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PubMedDate not supplied

Robust method for proteome analysis by MS/MS using an entire translated genome: demonstration on the ciliome of Tetrahymena thermophila.

To improve the utility of increasingly large numbers of available unannotated and initially poorly annotated genomic sequences for proteome analysis, we demonstrate that effective protein identification can be made on a large and unannotated genome. The strategy developed is to translate the unannotated genome sequence into amino acid sequence encoding putative proteins in all six reading frames, to identify peptides by tandem mass spectrometry (MS/MS), to localize them on the genome sequence, and to preliminarily annotate the protein via a similarity search by BLAST. These tasks have been optimized and automated. Optimization to obtain multiple peptide matches in effect extends the searchable region and results in more robust protein identification. The viability of this strategy is demonstrated with the identification of 223 cilia proteins in the unicellular eukaryotic model organism Tetrahymena thermophila, whose initial genomic sequence draft was released in November 2003. To the best of our knowledge, this is the first demonstration of large-scale protein identification based on such a large, unannotated genome. Of the 223 cilia proteins, 84 have no similarity to proteins in NCBI's nonredundant (nr) database. This methodology allows identifying the locations of the genes encoding these novel proteins, which is a necessary first step to downstream functional genomic experimentation.

Amino Acid Sequence↗
PubMedDate not supplied

Simple and robust two-layer matrix/sample preparation method for MALDI MS/MS analysis of peptides.

Recent advances in MALDI MS/MS instrumentation allow a high degree of automation in the efficient detection of peptide fragment ions that can be used for protein identification. However, the performance of the technique is dependent on the MALDI sample preparation. We present a simple and robust two-layer sample preparation method tailored for sensitive and reproducible generation of MALDI MS/MS data. This method produces a strong and uniform crystal layer which allows acquisition of high quality MS/MS spectra over the entire sample surface area. Furthermore, due to its crystal strength, the matrix/sample layer can be washed extensively on target, enabling direct analysis of samples containing impurities, such as salts and surfactants. This method is demonstrated to be very useful in routine analysis of in-gel tryptic digests of silver-stained protein gel spots, without the need of desalting steps or hunting for "hot" spots. As an example, seven threonine-phosphorylated proteins involved in signal transduction in response to growth factor stimulation within the lipid raft fractions of the IMR5 neuroblastoma cells have been identified using differential gel display, in-gel digestion and MALDI MS/MS with the new two-layer sample preparation method. Some of these proteins have the functions of maintaining raft structure or cell signaling.

Cell Line, Tumor↗
PubMed1997

Robust sensor fusion improves heart rate estimation: clinical evaluation.

OBJECTIVE: To determine if Robust Sensor Fusion (RSF), a method designed to fuse data from multiple sensors with redundant heart rate information can be used to improve the quality of heart rate data. To determine if the improved estimate of heart rate can reduce the number of false and missed heart rate alarms. METHODS: A total of 85 monitoring periods were investigated, 12 from the operating room, 60 from adult ICU and 13 from pediatric ICU. The operating room periods began with induction of anesthesia and ended at the completion of the anesthetic. For the ICU data, four hour blocks of time were studied. For each monitoring period, HR values were recorded at 5 second intervals or less from the ECG, SpO2 and IAC using a SpaceLabs Medical Gateway connected to a SpaceLabs Medical PC2. Fused estimates of HR were derived for every time point using RSF and all results accepted regardless of confidence value. Data were annotated manually to identify the "reference" HR (that HR value most likely to be correct) at all time points. All HR values from the sensors and the fused estimate that were different from the reference HR by more than +/- 5 beats/min were considered inaccurate. For each monitoring period, the total time per hour that data were either inaccurate or unavailable was calculated for each sensor as well as the fused estimates. The total time of false and missed HR alarms was found for all sensors and the fused estimate by comparing the data to thresholds for both high and low HR alarms at 150 bpm, 130 bpm, 110 bpm and 50 bpm, 40 bpm, 30 bpm respectively. RESULTS: The fused estimate of HR was consistently as good or better than the estimate available from any individual sensor. The fused estimates also consistently reduced the incidence of false alarms compared with individual sensors without an unacceptable incidence of missed alarms. DISCUSSION: Redundancy in sensor measurements can be used to improve HR estimation in the clinical setting. Methods like RSF which improve the quality of monitored data and reduce nuisance alarms will enhance the value of patient monitors to clinicians.

Adult↗
PubMedDate not supplied

Robustness of a neural network model for differencing.

A neural network, originally proposed as a model for nuclei in the auditory brainstem, uses gradients of cell thresholds to reliably compute the difference of inputs over wide input ranges. The encoding of difference is linear even though the individual components of the network are finite, saturating, nonlinear devices highly dependent on input level. Theorems are proven that explain the linear dependence of network output on difference and that show the robustness of the network to perturbations of the threshold gradients. There is some evidence that the network exists in the neural tissue of the auditory brainstem.

Action Potentials↗
PubMed2004

Mars -- robust automatic backbone assignment of proteins.

MARS a program for robust automatic backbone assignment of (13)C/(15)N labeled proteins is presented. MARS does not require tight thresholds for establishing sequential connectivity or detailed adjustment of these thresholds and it can work with a wide variety of NMR experiments. Using only (13)C(alpha)/(13)C(beta) connectivity information, MARS allows automatic, error-free assignment of 96% of the 370-residue maltose-binding protein. MARS can successfully be used when data are missing for a substantial portion of residues or for proteins with very high chemical shift degeneracy such as partially or fully unfolded proteins. Other sources of information, such as residue specific information or known assignments from a homologues protein, can be included into the assignment process. MARS exports its result in SPARKY format. This allows visual validation and integration of automated and manual assignment.

Algorithms↗
PubMed2003

Quantitative versus morphological assessment of liver fibrosis: semi-quantitative scores are more robust than digital image fibrosis area estimation.

BACKGROUND/AIM: Digital image analysis (DIA) allows quantitative assessment of fibrosis on liver biopsy. Accurate determination of a threshold greyscale level representing fibrous tissue is critical. This method has not been fully evaluated in clinical practice. METHODS: Digital images of stained liver biopsy sections were captured by microscopy and converted to greyscale. A novel method of determining the threshold greyscale value at which to measure fibrosis area was developed (peak proportion area change (PPAC)). Reproducibility was tested in comparison with standard interactive thresholding and with semi-quantitative scoring using the Histological activity index (HAI) system by a histopathologist. Fibrosis areas for different sections from the same biopsy core were also compared by each method. RESULTS: Comparison between PPAC and interactive thresholding method demonstrated superior reproducibility of the PPAC method: r > 0.7, P < 0.001 compared with r = 0.19-0.64 (not all reaching significance). On a single section, reproducibility was similar for PPAC and the modified HAI system. When different sections from the same core were compared, the HAI system was more robust. CONCLUSIONS: The PPAC method is superior to standard interactive thresholding. However, variability in DIA scores between sections invalidates the technique for clinical use and semi-quantitative scoring systems remain the gold standard for fibrosis assessment.

Fibrosis↗
PubMed1999

Deeper into the schizotypy taxon: on the robust nature of maximum covariance analysis.

Prior research has suggested that the latent structure of the schizotypy construct (P. E. Meehl, 1990) may be qualitative in nature and have a low base rate (L. Korfine & M. F. Lenzenweger, 1995; M. F. Lenzenweger & L. Korfine, 1992). These studies relied on the application of maximum covariance analysis (MAXCOV) to 8 true-false format items from a schizotypy measure. The current study sought to examine the robustness of those prior findings through MAXCOV analysis of fully quantitative measures of schizotypy. Measures of perceptual aberration, magical ideation, and referential thinking were analyzed using MAXCOV in a sample of 429 persons. The results of these analyses strongly support a latent taxonic structure for schizotypy and a low base rate for the schizotypy taxon. Furthermore, the members of the putative taxon reveal an increased level of deviance on a psychometric measure known to be associated with schizophrenia liability. The possibility that the dichotomous item format of those items analyzed previously with MAXCOV lead to spurious pseudotaxonicity is greatly diminished in light of these results.

Adolescent↗
PubMed2005

An alternative to Cohen's standardized mean difference effect size: a robust parameter and confidence interval in the two independent groups case.

The authors argue that a robust version of Cohen's effect size constructed by replacing population means with 20% trimmed means and the population standard deviation with the square root of a 20% Winsorized variance is a better measure of population separation than is Cohen's effect size. The authors investigated coverage probability for confidence intervals for the new effect size measure. The confidence intervals were constructed by using the noncentral t distribution and the percentile bootstrap. Over the range of distributions and effect sizes investigated in the study, coverage probability was better for the percentile bootstrap confidence interval.

Analysis of Variance↗
PubMed2003

Modern robust data analysis methods: measures of central tendency.

Various statistical methods, developed after 1970, offer the opportunity to substantially improve upon the power and accuracy of the conventional t test and analysis of variance methods for a wide range of commonly occurring situations. The authors briefly review some of the more fundamental problems with conventional methods based on means; provide some indication of why recent advances, based on robust measures of location (or central tendency), have practical value; and describe why modern investigations dealing with nonnormality find practical problems when comparing means, in contrast to earlier studies. Some suggestions are made about how to proceed when using modern methods.

Humans↗
PubMed1999

Genome complexity, robustness and genetic interactions in digital organisms.

Digital organisms are computer programs that self-replicate, mutate and adapt by natural selection. They offer an opportunity to test generalizations about living systems that may extend beyond the organic life that biologists usually study. Here we have generated two classes of digital organism: simple programs selected solely for rapid replication, and complex programs selected to perform mathematical operations that accelerate replication through a set of defined 'metabolic' rewards. To examine the differences in their genetic architecture, we introduced millions of single and multiple mutations into each organism and measured the effects on the organism's fitness. The complex organisms are more robust than the simple ones with respect to the average effects of single mutations. Interactions among mutations are common and usually yield higher fitness than predicted from the component mutations assuming multiplicative effects; such interactions are especially important in the complex organisms. Frequent interactions among mutations have also been seen in bacteria, fungi and fruitflies. Our findings support the view that interactions are a general feature of genetic systems.

Biological Evolution↗
PubMed2006

Communication between levels of transcriptional control improves robustness and adaptivity.

Regulation of eukaryotic gene expression depends on groups of related proteins acting at the levels of chromatin organization, transcriptional initiation, RNA processing, and nuclear transport. However, a unified understanding of how these different levels of transcriptional control interact has been lacking. Here, we combine genome-wide protein-DNA binding data from multiple sources to infer the connections between functional groups of regulators in Saccharomyces cerevisiae. Our resulting transcriptional network uncovers novel biological relationships; supporting experiments confirm new associations between actively transcribed genes and Sir2 and Esc1, two proteins normally linked to silencing chromatin. Analysis of the regulatory network also reveals an elegant architecture for transcriptional control. Using communication theory, we show that most protein regulators prefer to form modules within their functional class, whereas essential proteins maintain the sparse connections between different classes. Moreover, we provide evidence that communication between different regulatory groups improves the robustness and adaptivity of the cell.

Gene Expression Regulation, Fungal↗
PubMed2003

Role of duplicate genes in genetic robustness against null mutations.

Deleting a gene in an organism often has little phenotypic effect, owing to two mechanisms of compensation. The first is the existence of duplicate genes: that is, the loss of function in one copy can be compensated by the other copy or copies. The second mechanism of compensation stems from alternative metabolic pathways, regulatory networks, and so on. The relative importance of the two mechanisms has not been investigated except for a limited study, which suggested that the role of duplicate genes in compensation is negligible. The availability of fitness data for a nearly complete set of single-gene-deletion mutants of the Saccharomyces cerevisiae genome has enabled us to carry out a genome-wide evaluation of the role of duplicate genes in genetic robustness against null mutations. Here we show that there is a significantly higher probability of functional compensation for a duplicate gene than for a singleton, a high correlation between the frequency of compensation and the sequence similarity of two duplicates, and a higher probability of a severe fitness effect when the duplicate copy that is more highly expressed is deleted. We estimate that in S. cerevisiae at least a quarter of those gene deletions that have no phenotype are compensated by duplicate genes.

Evolution, Molecular↗
PubMed2005

Robust habit learning in the absence of awareness and independent of the medial temporal lobe.

Habit memory is thought to involve slowly acquired associations between stimuli and responses and to depend on the basal ganglia. Habit memory has been well studied in experimental animals but is poorly understood in humans because of their strong tendency to acquire information as conscious (declarative) knowledge. Here we show that humans have a robust capacity for gradual trial-and-error learning that operates outside awareness for what is learned and independently of the medial temporal lobe. We tested two patients with large medial temporal lobe lesions and no capacity for declarative memory. Both patients gradually acquired a standard eight-pair object discrimination task over many weeks but at the start of each session could not describe the task, the instructions or the objects. The acquired knowledge was rigidly organized, and performance collapsed when the task format was altered.

Aged↗
PubMed2006

A Cretaceous terrestrial snake with robust hindlimbs and a sacrum.

It has commonly been thought that snakes underwent progressive loss of their limbs by gradual diminution of their use. However, recent developmental and palaeontological discoveries suggest a more complex scenario of limb reduction, still poorly documented in the fossil record. Here we report a fossil snake with a sacrum supporting a pelvic girdle and robust, functional legs outside the ribcage. The new fossil, from the Upper Cretaceous period of Patagonia, fills an important gap in the evolutionary progression towards limblessness because other known fossil snakes with developed hindlimbs, the marine Haasiophis, Pachyrhachis and Eupodophis, lack a sacral region. Phylogenetic analysis shows that the new fossil is the most primitive (basal) snake known and that all other limbed fossil snakes are closer to the more advanced macrostomatan snakes, a group including boas, pythons and colubroids. The new fossil retains several features associated with a subterranean or surface dwelling life that are also present in primitive extant snake lineages, supporting the hypothesis of a terrestrial rather than marine origin of snakes.

Animals↗
PubMed2006

Sexual reproduction selects for robustness and negative epistasis in artificial gene networks.

The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path.

Animals↗
PubMed2005

Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis.

The structure of a protein depends critically on the complex interactions among its amino acid residues. It has long been hypothesized that interacting residues might tend to coevolve, but it is not known whether such coevolution is a general phenomenon across the proteome. Here, we describe a novel methodology called phylogeny-aided structural analysis, which uncovers robust signals of interacting-residue coevolution in mammalian proteomes. Furthermore, this new method allows the magnitude of coevolution to be quantified. Finally, it facilitates a comprehensive evaluation of various factors that affect interacting-residue coevolution, such as the physicochemical properties of the interactions between residues, solvent accessibility of the residues and their secondary structure context.

Amino Acid Sequence↗
PubMed2006

Robust free-standing nanomembranes of organic/inorganic interpenetrating networks.

Hybrid sol-gel materials have been a subject of intensive research during the past decades because these nanocomposites combine the versatility of organic polymers with the superior physical properties of glass. Here, we report the synthesis, by spin coating, of hybrid interpenetrating networks in the form of free-standing nanomembrane (around 35-nm thick) with unprecedented macroscopic size and characteristics. The quasi-2D interpenetration of the organic and inorganic networks brings to these materials a unique combination of properties that are not usually compatible within the same film: macroscopic robustness and homogeneity, nanoscale thickness, mechanical strength, high flexibility and optical transparency. Interestingly, such free-standing nanofilms of macroscopic size can seal large openings, are strong enough to hold amounts of liquid 70,000 times heavier than their own weight, and are flexible enough to reversibly pass through holes 30,000 times smaller than their own size.

Journal Article↗