| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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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.
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| 2. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
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Tidskriftsartikel (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 3. |
- Blunden, Jessica, et al.
(författare)
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State of the Climate in 2012
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Tidskriftsartikel (refereegranskat)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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| 4. |
- Sen, Partha, et al.
(författare)
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Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 34:6, s. 801-811
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Tidskriftsartikel (refereegranskat)abstract
- Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
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| 5. |
- Abdo, A. A., et al.
(författare)
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A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 524, s. A75-
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Tidskriftsartikel (refereegranskat)abstract
- Context. Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. The observation of this emission provides a powerful tool to assess the millisecond pulsar population of a cluster, is essential for understanding the importance of binary systems for the evolution of globular clusters, and provides complementary insights into magnetospheric emission processes. Aims. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. Methods. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Results. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices (0.7 < Gamma < 1.4) and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices (1.0 < Gamma < 1.7), however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. Conclusions. The observation of high-energy gamma-ray emission from globular clusters thus provides a reliable independent method to assess their millisecond pulsar populations.
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| 6. |
- Abdo, A. A., et al.
(författare)
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DETECTION OF GAMMA-RAY EMISSION FROM THE STARBURST GALAXIES M82 AND NGC 253 WITH THE LARGE AREA TELESCOPE ON FERMI
- 2010
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Ingår i: The Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 709:2, s. l152-L157
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Tidskriftsartikel (refereegranskat)abstract
- We report the detection of high-energy gamma-ray emission from two starburst galaxies using data obtained with the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. Steady point-like emission above 200 MeV has been detected at significance levels of 6.8 sigma and 4.8 sigma, respectively, from sources positionally coincident with locations of the starburst galaxies M82 and NGC 253. The total fluxes of the sources are consistent with gamma-ray emission originating from the interaction of cosmic rays with local interstellar gas and radiation fields and constitute evidence for a link between massive star formation and gamma-ray emission in star-forming galaxies.
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| 7. |
- Abdo, A. A., et al.
(författare)
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DETECTION OF HIGH-ENERGY GAMMA-RAY EMISSION DURING THE X-RAY FLARING ACTIVITY IN GRB 100728A
- 2011
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Ingår i: The Astrophysical Journal Letters. - 2041-8205. ; 734:2, s. L27-
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Tidskriftsartikel (refereegranskat)abstract
- We present the simultaneous Swift and Fermi observations of the bright GRB 100728A and its afterglow. The early X-ray emission is dominated by a vigorous flaring activity continuing until 1 ks after the burst. In the same time interval, high-energy emission is significantly detected by the Fermi/Large Area Telescope. Marginal evidence of GeV emission is observed up to later times. We discuss the broadband properties of this burst within both the internal and external shock scenarios, with a particular emphasis on the relation between X-ray flares, the GeV emission, and a continued long-duration central engine activity as their power source.
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| 8. |
- Abdo, A. A., et al.
(författare)
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Detection of the Small Magellanic Cloud in gamma-rays with Fermi/LAT
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 523, s. A46-
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Tidskriftsartikel (refereegranskat)abstract
- Context. The flux of gamma rays with energies greater than 100 MeV is dominated by diffuse emission coming from cosmic-rays (CRs) illuminating the interstellar medium (ISM) of our Galaxy through the processes of Bremsstrahlung, pion production and decay, and inverse-Compton scattering. The study of this diffuse emission provides insight into the origin and transport of cosmic rays. Aims. We searched for gamma-ray emission from the Small Magellanic Cloud (SMC) in order to derive constraints on the cosmic-ray population and transport in an external system with properties different from the Milky Way. Methods. We analysed the first 17 months of continuous all-sky observations by the Large Area Telescope (LAT) of the Fermi mission to determine the spatial distribution, flux and spectrum of the gamma-ray emission from the SMC. We also used past radio synchrotron observations of the SMC to study the population of CR electrons specifically. Results. We obtained the first detection of the SMC in high-energy gamma rays, with an integrated >100 MeV flux of (3.7 +/- 0.7) x 10(-8) ph cm(-2) s(-1), with additional systematic uncertainty of <= 16%. The emission is steady and from an extended source similar to 3 degrees in size. It is not clearly correlated with the distribution of massive stars or neutral gas, nor with known pulsars or supernova remnants, but a certain correlation with supergiant shells is observed. Conclusions. The observed flux implies an upper limit on the average CR nuclei density in the SMC of similar to 15% of the value measured locally in the Milky Way. The population of high-energy pulsars of the SMC may account for a substantial fraction of the gamma-ray flux, which would make the inferred CR nuclei density even lower. The average density of CR electrons derived from radio synchrotron observations is consistent with the same reduction factor but the uncertainties are large. From our current knowledge of the SMC, such a low CR density does not seem to be due to a lower rate of CR injection and rather indicates a smaller CR confinement volume characteristic size.
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| 9. |
- Abdo, A. A., et al.
(författare)
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DISCOVERY OF HIGH-ENERGY GAMMA-RAY EMISSION FROM THE BINARY SYSTEM PSR B1259-63/LS 2883 AROUND PERIASTRON WITH FERMI
- 2011
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Ingår i: Astrophysical Journal Letters. - 2041-8205. ; 736:1, s. L11-
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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.
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| 10. |
- Abdo, A. A., et al.
(författare)
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FERMI GAMMA-RAY SPACE TELESCOPE OBSERVATIONS OF THE GAMMA-RAY OUTBURST FROM 3C454.3 IN NOVEMBER 2010
- 2011
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Ingår i: The Astrophysical Journal Letters. - 2041-8205. ; 733:2, s. L26-
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Tidskriftsartikel (refereegranskat)abstract
- The flat-spectrum radio quasar 3C454.3 underwent an extraordinary 5 day gamma-ray outburst in 2010 November when the daily flux measured with the Fermi Large Area Telescope (LAT) at photon energies E > 100 MeV reached (66 +/- 2) x 10(-6) photons cm(-2) s(-1). This is a factor of three higher than its previous maximum flux recorded in 2009 December and greater than or similar to 5 times brighter than the Vela pulsar, which is normally the brightest source in the gamma-ray sky. The 3 hr peak flux was (85 +/- 5) x 10(-6) photons cm-2 s(-1), corresponding to an apparent isotropic luminosity of (2.1 +/- 0.2) x10(50) erg s(-1), the highest ever recorded for a blazar. In this Letter, we investigate the features of this exceptional event in the gamma-ray band of the Fermi-LAT. In contrast to previous flares of the same source observed with the Fermi-LAT, clear spectral changes are observed during the flare.
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