Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). ...Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.
Aims. The revised dataset of sunspot and group numbers (released by WDC-SILSO) and the sunspot number reconstruction based on dendrochronologically dated radiocarbon concentrations have been analyzed ...to provide a deeper characterization of the solar activity main periodicities and to investigate the role of the Gleissberg and Suess cycles in the grand minima occurrence. Methods. Empirical mode decomposition (EMD) has been used to isolate the time behavior of the different solar activity periodicities. A general consistency among the results from all the analyzed datasets verifies the reliability of the EMD approach. Results. The analysis on the revised sunspot data indicates that the highest energy content is associated with the Schwabe cycle. In correspondence with the grand minima (Maunder and Dalton), the frequency of this cycle changes to longer timescales of ~14 yr. The Gleissberg and Suess cycles, with timescales of 60−120 yr and ~ 200−300 yr, respectively, represent the most energetic contribution to sunspot number reconstruction records and are both found to be characterized by multiple scales of oscillation. The grand minima generation and the origin of the two expected distinct types of grand minima, Maunder and longer Spörer-like, are naturally explained through the EMD approach. We found that the grand minima sequence is produced by the coupling between Gleissberg and Suess cycles, the latter being responsible for the most intense and longest Spörer-like minima (with typical duration longer than 80 yr). Finally, we identified a non-solar component, characterized by a very long scale oscillation of ~ 7000 yr, and the Hallstatt cycle (~ 2000 yr), likely due to the solar activity. Conclusions. These results provide new observational constraints on the properties of the solar cycle periodicities, the grand minima generation, and thus the long-term behavior of the solar dynamo.
Migration is an important component of the life history of many animals, but persistence of large-scale terrestrial migrations is being challenged by environmental changes that fragment habitats and ...create obstacles to animal movements. In northern Alaska, the Central Arctic herd (CAH) of barren-ground caribou (Rangifer tarandus granti) is known to migrate over large distances, but the herd's seasonal distributions and migratory movements are not well documented. From 2003-2007, we used GPS radio-collars to determine seasonal ranges and migration routes of 54 female caribou from the CAH. We calculated Brownian bridges to model fall and spring migrations for each year and used the mean of these over all 4 years to identify areas that were used repeatedly. Annual estimates of sizes of seasonal ranges determined by 90% fixed kernel utilization distributions were similar between summer and winter (X̅ = 27,929 SE = 1,064 and X̅ = 26,585 SE = 4912 km2, respectively). Overlap between consecutive summer and winter ranges varied from 3.3-18.3%. Percent overlap between summer ranges used during consecutive years (X̅ = 62.4% SE = 3.7%) was higher than for winter ranges (X̅ = 42.8% SE = 5.9%). Caribou used multiple migration routes each year, but some areas were used by caribou during all years, suggesting that these areas should be managed to allow for continued utilization by caribou. Restoring migration routes after they have been disturbed or fragmented is challenging. However, prior knowledge of movements and threats may facilitate maintenance of migratory paths and seasonal ranges necessary for long-term persistence of migratory species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Massive black holes are key ingredients of the assembly and evolution of cosmic structures. Pulsar Timing Arrays (PTAs) currently provide the only means to observe gravitational radiation from ...massive black hole binary systems with masses 107M. The whole cosmic population produces a signal consisting of two components: (i) a stochastic background resulting from the incoherent superposition of radiation from the all the sources, and (ii) a handful of individually resolvable signals that raise above the background level and are produced by sources sufficiently close and/or massive. Considering a wide range of massive black hole binary assembly scenarios, we investigate both the level and shape of the background and the statistics of resolvable sources. We predict a characteristic background amplitude in the interval hc(f = 10-8 Hz) 5 X 10-16--5 X 10-15, within the detection range of the complete Parkes PTA. On average, at least one resolvable source produces timing residuals that integrated over the typical time of observation lay in the range ~5--50 ns. We also quantify the capability of PTAs of measuring the parameters of individual sources, focusing on the astrophysically more likely monochromatic signals produced by binaries in circular orbit. We investigate how the results depend on the number and distribution of pulsars in the array, by computing the variance--covariance matrix of the parameter measurements. For plausible Square Kilometre Array (SKA) observations (100 pulsars uniformly distributed in the sky), and assuming a coherent signal-to-noise ratio of 10, the sky position of massive black hole binaries can be located within an 40 deg2 error box, opening promising prospects for detecting a putative electromagnetic counterpart to the gravitational wave emission. The planned SKA can plausibly observe these unique systems, although the number of detections is likely to be small. These observations would naturally complement on the high-mass end of the black hole distribution function future surveys carried out by the Laser Interferometer Space Antenna (LISA).
The spatio-temporal dynamics of the solar magnetic field has been investigated by using NSO/Kitt Peak magnetic synoptic maps covering the period 1976 August-2003 September. The field radial ...component, for each heliographic latitude, has been decomposed in intrinsic mode functions through the Empirical Mode Decomposition in order to investigate the time evolution of the various characteristic oscillating modes at different latitudes. The same technique has also been applied on synoptic maps of the meridional and east-west components, which were derived from the observed line-of-sight projection of the field by using the differential rotation. Results obtained for the ~22 yr cycle, related to the polarity inversions of the large-scale dipolar field, show an antisymmetric behavior with respect to the equator in all the field components and a marked poleward flux migration in the radial and meridional components (from about -35degrees and +35degrees in the southern and northern hemispheres, respectively). The quasi-biennial oscillations (QBOs) are also identified as a fundamental timescale of variability of the magnetic field and associated with poleward magnetic flux migration from low latitudes around the maximum and descending phase of the solar cycle. Moreover, signs of an equatorward drift, at a ~2 yr rate, seem to appear in the radial and toroidal components. Hence, the QBO patterns suggest a link to a dynamo action. Finally, the high-frequency component of the magnetic field, at timescales less than 1 yr, provides the most energetic contribution and it is associated with the outbreaks of the bipolar regions on the solar surface.
Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species ...(ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The timing of radio pulsars in binary systems provides a superb testing ground of general relativity. Here we propose a Bayesian approach to carry out these tests, and a relevant efficient numerical ...implementation, that has several conceptual and practical advantages with respect to traditional methods based on least-squares fit that have been used so far: (i) it accounts for the actual structure of the likelihood function – and it is not predicated on the Laplace approximation which is implicitly built in least-squares fit that can potentially bias the inference – (ii) it provides the ratio of the evidences of any two models under consideration as the statistical quantity to compare different theories, and (iii) it allows us to put joint constraints from the monitoring of multiple systems, that can be expressed in terms of ratio of evidences or probability intervals of global (thus not system-dependent) parameters of the theory, if any exists. Our proposed approach optimally exploits the progress in timing of radio pulsars and the increase in the number of observed systems. We demonstrate the power of this framework using simulated data sets that are representative of current observations.
Adenosine is a ubiquitous molecule with key regulatory and cytoprotective mechanisms at times of metabolic imbalance in the body. Among a plethora of physiological actions, adenosine has an important ...role in attenuating ischaemia-reperfusion injury and modulating the ensuing fibrosis and tissue remodeling following myocardial damage. Adenosine exerts these actions through interaction with four adenosine G protein-coupled receptors expressed in the heart. The adenosine A
receptor (A
AR) is the most abundant adenosine receptor (AR) in cardiac fibroblasts and is largely responsible for the influence of adenosine on cardiac fibrosis.
and
studies demonstrate that acute A
AR stimulation can decrease fibrosis through the inhibition of fibroblast proliferation and reduction in collagen synthesis. However, in contrast, there is also evidence that chronic A
AR antagonism reduces tissue fibrosis. This review explores the opposing pro- and anti-fibrotic activity attributed to the activation of cardiac ARs and investigates the therapeutic potential of targeting ARs for the treatment of cardiac fibrosis.
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