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"Young, A R"
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Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours
in vivo
. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Journal Article
The photoprotective properties of α-tocopherol phosphate against long-wave UVA1 (385 nm) radiation in keratinocytes in vitro
UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm
2
UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly enhanced cell survival (88%, Alamar Blue) compared to control, whereas α-T pre-treatment had no effect survival (70%, Alamar Blue). Pre-treatment of cells with 100 μM α-TP or 100 μM α-T before 57 J/cm
2
UVA1 also significantly reduced ROS generation over 2 h (24.1% and 23.9% respectively) compared to the control and resulted in α-TP bioconversion into α-T. As α-TP displayed weak antioxidant activity in the cell-free assays thus its photoprotection was assigned to its bioconversion to α-T by cellular phosphatases. Through this mechanism α-TP prevented long-wave UVA1 induced cell death and scavenged UVA1 induced ROS in skin cells when added to the starved cell culture medium before UVA1 exposure by bioconversion into α-T.
Journal Article
Asian countries and the Arctic future
\"Over the last few years Asian governments have taken a stronger approach to the Arctic, culminating with permanent-observer status to the Arctic Council for China, India, Japan, Singapore and South-Korea in May 2013. This groundbreaking book brings together the latest research in emerging Asian interests for the Arctic region, and the implications thereof this change has for the future. This book covers Arctic shipping, fisheries and mineral extraction. It analyzes key Asian countries' policies, positions and activities. The book also demonstrates that there are common aspects which attract Asian countries to the Arctic, such as a concern for climate change, but there are also important national differences. From the Arctic Council to UNCLOS, Arctic governance mechanisms are thoroughly presented and analyzed\"-- Provided by publisher.
Book
Larmor power limit for cyclotron radiation of relativistic particles in a waveguide
Cyclotron radiation emission spectroscopy (CRES) is a modern technique for high-precision energy spectroscopy, in which the energy of a charged particle in a magnetic field is measured via the frequency of the emitted cyclotron radiation. The He6-CRES collaboration aims to use CRES to probe beyond the standard model physics at the TeV scale by performing high-resolution and low-background beta-decay spectroscopy of 6 He and 19 Ne . Having demonstrated the first observation of individual, high-energy (0.1–2.5 MeV) positrons and electrons via their cyclotron radiation, the experiment provides a novel window into the radiation of relativistic charged particles in a waveguide via the time-derivative (slope) of the cyclotron radiation frequency, d f c / d t . We show that analytic predictions for the total cyclotron radiation power emitted by a charged particle in circular and rectangular waveguides are approximately consistent with the Larmor formula, each scaling with the Lorentz factor of the underlying e ± as γ 4 . This hypothesis is corroborated with experimental CRES slope data.
Journal Article
Transcription of eukaryotic protein-coding genes
The past decade has seen an explosive increase in information about regulation of eukaryotic gene transcription, especially for protein-coding genes. The most striking advances in our knowledge of transcriptional regulation involve the chromatin template, the large complexes recruited by transcriptional activators that regulate chromatin structure and the transcription apparatus, the holoenzyme forms of RNA polymerase II involved in inititation and elongation, and the mechanisms taht link mRNA processing with its synthesis.
Journal Article
The Plasticity of Dendritic Cell Responses to Pathogens and Their Components
Dendritic cells are involved in the initiation of both innate and adaptive immunity. To systematically explore how dendritic cells modulate the immune system in response to different pathogens, we used oligonucleotide microarrays to measure gene expression profiles of dendritic cells in response to Escherichia coli, Candida albicans, and influenza virus as well as to their molecular components. Both a shared core response and pathogen-specific programs of gene expression were observed upon exposure to each of these pathogens. These results reveal that dendritic cells sense diverse pathogens and elicit tailored pathogen-specific immune responses.
Journal Article
Genome-Wide Location and Function of DNA Binding Proteins
Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast. A combination of location and expression profiles was used to identify genes whose expression is directly controlled by Gal4 and Ste12 as cells respond to changes in carbon source and mating pheromone, respectively. The results identify pathways that are coordinately regulated by each of the two activators and reveal previously unknown functions for Gal4 and Ste12. Genome-wide location analysis will facilitate investigation of gene regulatory networks, gene function, and genome maintenance.
Journal Article
Measurement of the neutron lifetime using a magneto-gravitational trap and in situ detection
Unlike the proton, whose lifetime is longer than the age of the universe, a free neutron decays with a lifetime of about 15 minutes. Measuring the exact lifetime of neutrons is surprisingly tricky; putting them in a container and monitoring their decay can lead to errors because some neutrons will be lost owing to interactions with the container walls. To overcome this problem, Pattie et al. measured the lifetime in a trap where ultracold polarized neutrons were levitated by magnetic fields, precluding interactions with the trap walls (see the Perspective by Mumm). This more precise determination of the neutron lifetime will aid our understanding of how the first nuclei formed after the Big Bang. Science , this issue p. 627 ; see also p. 605 Ultracold polarized neutrons are levitated in a trap to measure their lifetime with reduced systematic uncertainty. The precise value of the mean neutron lifetime, τ n , plays an important role in nuclear and particle physics and cosmology. It is used to predict the ratio of protons to helium atoms in the primordial universe and to search for physics beyond the Standard Model of particle physics. We eliminated loss mechanisms present in previous trap experiments by levitating polarized ultracold neutrons above the surface of an asymmetric storage trap using a repulsive magnetic field gradient so that the stored neutrons do not interact with material trap walls. As a result of this approach and the use of an in situ neutron detector, the lifetime reported here [877.7 ± 0.7 (stat) +0.4/–0.2 (sys) seconds] does not require corrections larger than the quoted uncertainties.
Journal Article