1,340 research outputs found
Cannibalism, cell survival, and endocrine resistance in breast cancer
Breast cancer cells often respond to an endocrine therapy by altering expression of specific estrogen-responsive genes and inducing autophagy, a cannibalistic lysosomal pathway. Autophagy eliminates damaged or other organelles, allowing the recovery of the energy stored in their macromolecules to attempt restoration of metabolic homeostasis. Induction of autophagy can result from activation of the unfolded protein response following metabolic stress, the final cell fate often being determined by the extent and duration of autophagy. A study by Gonzalez-Malerva and colleagues builds upon this extensive knowledge, adding HSPB8 to the list of altered genes associated with endocrine resistance in breast cancer and describing the ability of HSPB8 to regulate autophagy and confer tamoxifen resistance
Coalbed Methane Development in Indonesia: Design and Economic Analysis of Upstream Petroleum Fiscal Policy
Up-scaling, formative phases, and learning in the historical diffusion of energy technologies
The 20th century has witnessed wholesale transformation in the energy system marked by the pervasive diffusion of both energy supply and end-use technologies. Just as whole industries have grown, so too have unit sizes or capacities. Analysed in combination, these unit level and industry level growth patterns reveal some consistencies across very different energy technologies. First, the up-scaling or increase in unit size of an energy technology comes after an often prolonged period of experimentation with many smaller-scale units. Second, the peak growth phase of an industry can lag these increases in unit size by up to 20 years. Third, the rate and timing of up-scaling at the unit level is subject to countervailing influences of scale economies and heterogeneous market demand. These observed patterns have important implications for experience curve analyses based on time series data covering the up-scaling phases of energy technologies, as these are likely to conflate industry level learning effects with unit level scale effects. The historical diffusion of energy technologies also suggests that low carbon technology policies pushing for significant jumps in unit size before a ‘formative phase’ of experimentation with smaller-scale units are risky
Generation of Three-Qubit Entangled States using Superconducting Phase Qubits
Entanglement is one of the key resources required for quantum computation, so
experimentally creating and measuring entangled states is of crucial importance
in the various physical implementations of a quantum computer. In
superconducting qubits, two-qubit entangled states have been demonstrated and
used to show violations of Bell's Inequality and to implement simple quantum
algorithms. Unlike the two-qubit case, however, where all maximally-entangled
two-qubit states are equivalent up to local changes of basis, three qubits can
be entangled in two fundamentally different ways, typified by the states
and . Here we demonstrate the operation of three coupled
superconducting phase qubits and use them to create and measure
and states. The states are fully characterized
using quantum state tomography and are shown to satisfy entanglement witnesses,
confirming that they are indeed examples of three-qubit entanglement and are
not separable into mixtures of two-qubit entanglement.Comment: 9 pages, 5 figures. Version 2: added supplementary information and
fixed image distortion in Figure 2
Evidence for directional selection at a novel major histocompatibility class I marker in wild common frogs (Rana temporaria) exposed to a viral pathogen (Ranavirus).
(c) 2009 Teacher et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Whilst the Major Histocompatibility Complex (MHC) is well characterized in the anuran Xenopus, this region has not previously been studied in another popular model species, the common frog (Rana temporaria). Nor, to date, have there been any studies of MHC in wild amphibian host-pathogen systems. We characterise an MHC class I locus in the common frog, and present primers to amplify both the whole region, and specifically the antigen binding region. As no more than two expressed haplotypes were found in over 400 clones from 66 individuals, it is likely that there is a single class I locus in this species. This finding is consistent with the single class I locus in Xenopus, but contrasts with the multiple loci identified in axolotls, providing evidence that the diversification of MHC class I into multiple loci likely occurred after the Caudata/Anura divergence (approximately 350 million years ago) but before the Ranidae/Pipidae divergence (approximately 230 mya). We use this locus to compare wild populations of common frogs that have been infected with a viral pathogen (Ranavirus) with those that have no history of infection. We demonstrate that certain MHC supertypes are associated with infection status (even after accounting for shared ancestry), and that the diseased populations have more similar supertype frequencies (lower F(ST)) than the uninfected. These patterns were not seen in a suite of putatively neutral microsatellite loci. We interpret this pattern at the MHC locus to indicate that the disease has imposed selection for particular haplotypes, and hence that common frogs may be adapting to the presence of Ranavirus, which currently kills tens of thousands of amphibians in the UK each year
Influence of sediment characteristics on the composition of soft-sediment intertidal communities in the northern Gulf of Mexico
Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis
BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show the integrated roles of the antiapoptotic BCL-W and BCL2 in affecting responsiveness to the antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) and pharmacologic (YC137) approaches in three breast cancer variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 (ICI resistant), and LY2 (ICI resistant). YC137 inhibits BCL-W and BCL2 and restores ICI sensitivity in resistant cells. Co-inhibition of BCL-W and BCL2 is both necessary and sufficient to restore sensitivity to ICI, and explains mechanistically the action of YC137. These data implicate functional cooperation and/or redundancy in signaling between BCL-W and BCL2, and suggest that broad BCL2 family member inhibitors will have greater therapeutic value than targeting only individual proteins. Whereas ICI sensitive MCF-7/LCC1 cells undergo increased apoptosis in response to ICI following BCL-W±BCL2 co-inhibition, the consequent resensitization of resistant MCF-7/LCC9 and LY2 cells reflects increases in autophagy (LC3 cleavage; p62/SQSTM1 expression) and necrosis but not apoptosis or cell cycle arrest. Thus, de novo sensitive cells and resensitized resistant cells die through different mechanisms. Following BCL-W+BCL2 co-inhibition, suppression of functional autophagy by 3-methyladenine or BECN1 shRNA reduces ICI-induced necrosis but restores the ability of resistant cells to die through apoptosis. These data demonstrate the plasticity of cell fate mechanisms in breast cancer cells in the context of antiestrogen responsiveness. Restoration of ICI sensitivity in resistant cells appears to occur through an increase in autophagy-associated necrosis. BCL-W, BCL2, and BECN1 integrate important functions in determining antiestrogen responsiveness, and the presence of functional autophagy may influence the balance between apoptosis and necrosis
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family
Models of Star-Planet Magnetic Interaction
Magnetic interactions between a planet and its environment are known to lead
to phenomena such as aurorae and shocks in the solar system. The large number
of close-in exoplanets that were discovered triggered a renewed interest in
magnetic interactions in star-planet systems. Multiple other magnetic effects
were then unveiled, such as planet inflation or heating, planet migration,
planetary material escape, and even modification of the host star properties.
We review here the recent efforts in modelling and understanding magnetic
interactions between stars and planets in the context of compact systems. We
first provide simple estimates of the effects of magnetic interactions and then
detail analytical and numerical models for different representative scenarii.
We finally lay out a series of future developments that are needed today to
better understand and constrain these fascinating interactions.Comment: 23 pages, 10 figures, accepted as a chapter in the Handbook of
Exoplanet
Association between objectively measured physical activity and opioid, hypnotic, or anticholinergic medication use in older people – data from the Physical Activity Cohort Scotland study
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