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1.
  • Tidskriftsartikel (refereegranskat)
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2.
  • Nicholls, Thomas J., et al. (författare)
  • Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA
  • 2018
  • Ingår i: Molecular Cell. - 1097-2765 .- 1097-4164. ; 69:1, s. 9-23.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation. © 2017 Elsevier Inc.
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3.
  • Wang, Haidong, et al. (författare)
  • Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013
  • 2014
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 384:9947, s. 957-979
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
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4.
  • Abellán, F. J., et al. (författare)
  • Very Deep inside the SN 1987A Core Ejecta : Molecular Structures Seen in 3D
  • 2017
  • Ingår i: Astrophysical Journal Letters. - : Institute of Physics Publishing. - 2041-8205 .- 2041-8213. ; 842:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Most massive stars end their lives in core-collapse supernova explosions and enrich the interstellar medium with explosively nucleosynthesized elements. Following core collapse, the explosion is subject to instabilities as the shock propagates outward through the progenitor star. Observations of the composition and structure of the innermost regions of a core-collapse supernova provide a direct probe of the instabilities and nucleosynthetic products. SN 1987A in the Large Magellanic Cloud is one of very few supernovae for which the inner ejecta can be spatially resolved but are not yet strongly affected by interaction with the surroundings. Our observations of SN 1987A with the Atacama Large Millimeter/submillimeter Array are of the highest resolution to date and reveal the detailed morphology of cold molecular gas in the innermost regions of the remnant. The 3D distributions of carbon and silicon monoxide (CO and SiO) emission differ, but both have a central deficit, or torus-like distribution, possibly a result of radioactive heating during the first weeks (nickel heating). The size scales of the clumpy distribution are compared quantitatively to models, demonstrating how progenitor and explosion physics can be constrained.
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5.
  • Cepeda, Diana, et al. (författare)
  • CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
  • 2013
  • Ingår i: EMBO Molecular Medicine. - : Federation of European Neuroscience Societies and Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684. ; 5:7, s. 1067-1086
  • Tidskriftsartikel (refereegranskat)abstract
    • SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.
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6.
  • Tidskriftsartikel (refereegranskat)
  •  
7.
  • Kamae, Tuneyoshi, et al. (författare)
  • PoGOLite - A high sensitivity balloon-borne soft gamma-ray polarimeter
  • 2008
  • Ingår i: Astroparticle physics. - 0927-6505 .- 1873-2852. ; 30:2, s. 72-84
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a new balloon-borne instrument (PoGOLite) capable of detecting 10% polarisation from 200 mCrab point-like sources between 25 and 80 keV in one 6-h flight. Polarisation measurements in the soft gamma-ray band are expected to provide a powerful probe into high energy emission mechanisms as well as the distribution of magnetic fields, radiation fields and interstellar matter. Synchrotron radiation, inverse Compton scattering and propagation through high magnetic fields are likely to produce high degrees of polarisation in the energy band of the instrument. We demonstrate, through tests at accelerators, with radioactive sources and through computer simulations, that PoGOLite will be able to detect degrees of polarisation as predicted by models for several classes of high energy sources. At present, only exploratory polarisation measurements have been carried out in the soft gamma-ray band. Reduction of the large background produced by cosmic-ray particles while securing a large effective area has been the greatest challenge. PoGOLite uses Compton scattering and photo-absorption in an array of 217 well-type phoswich detector cells made of plastic and BGO scintillators surrounded by a BGO anticoincidence shield and a thick polyethylene neutron shield. The narrow Held of view (FWHM = 1.25 msr, 2.0 deg x 2.0 deg) obtained with detector cells and the use of thick background shields warrant a large effective area for polarisation measurements (similar to 228 cm(2) at E = 40 keV) without sacrificing the signal-to-noise ratio. Simulation studies for an atmospheric overburden of 3-4 g/cm(2) indicate that neutrons and gamma-rays entering the PDC assembly through the shields are dominant backgrounds. Off-line event selection based on recorded phototube waveforms and Compton kinematics reduce the background to that expected for a similar to 100 mCrab source between 25 and 50 keV. A 6-h observation of the Crab pulsar will differentiate between the Polar Cap/Slot Gap, Outer Gap, and Caustic models with greater than 5 sigma significance; and also cleanly identify the Compton reflection component in the Cygnus X-1 hard state. Long-duration flights will measure the dependence of the polarisation across the cyclotron absorption line in Hercules X-1. A scaled-down instrument will be flown as a pathfinder mission from the north of Sweden in 2010. The first science flight is planned to take place shortly thereafter.
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8.
  • Kamae, Tuneyoshi, et al. (författare)
  • PoGOLite - A high sensitivity balloon-borne soft gamma-ray polarimeter
  • 2008
  • Ingår i: Astroparticle physics. - 0927-6505 .- 1873-2852. ; 30:2, s. 72-84
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a new balloon-borne instrument (PoGOLite) capable of detecting 10% polarisation from 200 mCrab point-like sources between 25 and 80 keV in one 6-h flight. Polarisation measurements in the soft gamma-ray band are expected to provide a powerful probe into high energy emission mechanisms as well as the distribution of magnetic fields, radiation fields and interstellar matter. Synchrotron radiation, inverse Compton scattering and propagation through high magnetic fields are likely to produce high degrees of polarisation in the energy band of the instrument. We demonstrate, through tests at accelerators, with radioactive sources and through computer simulations, that PoGOLite will be able to detect degrees of polarisation as predicted by models for several classes of high energy sources. At present, only exploratory polarisation measurements have been carried out in the soft gamma-ray band. Reduction of the large background produced by cosmic-ray particles while securing a large effective area has been the greatest challenge. PoGOLite uses Compton scattering and photo-absorption in an array of 217 well-type phoswich detector cells made of plastic and BGO scintillators surrounded by a BGO anticoincidence shield and a thick polyethylene neutron shield. The narrow Held of view (FWHM = 1.25 msr, 2.0 deg x 2.0 deg) obtained with detector cells and the use of thick background shields warrant a large effective area for polarisation measurements (similar to 228 cm(2) at E = 40 keV) without sacrificing the signal-to-noise ratio. Simulation studies for an atmospheric overburden of 3-4 g/cm(2) indicate that neutrons and gamma-rays entering the PDC assembly through the shields are dominant backgrounds. Off-line event selection based on recorded phototube waveforms and Compton kinematics reduce the background to that expected for a similar to 100 mCrab source between 25 and 50 keV. A 6-h observation of the Crab pulsar will differentiate between the Polar Cap/Slot Gap, Outer Gap, and Caustic models with greater than 5 sigma significance; and also cleanly identify the Compton reflection component in the Cygnus X-1 hard state. Long-duration flights will measure the dependence of the polarisation across the cyclotron absorption line in Hercules X-1. A scaled-down instrument will be flown as a pathfinder mission from the north of Sweden in 2010. The first science flight is planned to take place shortly thereafter. 
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9.
  • Kassebaum, Nicholas J, et al. (författare)
  • Global, regional, and national levels and causes of maternal mortality during 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013
  • 2014
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 384:9947, s. 980-1004
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.FINDINGS: 292 982 (95% UI 261 017-327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483-407 574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
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10.
  • Kassebaum, Nicholas J., et al. (författare)
  • Global, regional, and national levels of maternal mortality, 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015
  • 2016
  • Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1775-1812
  • Tidskriftsartikel (refereegranskat)abstract
    • Background In transitioning from the Millennium Development Goal to the Sustainable Development Goal era, it is imperative to comprehensively assess progress toward reducing maternal mortality to identify areas of success, remaining challenges, and frame policy discussions. We aimed to quantify maternal mortality throughout the world by underlying cause and age from 1990 to 2015. Methods We estimated maternal mortality at the global, regional, and national levels from 1990 to 2015 for ages 10-54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories, 11 of which were analysed at the subnational level. We quantified eight underlying causes of maternal death and four timing categories, improving estimation methods since GBD 2013 for adult all-cause mortality, HIV-related maternal mortality, and late maternal death. Secondary analyses then allowed systematic examination of drivers of trends, including the relation between maternal mortality and coverage of specific reproductive health-care services as well as assessment of observed versus expected maternal mortality as a function of Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Findings Only ten countries achieved MDG 5, but 122 of 195 countries have already met SDG 3.1. Geographical disparities widened between 1990 and 2015 and, in 2015, 24 countries still had a maternal mortality ratio greater than 400. The proportion of all maternal deaths occurring in the bottom two SDI quintiles, where haemorrhage is the dominant cause of maternal death, increased from roughly 68% in 1990 to more than 80% in 2015. The middle SDI quintile improved the most from 1990 to 2015, but also has the most complicated causal profile. Maternal mortality in the highest SDI quintile is mostly due to other direct maternal disorders, indirect maternal disorders, and abortion, ectopic pregnancy, and/or miscarriage. Historical patterns suggest achievement of SDG 3.1 will require 91% coverage of one antenatal care visit, 78% of four antenatal care visits, 81% of in-facility delivery, and 87% of skilled birth attendance. Interpretation Several challenges to improving reproductive health lie ahead in the SDG era. Countries should establish or renew systems for collection and timely dissemination of health data; expand coverage and improve quality of family planning services, including access to contraception and safe abortion to address high adolescent fertility; invest in improving health system capacity, including coverage of routine reproductive health care and of more advanced obstetric care-including EmOC; adapt health systems and data collection systems to monitor and reverse the increase in indirect, other direct, and late maternal deaths, especially in high SDI locations; and examine their own performance with respect to their SDI level, using that information to formulate strategies to improve performance and ensure optimum reproductive health of their population.
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