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| 8. |
- 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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| 9. |
- Abbasi, R., et al.
(författare)
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Search for point sources of high energy neutrinos with final data from AMANDA-II
- 2009
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 79, s. 062001-
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Tidskriftsartikel (refereegranskat)abstract
- We present a search for point sources of high energy neutrinos using 3.8 yr of data recorded by AMANDA-II during 2000-2006. After reconstructing muon tracks and applying selection criteria designed to optimally retain neutrino-induced events originating in the northern sky, we arrive at a sample of 6595 candidate events, predominantly from atmospheric neutrinos with primary energy 100 GeV to 8 TeV. Our search of this sample reveals no indications of a neutrino point source. We place the most stringent limits to date on E(-2) neutrino fluxes from points in the northern sky, with an average upper limit of E(2)Phi(nu mu)+nu(tau)<= 5.2x10(-11) TeV cm(-2) s(-1) on the sum of nu(mu) and nu(tau) fluxes, assumed equal, over the energy range from 1.9 TeV to 2.5 PeV.
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| 10. |
- Abbasi, R., et al.
(författare)
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Solar energetic particle spectrum on 2006 December 13 determined by IceTop
- 2008
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 689:1, s. L65-L68
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Tidskriftsartikel (refereegranskat)abstract
- On 2006 December 13 the IceTop air shower array at the South Pole detected a major solar particle event. By numerically simulating the response of the IceTop tanks, which are thick Cerenkov detectors with multiple thresholds deployed at high altitude with no geomagnetic cutoff, we determined the particle energy spectrum in the energy range 0.6-7.6 GeV. This is the first such spectral measurement using a single instrument with a well-defined viewing direction. We compare the IceTop spectrum and its time evolution with previously published results and outline plans for improved resolution of future solar particle spectra.
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| 11. |
- Abbasi, R., et al.
(författare)
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The IceCube data acquisition system : Signal capture, digitization, and timestamping
- 2009
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 601:3, s. 294-316
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Tidskriftsartikel (refereegranskat)abstract
- IceCube is a km-scale neutrino observatory under construction at the South Pole with sensors both in the deep ice (InIce) and on the surface (IceTop). The sensors, called Digital Optical Modules (DOMs). detect, digitize and timestamp the signals from optical Cherenkov-radiation photons. The DOM Main Board (MB) data acquisition subsystem is connected to the central DAQ in the IceCube Laboratory (ICL) by a single twisted copper wire-pair and transmits packetized data on demand. Time calibration is maintained throughout the array by regular transmission to the DOMs of precisely timed analog signals, synchronized to a central GPS-disciplined clock. The design goals and consequent features, functional capabilities, and initial performance of the DOM MB, and the operation of a combined array of DOMs as a system, are described here. Experience with the first InIce strings and the IceTop stations indicates that the system design and performance goals have been achieved. (c) 2009 Elsevier B.V. All rights reserved.
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| 12. |
- Ackermann, M., et al.
(författare)
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Search for ultra-high-energy neutrinos with amanda-II
- 2008
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 675:2, s. 1014-1024
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Tidskriftsartikel (refereegranskat)abstract
- A search for diffuse neutrinos with energies in excess of 10(5) GeV is conducted with AMANDA-II data recorded between 2000 and 2002. Above 10(7) GeV, the Earth is essentially opaque to neutrinos. This fact, combined with the limited overburden of the AMANDA-II detector ( roughly 1.5 km), concentrates these ultra-high-energy neutrinos at the horizon. The primary background for this analysis is bundles of downgoing, high-energy muons from the interaction of cosmic rays in the atmosphere. No statistically significant excess above the expected background is seen in the data, and an upper limit is set on the diffuse all-flavor neutrino flux of E-2 Phi(90%CL) < 2.7x10(-7) GeV cm(-2) s(-1) sr(-1) valid over the energy range of 2x10(5) to 10(9) GeV. A number of models that predict neutrino fluxes from active galactic nuclei are excluded at the 90% confidence level.
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| 13. |
- Achterberg, A., et al.
(författare)
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Detection of atmospheric muon neutrinos with the IceCube 9-string detector
- 2007
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Ingår i: Physical Review D - Particles, Fields, Gravitation and Cosmology. - 1550-7998. ; 76:2, s. 027101-
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Tidskriftsartikel (refereegranskat)abstract
- The IceCube neutrino detector is a cubic kilometer TeV to PeV neutrino detector under construction at the geographic South Pole. The dominant population of neutrinos detected in IceCube is due to meson decay in cosmic-ray air showers. These atmospheric neutrinos are relatively well understood and serve as a calibration and verification tool for the new detector. In 2006, the detector was approximately 10% completed, and we report on data acquired from the detector in this configuration. We observe an atmospheric neutrino signal consistent with expectations, demonstrating that the IceCube detector is capable of identifying neutrino events. In the first 137.4 days of live time, 234 neutrino candidates were selected with an expectation of 211 +/- 76.1(syst)+/- 14.5(stat) events from atmospheric neutrinos.
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| 15. |
- Achterberg, A., et al.
(författare)
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Multiyear search for a diffuse flux of muon neutrinos with AMANDA-II
- 2007
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Ingår i: Physical Review D - Particles, Fields, Gravitation and Cosmology. - 1550-7998. ; 76:4, s. 042008-
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Tidskriftsartikel (refereegranskat)abstract
- A search for TeV-PeV muon neutrinos from unresolved sources was performed on AMANDA-II data collected between 2000 and 2003 with an equivalent live time of 807 days. This diffuse analysis sought to find an extraterrestrial neutrino flux from sources with nonthermal components. The signal is expected to have a harder spectrum than the atmospheric muon and neutrino backgrounds. Since no excess of events was seen in the data over the expected background, an upper limit of E-2 Phi(90%C.L.)< 7.4x10(-8) GeV cm(-2) s(-1) sr(-1) is placed on the diffuse flux of muon neutrinos with a Phi proportional to E-2 spectrum in the energy range 16 TeV to 2.5 PeV. This is currently the most sensitive Phi proportional to E-2 diffuse astrophysical neutrino limit. We also set upper limits for astrophysical and prompt neutrino models, all of which have spectra different from Phi proportional to E-2.
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| 16. |
- Achterberg, A., et al.
(författare)
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The search for muon neutrinos from northern hemisphere gamma-ray bursts with AMANDA
- 2008
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 674:1, s. 357-370
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Tidskriftsartikel (refereegranskat)abstract
- We present the results of the analysis of neutrino observations by the Antarctic Muon and Neutrino Detector Array (AMANDA) correlated with photon observations of more than 400 gamma-ray bursts (GRBs) in the northern hemisphere from 1997 to 2003. During this time period, AMANDA's effective collection area for muon neutrinos was larger than that of any other existing detector. After the application of various selection criteria to our data, we expect similar to 1 neutrino event and <2 background events. Based on our observations of zero events during and immediately prior to the GRBs in the data set, we set the most stringent upper limit on muon neutrino emission correlated with GRBs. Assuming a Waxman-Bahcall spectrum and incorporating all systematic uncertainties, our flux upper limit has a normalization at 1 PeV of E-2 Phi(nu) <= 6.3 x 10(-9) GeV cm(-2) s(-1) sr(-1), with 90% of the events expected within the energy range of similar to 10 TeV to similar to 3 PeV. The impact of this limit on several theoretical models of GRBs is discussed, as well as the future potential for detection of GRBs by next-generation neutrino telescopes. Finally, we briefly describe several modifications to this analysis in order to apply it to other types of transient point sources.
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| 17. |
- Zillikens, M. C., et al.
(författare)
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
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| 19. |
- Durno, C., et al.
(författare)
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Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
- 2021
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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| 20. |
- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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| 22. |
- Razavi, H., et al.
(författare)
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Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study
- 2017
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 2:5, s. 325-336
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Tidskriftsartikel (refereegranskat)abstract
- Background Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide. In the European Union (EU), treatment and cure of HCV with direct-acting antiviral therapies began in 2014. WHO targets are to achieve a 65% reduction in liver-related deaths, a 90% reduction of new viral hepatitis infections, and 90% of patients with viral hepatitis infections being diagnosed by 2030. This study assessed the prevalence of HCV in the EU and the level of intervention required to achieve WHO targets for HCV elimination. Methods We populated country Markov models for the 28 EU countries through a literature search of PubMed and Embase between Jan 1, 2000, and March 31, 2016, and a Delphi process to gain expert consensus and validate inputs. We aggregated country models to create a regional EU model. We used the EU model to forecast HCV disease progression (considering the effect of immigration) and developed a strategy to acehive WHO targets. We used weighted average sustained viral response rates and fibrosis restrictions to model the effect of current therapeutic guidelines. We used the EU model to forecast HCV disease progression (considering the effect of immigration) under current screening and therapeutic guidelines. Additionally, we back-calculated the total number of patients needing to be screened and treated to achieve WHO targets. Findings We estimated the number of viraemic HCV infections in 2015 to be 3 238 000 (95% uncertainty interval [UI] 2 106 000-3 795 000) of a total population of 509 868 000 in the EU, equating to a prevalence of viraemic HCV of 0.64% (95% UI 0.41-0.74). We estimated that 1 180 000 (95% UI 1 003 000-1 357 000) people were diagnosed with viraemia (36.4%), 150 000 (12 000-180 000) were treated (4.6% of the total infected population or 12.7% of the diagnosed population), 133 000 (106 000-160 000) were cured (4.1%), and 57 900 (43 900-67 300) were newly infected (1.8%) in 2015. Additionally, 30 400 (26 600-42 500) HCV-positive immigrants entered the EU. To achieve WHO targets, unrestricted treatment needs to increase from 150 000 patients in 2015 to 187 000 patients in 2025 and diagnosis needs to increase from 88 800 new cases annually in 2015 to 180 000 in 2025. Interpretation Given its advanced health-care infrastructure, the EU is uniquely poised to eliminate HCV; however, expansion of screening programmes is essential to increase treatment to achieve the WHO targets. A united effort, grounded in sound epidemiological evidence, will also be necessary.
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