767 research outputs found
Contracts: Is a Promise to Perform That Which Is Due a Third Party Sufficient Consideration to Support a Promise?
Contracts: Is a Promise to Perform That Which Is Due a Third Party Sufficient Consideration to Support a Promise
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Evolutionary and molecular foundations of multiple contemporary functions of the nitroreductase superfamily.
Insight regarding how diverse enzymatic functions and reactions have evolved from ancestral scaffolds is fundamental to understanding chemical and evolutionary biology, and for the exploitation of enzymes for biotechnology. We undertook an extensive computational analysis using a unique and comprehensive combination of tools that include large-scale phylogenetic reconstruction to determine the sequence, structural, and functional relationships of the functionally diverse flavin mononucleotide-dependent nitroreductase (NTR) superfamily (>24,000 sequences from all domains of life, 54 structures, and >10 enzymatic functions). Our results suggest an evolutionary model in which contemporary subgroups of the superfamily have diverged in a radial manner from a minimal flavin-binding scaffold. We identified the structural design principle for this divergence: Insertions at key positions in the minimal scaffold that, combined with the fixation of key residues, have led to functional specialization. These results will aid future efforts to delineate the emergence of functional diversity in enzyme superfamilies, provide clues for functional inference for superfamily members of unknown function, and facilitate rational redesign of the NTR scaffold
Biases in the Experimental Annotations of Protein Function and their Effect on Our Understanding of Protein Function Space
The ongoing functional annotation of proteins relies upon the work of
curators to capture experimental findings from scientific literature and apply
them to protein sequence and structure data. However, with the increasing use
of high-throughput experimental assays, a small number of experimental studies
dominate the functional protein annotations collected in databases. Here we
investigate just how prevalent is the "few articles -- many proteins"
phenomenon. We examine the experimentally validated annotation of proteins
provided by several groups in the GO Consortium, and show that the distribution
of proteins per published study is exponential, with 0.14% of articles
providing the source of annotations for 25% of the proteins in the UniProt-GOA
compilation. Since each of the dominant articles describes the use of an assay
that can find only one function or a small group of functions, this leads to
substantial biases in what we know about the function of many proteins.
Mass-spectrometry, microscopy and RNAi experiments dominate high throughput
experiments. Consequently, the functional information derived from these
experiments is mostly of the subcellular location of proteins, and of the
participation of proteins in embryonic developmental pathways. For some
organisms, the information provided by different studies overlap by a large
amount. We also show that the information provided by high throughput
experiments is less specific than those provided by low throughput experiments.
Given the experimental techniques available, certain biases in protein function
annotation due to high-throughput experiments are unavoidable. Knowing that
these biases exist and understanding their characteristics and extent is
important for database curators, developers of function annotation programs,
and anyone who uses protein function annotation data to plan experiments.Comment: Accepted to PLoS Computational Biology. Press embargo applies. v4:
text corrected for style and supplementary material inserte
Can sequence determine function?
The functional annotation of proteins identified in genome sequencing projects is based on similarities to homologs in the databases. As a result of the possible strategies for divergent evolution, homologous enzymes frequently do not catalyze the same reaction, and we conclude that assignment of function from sequence information alone should be viewed with some skepticism
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High-frequency oscillatory ventilation in pediatric acute hypoxemic respiratory failure: disease-specific morbidity survival analysis.
BackgroundMultiple ventilatory strategies for acute hypoxemic respiratory failure (AHRF) in children have been advocated, including high-frequency oscillatory ventilation (HFOV). Despite the frequent deployment of HFOV, randomized controlled trials remain elusive and currently there are no pediatric trials looking at its use. Our longitudinal study analyzed the predictive clinical outcome of HFOV in pediatric AHRF given disease-specific morbidity.MethodsA retrospective 8-year review on pediatric intensive care unit admissions with AHRF ventilated by HFOV was performed. Primary outcomes included survival, morbidity, length of stay (LOS), and factors associated with survival or mortality.ResultsA total of 102 patients underwent HFOV with a 66 % overall survival rate. Survivors had a greater LOS than nonsurvivors (p = 0.001). Mortality odds ratio (OR) for patients without bronchiolitis was 8.19 (CI = 1.02, 65.43), and without pneumonia it was 3.07 (CI = 1.12, 8.39). A lower oxygenation index (OI) after HFOV commencement and at subsequent time points analyzed predicted survival. After 24 h, mortality was associated with an OI > 35 [OR = 31.11 (CI = 3.25, 297.98)]. Sepsis-related mortality was associated with a higher baseline FiO(2) (0.88 vs. 0.65), higher OI (42 vs. 22), and augmented metabolic acidosis (pH of 7.25 vs. 7.32) evaluated 4 h on HFOV (p < 0.05).ConclusionHigh-frequency oscillatory ventilation may be safely utilized. It has a 66 % overall survival rate in pediatric AHRF of various etiologies. Patients with morbidity limited to the respiratory system and optimized oxygenation indices are most likely to survive on HFOV
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