75 research outputs found
Is There a Classical Nonsense-Mediated Decay Pathway in Trypanosomes?
In many eukaryotes, messenger RNAs with premature termination codons are destroyed by a process called “nonsense-mediated decay”, which requires the RNA helicase Upf1 and also, usually, an interacting factor, Upf2. Recognition of premature termination codons may rely on their distance from either a splice site or the polyadenylation site, and long 3′-untranslated regions can trigger mRNA decay. The protist Trypanosoma brucei relies heavily on mRNA degradation to determine mRNA levels, and 3′-untranslated regions play a major role in control of mRNA decay. We show here that trypanosomes have a homologue of Upf1, TbUPF1, which interacts with TbUPF2 and (in an RNA-dependent fashion) with poly(A) binding protein 1, PABP1. Introduction of a premature termination codon in either an endogenous gene or a reporter gene decreased mRNA abundance, as expected for nonsense-mediated decay, but a dependence of this effect on TbUPF1 could not be demonstrated, and depletion of TbUPF1 by over 95% had no effect on parasite growth or the mRNA transcriptome. Further investigations of the reporter mRNA revealed that increases in open reading frame length tended to increase mRNA abundance. In contrast, inhibition of translation, either using 5′-secondary structures or by lengthening the 5′-untranslated region, usually decreased reporter mRNA abundance. Meanwhile, changing the length of the 3′-untranslated region had no consistent effect on mRNA abundance. We suggest that in trypanosomes, translation per se may inhibit mRNA decay, and interactions with multiple RNA-binding proteins preclude degradation based on 3′-untranslated region length alone
Pinhão-manso: crescimento sob condições diferenciadas de irrigação e de adubação no semiárido nordestino
Sustainability of Wood Productivity of Pinus TaedaBased on Nutrient Export and Stocks in the Biomass and in the Soil
Intraurban variations in adult mortality in a large Latin American City
Abstract Urbanization is high and growing in low- and middle-income countries, but intraurban variations in adult health have been infrequently examined. We used spatial analysis methods to investigate spatial variation in total, cardiovascular disease, respiratory disease, and neoplasm adult mortality in Buenos Aires, Argentina, a large city within a middle-income country in Latin America. Conditional autoregressive models were used to examine the contribution of socioeconomic inequalities to the spatial patterning observed. Spatial autocorrelation was present in both men and women for total deaths, cardiovascular deaths, and other causes of death (Moran’s Is ranging from 0.15 to 0.37). There was some spatial autocorrelation for respiratory deaths, which was stronger in men than in women. Neoplasm deaths were not spatially patterned. Socioeconomic disadvantage explained some of this spatial patterning and was strongly associated with death from all causes except respiratory deaths in women and neoplasms in men and women [relative rates (RR) for 90th vs 10th percentile of percent of adults with incomplete high school and 95% confidence intervals: 1.23 and 1.09–1.39 vs 1.24 and 1.08–1.42 for total deaths in men and women, respectively; 1.36 and 1.15–1.60 vs 1.22 and 1.01–1.47 for cardiovascular deaths; 1.21 and 0.97–1.52 vs 1.07 and 0.85–1.34 for respiratory deaths; 0.94 and 0.85–1.04 vs 1.03 and 0.87–1.22 for neoplasms; and 1.49 and 1.20–1.85 vs 1.63 and 1.31–2.03 for other deaths].There is substantial intraurban variation in risk of death within cities. This spatial variability was present for multiple causes of death and is partly explained by the spatial patterning of socioeconomic disadvantage. Our results highlight the pervasive role of space and social inequalities in shaping life and death within large cities.http://deepblue.lib.umich.edu/bitstream/2027.42/57778/1/Intraurban variations in Adult Mortality in a large Latin American City.pd
All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run
We present results from a search for gravitational-wave bursts in the data
collected by the LIGO and Virgo detectors between July 7, 2009 and October 20,
2010: data are analyzed when at least two of the three LIGO-Virgo detectors are
in coincident operation, with a total observation time of 207 days. The
analysis searches for transients of duration < 1 s over the frequency band
64-5000 Hz, without other assumptions on the signal waveform, polarization,
direction or occurrence time. All identified events are consistent with the
expected accidental background. We set frequentist upper limits on the rate of
gravitational-wave bursts by combining this search with the previous LIGO-Virgo
search on the data collected between November 2005 and October 2007. The upper
limit on the rate of strong gravitational-wave bursts at the Earth is 1.3
events per year at 90% confidence. We also present upper limits on source rate
density per year and Mpc^3 for sample populations of standard-candle sources.
As in the previous joint run, typical sensitivities of the search in terms of
the root-sum-squared strain amplitude for these waveforms lie in the range 5
10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs
entails the most sensitive all-sky search for generic gravitational-wave bursts
and synthesizes the results achieved by the initial generation of
interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at
https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see
also the public announcement at
http://www.ligo.org/science/Publication-S6BurstAllSky
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
Trypanosomatid comparative genomics: contributions to the study of parasite biology and different parasitic diseases
The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients
The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease
The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011
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