148 research outputs found
Engineered LINE-1 retrotransposition in nondividing human neurons
Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.We thank current members of the J.L.G.-P. laboratory for helpful discussions. We also thank Drs. Geoffrey Faulkner (Mater Research, Australia) and John V. Moran (University of Michigan) for sharing unpublished data and for critical input during the project; Ms. Raquel Marrero (Microscopy Unit, Genyo) for technical support; Simon Mendez-Ferrer (CNIC, Spain) for providing total RNA isolated from human mesenspheres; Dr. Oliver Weichenrieder (Max-Planck, Tubingen, Germany) for providing a polyclonal L1-ORF1p antibody; and Dr. Aurelien Doucet (IRCAN, Nice, France) for providing a plasmid containing an UBC-driven EGFP retrotransposition indicator cassette. J.L.G. was funded by the US Department of Defense, Breast Cancer Research Program (award #BC051386), the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (1R03NS087290-01), and the ALS Therapy Alliance (2013-F-067). A.M. has been partially funded by a Marie Curie IRG project (FP7-PEOPLE-2007-4-3-IRG: SOMATIC LINE-1). J.L.G.-P's laboratory is supported by CICE-FEDER-P09-CTS-4980, CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2008–2011 and 2013–2016 (FIS-FEDER-PI11/01489 and FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), and by The Wellcome Trust–University of Edinburgh Institutional Strategic Support Fund (ISFF2).S
Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF
The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at
the Fermilab Long-Baseline Neutrino Facility (LBNF) is described
Altered Germination and Subcellular Localization Patterns for PUB44/SAUL1 in Response to Stress and Phytohormone Treatments
BACKGROUND: In plants, the ubiquitin-proteasome system is emerging as a significant regulatory system throughout the plant lifecycle. The ubiquitination of a target protein requires the sequential actions of the E1, E2 and E3 enzymes, with the latter E3 enzyme conferring target selection in this process. There are a large number of predicted E3 enzymes in plant genomes, and very little is known about the functions of many of these predicted genes. Here we report here an analysis of two closely-related members of the Arabidopsis Plant U-box (PUB) family of E3 ubiquitin ligases, PUB43 and PUB44. PRINCIPAL FINDINGS: Homozygous pub44/pub44 mutant seedlings were found displayed a seedling lethal phenotype and this corresponded with widespread cell death lesions throughout the cotyledons and roots. Interestingly, heterozygous PUB44/pub44 seedlings were wild-type in appearance yet displayed intermediate levels of cell death lesions in comparison to pub44/pub44 seedlings. In contrast, homozygous pub43/pub43 mutants were viable and did not show any signs of cell death despite the PUB43 gene being more highly expressed than PUB44. The PUB44 mutants are not classical lesion mimic mutants as they did not have increased resistance to plant pathogens. We also observed increased germination rates in mutant seeds for both PUB44 and PUB43 under inhibitory concentrations of abscisic acid. Finally, the subcellular localization of PUB44 was investigated with transient expression assays in BY-2 cells. Under varying conditions, PUB44 was observed to be localized to the cytoplasm, plasma membrane, or nucleus. CONCLUSIONS: Based on mutant plant analyses, the Arabidopsis PUB43 and PUB44 genes are proposed to function during seed germination and early seedling growth. Given PUB44's ability to shuttle from the nucleus to the plasma membrane, PUB44 may be active in different subcellular compartments as part of these biological functions
Shortened Version of the Token Test: Normative data for Spanish-speaking pediatric population
OBJECTIVE: To generate normative data for the Shortened Version of the Token Test in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the Shortened Version of the Token Test as part of a larger neuropsychological battery. Shortened Version of the Token Test total scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models showed main effects for age in all countries, such that score increased linearly as a function of age. In addition, age2 had a significant effect in all countries, except Guatemala and Puerto Rico. Models showed that children whose parent(s) had a MLPE >12 years obtained higher score compared to children whose parents had a MLPE ≤12 years in Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, Puerto Rico, and Spain. The child’s sex did not have an effect in the Shortened Version of the Token Test total score for any of the countries. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate interpretation of the Shortened Version of the Token Test when used in pediatric populations
State of the climate in 2013
In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earths surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series. © 2014, American Meteorological Society. All rights reserved
Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors
BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location
ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis
<p>Abstract</p> <p>Background</p> <p>Most current guidelines recommend two serological tests to diagnose chronic Chagas disease. When serological tests are persistently inconclusive, some guidelines recommend molecular tests. The aim of this investigation was to review chronic Chagas disease diagnosis literature and to summarize results of ELISA and PCR performance.</p> <p>Methods</p> <p>A systematic review was conducted searching remote databases (MEDLINE, LILACS, EMBASE, SCOPUS and ISIWeb) and full texts bibliography for relevant abstracts. In addition, manufacturers of commercial tests were contacted. Original investigations were eligible if they estimated sensitivity and specificity, or reliability -or if their calculation was possible - of ELISA or PCR tests, for chronic Chagas disease.</p> <p>Results</p> <p>Heterogeneity was high within each test (ELISA and PCR) and threshold effect was detected only in a particular subgroup. Reference standard blinding partially explained heterogeneity in ELISA studies, and pooled sensitivity and specificity were 97.7% [96.7%-98.5%] and 96.3% [94.6%-97.6%] respectively. Commercial ELISA with recombinant antigens studied in phase three investigations partially explained heterogeneity, and pooled sensitivity and specificity were 99.3% [97.9%-99.9%] and 97.5% [88.5%-99.5%] respectively. ELISA's reliability was seldom studied but was considered acceptable. PCR heterogeneity was not explained, but a threshold effect was detected in three groups created by using guanidine and boiling the sample before DNA extraction. PCR sensitivity is likely to be between 50% and 90%, while its specificity is close to 100%. PCR reliability was never studied.</p> <p>Conclusions</p> <p>Both conventional and recombinant based ELISA give useful information, however there are commercial tests without technical reports and therefore were not included in this review. Physicians need to have access to technical reports to understand if these serological tests are similar to those included in this review and therefore correctly order and interpret test results. Currently, PCR should not be used in clinical practice for chronic Chagas disease diagnosis and there is no PCR test commercially available for this purpose. Tests limitations and directions for future research are discussed.</p
Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.
BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700
Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study
Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised
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