| 1. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
-
Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
|
|
| 2. |
- Zhang, Guojie, et al.
(författare)
-
Comparative genomics reveals insights into avian genome evolution and adaptation
- 2014
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1311-1320
-
Tidskriftsartikel (refereegranskat)abstract
- Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
|
|
| 3. |
- Yi, Chuixiang, et al.
(författare)
-
Climate control of terrestrial carbon exchange across biomes and continents
- 2010
-
Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 5:3
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2 exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid-and high-latitudes, (2) a strong function of dryness at mid-and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45 degrees N). The sensitivity of NEE to mean annual temperature breaks down at similar to 16 degrees C (a threshold value of mean annual temperature), above which no further increase of CO2 uptake with temperature was observed and dryness influence overrules temperature influence.
|
|
| 4. |
- Abdo, A. A., et al.
(författare)
-
The first fermi large area telescope catalog of gamma-ray pulsars
- 2010
-
Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 187:2, s. 460-494
-
Tidskriftsartikel (refereegranskat)abstract
- The dramatic increase in the number of known gamma-ray pulsars since the launch of the Fermi Gamma-ray Space Telescope (formerly GLAST) offers the first opportunity to study a sizable population of these high-energy objects. This catalog summarizes 46 high-confidence pulsed detections using the first six months of data taken by the Large Area Telescope (LAT), Fermi's main instrument. Sixteen previously unknown pulsars were discovered by searching for pulsed signals at the positions of bright gamma-ray sources seen with the LAT, or at the positions of objects suspected to be neutron stars based on observations at other wavelengths. The dimmest observed flux among these gamma-ray-selected pulsars is 6.0 x 10(-8) ph cm(-2) s(-1) (for E > 100 MeV). Pulsed gamma-ray emission was discovered from 24 known pulsars by using ephemerides (timing solutions) derived from monitoring radio pulsars. Eight of these new gamma-ray pulsars are millisecond pulsars. The dimmest observed flux among the radio-selected pulsars is 1.4 x 10(-8) ph cm(-2) s(-1) (for E > 100 MeV). The remaining six gamma-ray pulsars were known since the Compton Gamma Ray Observatory mission, or before. The limiting flux for pulse detection is non-uniform over the sky owing to different background levels, especially near the Galactic plane. The pulsed energy spectra can be described by a power law with an exponential cutoff, with cutoff energies in the range similar to 1-5 GeV. The rotational energy-loss rate ((E) over dot) of these neutron stars spans five decades, from similar to 3 x 10(33) erg s(-1) to 5 x 10(38) erg s(-1), and the apparent efficiencies for conversion to gammaray emission range from similar to 0.1% to similar to unity, although distance uncertainties complicate efficiency estimates. The pulse shapes show substantial diversity, but roughly 75% of the gamma-ray pulse profiles have two peaks, separated by greater than or similar to 0.2 of rotational phase. For most of the pulsars, gamma-ray emission appears to come mainly from the outer magnetosphere, while polar-cap emission remains plausible for a remaining few. Spatial associations imply that many of these pulsars power pulsar wind nebulae. Finally, these discoveries suggest that gamma-ray-selected young pulsars are born at a rate comparable to that of their radio-selected cousins and that the birthrate of all young gamma-ray-detected pulsars is a substantial fraction of the expected Galactic supernova rate.
|
|
| 5. |
- Jarvis, Erich D., et al.
(författare)
-
Whole-genome analyses resolve early branches in the tree of life of modern birds
- 2014
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1320-1331
-
Tidskriftsartikel (refereegranskat)abstract
- To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
|
|
| 6. |
|
|
| 7. |
- Abdo, A. A., et al.
(författare)
-
DISCOVERY OF HIGH-ENERGY GAMMA-RAY EMISSION FROM THE BINARY SYSTEM PSR B1259-63/LS 2883 AROUND PERIASTRON WITH FERMI
- 2011
-
Ingår i: Astrophysical Journal Letters. - 2041-8205. ; 736:1, s. L11-
-
Tidskriftsartikel (refereegranskat)abstract
- We report on the discovery of >= 100 MeV gamma-rays from the binary system PSR B1259-63/LS 2883 using the Large Area Telescope (LAT) on board Fermi. The system comprises a radio pulsar in orbit around a Be star. We report on LAT observations from near apastron to similar to 128 days after the time of periastron, t(p), on 2010 December 15. No gamma-ray emission was detected from this source when it was far from periastron. Faint gamma-ray emission appeared as the pulsar approached periastron. At similar to t(p) + 30 days, the >= 100 MeV gamma-ray flux increased over a period of a few days to a peak flux 20-30 times that seen during the pre-periastron period, but with a softer spectrum. For the following month, it was seen to be variable on daily timescales, but remained at similar to(1-4) x 10(-6) cm(-2) s(-1) before starting to fade at similar to t(p) + 57 days. The total gamma-ray luminosity observed during this period is comparable to the spin-down power of the pulsar. Simultaneous radio and X-ray observations of the source showed no corresponding dramatic changes in radio and X-ray flux between the pre-periastron and post-periastron flares. We discuss possible explanations for the observed gamma-ray-only flaring of the source.
|
|
| 8. |
- Abdo, A. A., et al.
(författare)
-
FERMI LARGE AREA TELESCOPE FIRST SOURCE CATALOG
- 2010
-
Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 188:2, s. 405-436
-
Tidskriftsartikel (refereegranskat)abstract
- We present a catalog of high-energy gamma-ray sources detected by the Large Area Telescope (LAT), the primary science instrument on the Fermi Gamma-ray Space Telescope (Fermi), during the first 11 months of the science phase of the mission, which began on 2008 August 4. The First Fermi-LAT catalog (1FGL) contains 1451 sources detected and characterized in the 100 MeV to 100 GeV range. Source detection was based on the average flux over the 11 month period, and the threshold likelihood Test Statistic is 25, corresponding to a significance of just over 4 sigma. The 1FGL catalog includes source location regions, defined in terms of elliptical fits to the 95% confidence regions and power-law spectral fits as well as flux measurements in five energy bands for each source. In addition, monthly light curves are provided. Using a protocol defined before launch we have tested for several populations of gamma-ray sources among the sources in the catalog. For individual LAT-detected sources we provide firm identifications or plausible associations with sources in other astronomical catalogs. Identifications are based on correlated variability with counterparts at other wavelengths, or on spin or orbital periodicity. For the catalogs and association criteria that we have selected, 630 of the sources are unassociated. Care was taken to characterize the sensitivity of the results to the model of interstellar diffuse gamma-ray emission used to model the bright foreground, with the result that 161 sources at low Galactic latitudes and toward bright local interstellar clouds are flagged as having properties that are strongly dependent on the model or as potentially being due to incorrectly modeled structure in the Galactic diffuse emission.
|
|
| 9. |
- Abdo, A. A., et al.
(författare)
-
Fermi large area telescope observations of PSR J1836+5925
- 2010
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 712:2, s. 1209-1218
-
Tidskriftsartikel (refereegranskat)abstract
- The discovery of the gamma-ray pulsar PSR J1836+5925, powering the formerly unidentified EGRET source 3EG J1835+5918, was one of the early accomplishments of the Fermi Large Area Telescope (LAT). Sitting 25 degrees off the Galactic plane, PSR J1836+5925 is a 173 ms pulsar with a characteristic age of 1.8 million years, a spindown luminosity of 1.1 x 10(34) erg s(-1), and a large off-peak (OP) emission component, making it quite unusual among the known gamma-ray pulsar population. We present an analysis of one year of LAT data, including an updated timing solution, detailed spectral results, and a long-term light curve showing no indication of variability. No evidence for a surrounding pulsar wind nebula is seen and the spectral characteristics of the OP emission indicate it is likely magnetospheric. Analysis of recent XMM-Newton observations of the X-ray counterpart yields a detailed characterization of its spectrum, which, like Geminga, is consistent with that of a neutron star showing evidence for both magnetospheric and thermal emission.
|
|
| 10. |
- Abdo, A. A., et al.
(författare)
-
FERMI LARGE AREA TELESCOPE OBSERVATIONS OF THE VELA-X PULSAR WIND NEBULA
- 2010
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713:1, s. 146-153
-
Tidskriftsartikel (refereegranskat)abstract
- We report on gamma-ray observations in the off-pulse window of the Vela pulsar PSR B0833-45 using 11 months of survey data from the Fermi Large Area Telescope (LAT). This pulsar is located in the 8 degrees diameter Vela supernova remnant, which contains several regions of non-thermal emission detected in the radio, X-ray, and gamma-ray bands. The gamma-ray emission detected by the LAT lies within one of these regions, the 2 degrees x 3 degrees area south of the pulsar known as Vela-X. The LAT flux is significantly spatially extended with a best-fit radius of 0.degrees 88 +/- 0.degrees 12 for an assumed radially symmetric uniform disk. The 200 MeV to 20 GeV LAT spectrum of this source is well described by a power law with a spectral index of 2.41 +/- 0.09 +/- 0.15 and integral flux above 100 MeV of (4.73 +/- 0.63 +/- 1.32) x 10(-7) cm(-2) s(-1). The first errors represent the statistical error on the fit parameters, while the second ones are the systematic uncertainties. Detailed morphological and spectral analyses give strong constraints on the energetics and magnetic field of the pulsar wind nebula system and favor a scenario with two distinct electron populations.
|
|
| 11. |
- Abdo, A. A., et al.
(författare)
-
Gamma-ray emission concurrent with the nova in the symbiotic binary V407 cygni
- 2010
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 329:5993, s. 817-821
-
Tidskriftsartikel (refereegranskat)abstract
- Novae are thermonuclear explosions on a white dwarf surface fueled by mass accreted from a companion star. Current physical models posit that shocked expanding gas from the nova shell can produce x-ray emission, but emission at higher energies has not been widely expected. Here, we report the Fermi Large Area Telescope detection of variable γ-ray emission (0.1 to 10 billion electron volts) from the recently detected optical nova of the symbiotic star V407 Cygni. We propose that the material of the nova shell interacts with the dense ambient medium of the red giant primary and that particles can be accelerated effectively to produce π0 decay γ-rays from proton-proton interactions. Emission involving inverse Compton scattering of the red giant radiation is also considered and is not ruled out.
|
|
| 12. |
- Abdo, A. A., et al.
(författare)
-
Gamma-Ray Flares from the Crab Nebula
- 2011
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 331:6018, s. 739-742
-
Tidskriftsartikel (refereegranskat)abstract
- A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (10(15) electron volts) electrons in a region smaller than 1.4 x 10(-2) parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.
|
|
| 13. |
- Abdo, A. A., et al.
(författare)
-
The second Fermi large area telescope catalog of gamma-ray pulsars
- 2013
-
Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 208:2, s. 17-
-
Tidskriftsartikel (refereegranskat)abstract
- This catalog summarizes 117 high-confidence ≥0.1 GeV gamma-ray pulsar detections using three years of data acquired by the Large Area Telescope (LAT) on the Fermi satellite. Half are neutron stars discovered using LAT data through periodicity searches in gamma-ray and radio data around LAT unassociated source positions. The 117 pulsars are evenly divided into three groups: millisecond pulsars, young radio-loud pulsars, and young radio-quiet pulsars. We characterize the pulse profiles and energy spectra and derive luminosities when distance information exists. Spectral analysis of the off-peak phase intervals indicates probable pulsar wind nebula emission for four pulsars, and off-peak magnetospheric emission for several young and millisecond pulsars. We compare the gamma-ray properties with those in the radio, optical, and X-ray bands. We provide flux limits for pulsars with no observed gamma-ray emission, highlighting a small number of gamma-faint, radio-loud pulsars. The large, varied gamma-ray pulsar sample constrains emission models. Fermi's selection biases complement those of radio surveys, enhancing comparisons with predicted population distributions.
|
|
| 14. |
- Abdo, A. A., et al.
(författare)
-
THE VELA PULSAR : RESULTS FROM THE FIRST YEAR OF FERMI LAT OBSERVATIONS
- 2010
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713:1, s. 154-165
-
Tidskriftsartikel (refereegranskat)abstract
- We report on analysis of timing and spectroscopy of the Vela pulsar using 11 months of observations with the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. The intrinsic brightness of Vela at GeV energies combined with the angular resolution and sensitivity of the LAT allows us to make the most detailed study to date of the energy-dependent light curves and phase-resolved spectra, using a LAT-derived timing model. The light curve consists of two peaks (P1 and P2) connected by bridge emission containing a third peak (P3). We have confirmed the strong decrease of the P1/P2 ratio with increasing energy seen with EGRET and previous Fermi LAT data, and observe that P1 disappears above 20 GeV. The increase with energy of the mean phase of the P3 component can be followed with much greater detail, showing that P3 and P2 are present up to the highest energies of pulsation. We find significant pulsed emission at phases outside the main profile, indicating that magnetospheric emission exists over 80% of the pulsar period. With increased high-energy counts the phase-averaged spectrum is seen to depart from a power law with simple exponential cutoff, and is better fit with a more gradual cutoff. The spectra in fixed-count phase bins are well fit with power laws with exponential cutoffs, revealing a strong and complex phase dependence of the cutoff energy, especially in the peaks. By combining these results with predictions of the outer magnetosphere models that map emission characteristics to phase, it will be possible to probe the particle acceleration and the structure of the pulsar magnetosphere with unprecedented detail.
|
|
| 15. |
- Ackermann, M., et al.
(författare)
-
A STATISTICAL APPROACH TO RECOGNIZING SOURCE CLASSES FOR UNASSOCIATED SOURCES IN THE FIRST FERMI-LAT CATALOG
- 2012
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 753:1, s. 83-
-
Tidskriftsartikel (refereegranskat)abstract
- The Fermi Large Area Telescope (LAT) First Source Catalog (1FGL) provided spatial, spectral, and temporal properties for a large number of gamma-ray sources using a uniform analysis method. After correlating with the most-complete catalogs of source types known to emit gamma rays, 630 of these sources are unassociated (i.e., have no obvious counterparts at other wavelengths). Here, we employ two statistical analyses of the primary gamma-ray characteristics for these unassociated sources in an effort to correlate their gamma-ray properties with the active galactic nucleus (AGN) and pulsar populations in 1FGL. Based on the correlation results, we classify 221 AGN-like and 134 pulsar-like sources in the 1FGL unassociated sources. The results of these source classifications appear to match the expected source distributions, especially at high Galactic latitudes. While useful for planning future multiwavelength follow-up observations, these analyses use limited inputs, and their predictions should not be considered equivalent to probable source classes for these sources. We discuss multiwavelength results and catalog cross-correlations to date, and provide new source associations for 229 Fermi-LAT sources that had no association listed in the 1FGL catalog. By validating the source classifications against these new associations, we find that the new association matches the predicted source class in similar to 80% of the sources.
|
|
| 16. |
- Ackermann, M., et al.
(författare)
-
Fermi-LAT search for pulsar wind nebulae around gamma-ray pulsars
- 2011
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 726:1, s. 35-
-
Tidskriftsartikel (refereegranskat)abstract
- The high sensitivity of the Fermi-LAT (Large Area Telescope) offers the first opportunity to study faint and extended GeV sources such as pulsar wind nebulae (PWNe). After one year of observation the LAT detected and identified three PWNe: the Crab Nebula, Vela-X, and the PWN inside MSH 15-52. In the meantime, the list of LAT detected pulsars increased steadily. These pulsars are characterized by high energy loss rates ((E) over dot) from similar to 3 x 10(33) erg s(-1) to 5 x 10(38) erg s(-1) and are therefore likely to power a PWN. This paper summarizes the search for PWNe in the off-pulse windows of 54 LAT-detected pulsars using 16 months of survey observations. Ten sources show significant emission, seven of these likely being of magnetospheric origin. The detection of significant emission in the off-pulse interval offers new constraints on the gamma-ray emitting regions in pulsar magnetospheres. The three other sources with significant emission are the Crab Nebula, Vela-X, and a new PWN candidate associated with the LAT pulsar PSR J1023-5746, coincident with the TeV source HESS J1023-575. We further explore the association between the HESS and the Fermi source by modeling its spectral energy distribution. Flux upper limits derived for the 44 remaining sources are used to provide new constraints on famous PWNe that have been detected at keV and/or TeV energies.
|
|
| 17. |
|
|
| 18. |
- Freire, P. C. C., et al.
(författare)
-
Fermi Detection of a Luminous gamma-Ray Pulsar in a Globular Cluster
- 2011
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 334:6059, s. 1107-1110
-
Tidskriftsartikel (refereegranskat)abstract
- We report on the Fermi Large Area Telescope's detection of gamma-ray (>100 mega-electron volts) pulsations from pulsar J1823-3021A in the globular cluster NGC 6624 with high significance (similar to 7 sigma). Its gamma-ray luminosity, L(gamma) = (8.4 +/- 1.6) x 10(34) ergs per second, is the highest observed for any millisecond pulsar (MSP) to date, and it accounts for most of the cluster emission. The nondetection of the cluster in the off-pulse phase implies that it contains <32 gamma-ray MSPs, not similar to 100 as previously estimated. The gamma-ray luminosity indicates that the unusually large rate of change of its period is caused by its intrinsic spin-down. This implies that J1823-3021A has the largest magnetic field and is the youngest MSP ever detected and that such anomalous objects might be forming at rates comparable to those of the more normal MSPs.
|
|
| 19. |
- Hsu, Ya-Ching, et al.
(författare)
-
Methadone concentrations in blood, plasma, and oral fluid determined by isotope-dilution gas chromatography-mass spectrometry
- 2013
-
Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Verlag (Germany). - 1618-2642 .- 1618-2650. ; 405:12, s. 3921-3928
-
Tidskriftsartikel (refereegranskat)abstract
- Methadone (MTD) is widely used for detoxification of heroin addicts and also in pain management programs. Information about the distribution of methadone between blood, plasma, and alternative specimens, such as oral fluid (OF), is needed in clinical, forensic, and traffic medicine when analytical results are interpreted. We determined MTD and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in blood, plasma, blood cells, and OF by gas chromatography-mass spectrometry (GC-MS) after adding deuterium-labeled internal standards. The analytical limits of quantitation for MTD and EDDP by this method were 20 and 3 ng/mL, respectively. The amounts of MTD and EDDP were higher in plasma (80.4 % and 76.5 %) compared with blood cells (19.6 % and 23.5 %) and we found that repeated washing of blood cells with phosphate-buffered saline increased the amounts in plasma (93.6 % and 88.6 %). Mean plasma/blood concentration ratios of MTD and EDDP in spiked samples (N = 5) were 1.27 and 1.21, respectively. In clinical samples from patients (N = 46), the concentrations of MTD in plasma and whole blood were highly correlated (r = 0.92, p andlt; 0.001) and mean (median) plasma/blood distribution ratios were 1.43 (1.41). The correlations between MTD in OF and plasma (r = 0.46) and OF and blood (r = 0.52) were also statistically significant (p andlt; 0.001) and the mean OF/plasma and OF/blood distribution ratios were 0.55 and 0.77, respectively. The MTD concentration in OF decreased as salivary pH increased (more basic). These results will prove useful in clinical and forensic medicine when MTD concentrations in alternative specimens are compared and contrasted.
|
|
| 20. |
- McKay, James D., et al.
(författare)
-
A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
|
|
| 21. |
- Noutsos, A., et al.
(författare)
-
Radio and γ-ray constraints on the emission geometry and birthplace of PSR j2043+2740
- 2011
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 728:2, s. 77-
-
Tidskriftsartikel (refereegranskat)abstract
- We report on the first year of Fermi γ-ray observations of pulsed high-energy emission from the old PSR J2043 + 2740. The study of the γ-ray efficiency of such old pulsars gives us an insight into the evolution of pulsars' ability to emit in γ rays as they age. The y-ray light curve of this pulsar above 0.1 GeV is clearly defined by two sharp peaks, 0.353 ± 0.035 periods apart. We have combined the γ-ray profile characteristics of PSR J2043 + 2740 with the geometrical properties of the pulsar's radio emission, derived from radio-polarization data, and constrained the pulsar-beam geometry in the framework of a two-pole caustic (TPC) and an outer gap (OG) model. The ranges of magnetic inclination and viewing angle were determined to be {α, ζ} ∼ {52°-57°, 61°-68°} for the TPC model, and {α, ζ} ∼ {62°-73°, 74°-81°} and {α, ζ,} ∼ {72°-83°, 60°-75°} for the OG model. Based on this geometry, we assess possible birth locations for this pulsar and derive a likely proper motion, sufficiently high to be measurable with VLBI. At a characteristic age of 1.2 Myr, PSR J2043 + 2740 is the third oldest of all discovered, non-recycled, γ-ray pulsars: it is twice as old as the next oldest, PSR J0357 + 32, and younger only than the recently discovered PSR J1836 + 5925 and PSR J2055 + 25, both of which are at least five and ten times less energetic, respectively.
|
|
| 22. |
|
|
| 23. |
- Zhukova, Nataliya, et al.
(författare)
-
WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
- 2014
-
Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
-
Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
|
|
