly biased toward humans over nonhuman primates. This ascertainment bias makes it challenging to discover human-specific exon loss events. We carried out a transcriptome-wide search of human-specific exon loss events, by taking advantage of RNA sequencing (RNA-seq) as a powerful and unbiased tool for exon discovery and annotation. Using RNA-seq data of humans, chimpanzees, and other primates, we reconstructed and compared transcript structures across the primate phylogeny. We discovered 33 candidate human-specific exon loss events, among which six exons passed stringent experimental filters for the complete loss of splicing activities in diverse human tissues. These events may result from human-specific deletion of genomic DNA, or small-scale sequence changes that inactivated splicing signals. The impact of human-specific exon loss events is predominantly regulatory. Three of the six events occurred in the 5' untranslated region (5'-UTR) and affected cis-regulatory elements of mRNA translation. In SLC7A6 , a gene encoding an amino acid transporter, luciferase reporter assays suggested that both a human-specific exon loss event and an independent human-specific single nucleotide substitution in the 5'-UTR increased mRNA translational efficiency. Our study provides novel insights into the molecular mechanisms and evolutionary consequences of exon loss during human evolution.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 3
    Publication Date: 2011-11-16
    Description: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2014-10-17
    Description: Article Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophila locomotor behaviour that can be reversed by enhancing tubulin acetylation. Nature Communications doi: 10.1038/ncomms6245 Authors: Vinay K. Godena, Nicholas Brookes-Hocking, Annekathrin Moller, Gary Shaw, Matthew Oswald, Rosa M. Sancho, Christopher C. J. Miller, Alexander J. Whitworth, Kurt J. De Vos
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 5
    Publication Date: 2014-06-05
    Description: Article Mutations in the protein TDP-43 are implicated in amyotrophic lateral sclerosis. Here, the authors show that mutant TDP-43 perturbs endoplasmic reticulum (ER)–mitochondria associations by altering interactions between the mitochondrial protein PTPIP51 and the ER protein VAPB. Nature Communications doi: 10.1038/ncomms4996 Authors: Radu Stoica, Kurt J. De Vos, Sébastien Paillusson, Sarah Mueller, Rosa M. Sancho, Kwok-Fai Lau, Gema Vizcay-Barrena, Wen-Lang Lin, Ya-Fei Xu, Jada Lewis, Dennis W. Dickson, Leonard Petrucelli, Jacqueline C. Mitchell, Christopher E. Shaw, Christopher C. J. Miller
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 6
    Publication Date: 1999-10-16
    Description: Analysis of rhesus macaque leukocytes disclosed the presence of an 18-residue macrocyclic, tridisulfide antibiotic peptide in granules of neutrophils and monocytes. The peptide, termed rhesus theta defensin-1 (RTD-1), is microbicidal for bacteria and fungi at low micromolar concentrations. Antibacterial activity of the cyclic peptide was threefold greater than that of an open-chain analog, and the cyclic conformation was required for antimicrobial activity in the presence of 150 millimolar sodium chloride. Biosynthesis of RTD-1 involves the head-to-tail ligation of two alpha-defensin-related nonapeptides, requiring the formation of two new peptide bonds. Thus, host defense cells possess mechanisms for synthesis and granular packaging of macrocyclic antibiotic peptides that are components of the phagocyte antimicrobial armamentarium.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Y Q -- Yuan, J -- Osapay, G -- Osapay, K -- Tran, D -- Miller, C J -- Ouellette, A J -- Selsted, M E -- AI22931/AI/NIAID NIH HHS/ -- DK33506/DK/NIDDK NIH HHS/ -- DK44632/DK/NIDDK NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Oct 15;286(5439):498-502.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, College of Medicine, University of California, Irvine, CA 92697, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10521339" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Anti-Bacterial Agents ; Anti-Infective Agents/chemistry/*metabolism/pharmacology ; Bacteria/drug effects ; Cloning, Molecular ; Defensins ; Disulfides/chemistry ; Fungi/drug effects ; Humans ; Leukopoiesis ; Macaca mulatta ; Molecular Sequence Data ; Monocytes/*metabolism ; Neutrophils/*metabolism ; Oligopeptides/chemistry/genetics/metabolism ; Osmolar Concentration ; Peptides, Cyclic/*biosynthesis/chemistry/genetics/pharmacology ; *Protein Biosynthesis ; Protein Conformation ; Protein Precursors/chemistry/genetics/metabolism ; Protein Processing, Post-Translational ; Proteins/chemistry/genetics/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 1999-11-13
    Description: In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Z -- Schuler, T -- Zupancic, M -- Wietgrefe, S -- Staskus, K A -- Reimann, K A -- Reinhart, T A -- Rogan, M -- Cavert, W -- Miller, C J -- Veazey, R S -- Notermans, D -- Little, S -- Danner, S A -- Richman, D D -- Havlir, D -- Wong, J -- Jordan, H L -- Schacker, T W -- Racz, P -- Tenner-Racz, K -- Letvin, N L -- Wolinsky, S -- Haase, A T -- AI 28246/AI/NIAID NIH HHS/ -- AI 38565/AI/NIAID NIH HHS/ -- RR 00168/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 1999 Nov 12;286(5443):1353-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10558989" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-HIV Agents/therapeutic use ; CD4-Positive T-Lymphocytes/cytology/immunology/*virology ; Cell Cycle ; Cervix Uteri/virology ; Epithelial Cells/virology ; Female ; HIV Infections/drug therapy/*transmission/virology ; HIV-1/*physiology ; Lymph Nodes/virology ; *Lymphocyte Activation ; Macaca mulatta ; RNA, Viral/analysis ; Simian Acquired Immunodeficiency Syndrome/*transmission/virology ; Simian Immunodeficiency Virus/*physiology ; Time Factors ; Virus Replication
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2001-05-26
    Description: During its first approximately 100,000 years, the universe was a fully ionized plasma with a tight coupling by Thompson scattering between the photons and matter. The trade-off between gravitational collapse and photon pressure causes acoustic oscillations in this primordial fluid. These oscillations will leave predictable imprints in the spectra of the cosmic microwave background and the present-day matter-density distribution. Recently, the BOOMERANG and MAXIMA teams announced the detection of these acoustic oscillations in the cosmic microwave background (observed at redshift approximately 1000). Here, we compare these CMB detections with the corresponding acoustic oscillations in the matter-density power spectrum (observed at redshift approximately 0.1). These consistent results, from two different cosmological epochs, provide further support for our standard Hot Big Bang model of the universe.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, C J -- Nichol, R C -- Batuski, D J -- New York, N.Y. -- Science. 2001 Jun 22;292(5525):2302-3. Epub 2001 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11375481" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2009-04-03
    Description: The current consensus is that galaxies begin as small density fluctuations in the early Universe and grow by in situ star formation and hierarchical merging. Stars begin to form relatively quickly in sub-galactic-sized building blocks called haloes which are subsequently assembled into galaxies. However, exactly when this assembly takes place is a matter of some debate. Here we report that the stellar masses of brightest cluster galaxies, which are the most luminous objects emitting stellar light, some 9 billion years ago are not significantly different from their stellar masses today. Brightest cluster galaxies are almost fully assembled 4-5 billion years after the Big Bang, having grown to more than 90 per cent of their final stellar mass by this time. Our data conflict with the most recent galaxy formation models based on the largest simulations of dark-matter halo development. These models predict protracted formation of brightest cluster galaxies over a Hubble time, with only 22 per cent of the stellar mass assembled at the epoch probed by our sample. Our findings suggest a new picture in which brightest cluster galaxies experience an early period of rapid growth rather than prolonged hierarchical assembly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collins, Chris A -- Stott, John P -- Hilton, Matt -- Kay, Scott T -- Stanford, S Adam -- Davidson, Michael -- Hosmer, Mark -- Hoyle, Ben -- Liddle, Andrew -- Lloyd-Davies, Ed -- Mann, Robert G -- Mehrtens, Nicola -- Miller, Christopher J -- Nichol, Robert C -- Romer, A Kathy -- Sahlen, Martin -- Viana, Pedro T P -- West, Michael J -- England -- Nature. 2009 Apr 2;458(7238):603-6. doi: 10.1038/nature07865.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Astrophysics Research Institute, Liverpool John Moores University, Twelve Quays House, Egerton Wharf, Birkenhead, CH41 1LD, UK. cac@astro.livjm.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19340075" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2008-07-26
    Description: After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835691/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835691/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grant, Robert M -- Hamer, Dean -- Hope, Thomas -- Johnston, Rowena -- Lange, Joep -- Lederman, Michael M -- Lieberman, Judy -- Miller, Christopher J -- Moore, John P -- Mosier, Donald E -- Richman, Douglas D -- Schooley, Robert T -- Springer, Marty S -- Veazey, Ronald S -- Wainberg, Mark A -- U19 AI076981/AI/NIAID NIH HHS/ -- U19 AI076981-01/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2008 Jul 25;321(5888):532-4. doi: 10.1126/science.1160355.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉J. David Gladstone Institutes, University of California-San Francisco, San Francisco, CA 94518, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18653884" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Intravaginal ; Animals ; Anti-HIV Agents/*administration & dosage/pharmacology/therapeutic use ; Anti-Infective Agents, Local/*administration & dosage/pharmacology/therapeutic ; use ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Female ; HIV Infections/drug therapy/*prevention & control/transmission ; HIV-1/*drug effects ; Humans ; Male ; Patient Compliance ; Polymers/*administration & dosage/pharmacology/therapeutic use ; Primates ; Reverse Transcriptase Inhibitors/*administration & ; dosage/pharmacology/therapeutic use ; Vaginal Diseases/drug therapy/*prevention & control
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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