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Results for “functional inference”

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PubMed2004

Reconstruction of ancestral protein sequences and its applications.

BACKGROUND: Modern-day proteins were selected during long evolutionary history as descendants of ancient life forms. In silico reconstruction of such ancestral protein sequences facilitates our understanding of evolutionary processes, protein classification and biological function. Additionally, reconstructed ancestral protein sequences could serve to fill in sequence space thus aiding remote homology inference. RESULTS: We developed ANCESCON, a package for distance-based phylogenetic inference and reconstruction of ancestral protein sequences that takes into account the observed variation of evolutionary rates between positions that more precisely describes the evolution of protein families. To improve the accuracy of evolutionary distance estimation and ancestral sequence reconstruction, two approaches are proposed to estimate position-specific evolutionary rates. Comparisons show that at large evolutionary distances our method gives more accurate ancestral sequence reconstruction than PAML, PHYLIP and PAUP*. We apply the reconstructed ancestral sequences to homology inference and functional site prediction. We show that the usage of hypothetical ancestors together with the present day sequences improves profile-based sequence similarity searches; and that ancestral sequence reconstruction methods can be used to predict positions with functional specificity. CONCLUSIONS: As a computational tool to reconstruct ancestral protein sequences from a given multiple sequence alignment, ANCESCON shows high accuracy in tests and helps detection of remote homologs and prediction of functional sites. ANCESCON is freely available for non-commercial use. Pre-compiled versions for several platforms can be downloaded from ftp://iole.swmed.edu/pub/ANCESCON/.

Amino Acid Sequence↗

PubMed1996

Analysis of diffuse parenchymal liver disease by liver scintigrams: differential diagnosis using neuro and fuzzy.

In colloid liver scintigraphy, diagnosis of diffuse parenchymal liver disease such as chronic hepatitis or cirrhosis is evaluated by size and distortion of the liver, distribution of tracer in the liver, size and activities of tracer in the spleen, visualization of the bone marrow and so on. It is not difficult to read a scintigram which shows a typical pattern of normal, chronic hepatitis and cirrhosis; however in some cases it is difficult to distinguish normal or chronic hepatitis and chronic hepatitis or cirrhosis visually. Therefore, we tried to use fuzzy inferences to perform differential diagnosis in chronic hepatitis (CH), severe fibrosis (SF) and liver cirrhosis (LC). First, five features in colloid liver scintigrams were measured or evaluated visually. These features were liver size index (left lobe/right lobe), splenomegaly, the degree of visualization of the bone marrow, liver deformity, and distribution of tracer in the liver. Having fuzziness in these data, certain characteristics of these features were considered to be fuzzy sets and thus could be expressed in membership functions. Fuzzy inference was carried out using these data and fuzzy rules. Using fuzzy inference, differential diagnosis in LC could be performed up to 100%, but those of CH and SF could not be performed sufficiently. Using neural network CH, SF and LC could be diagnosed up to 63%, 80%, and 88%, respectively. But fuzzy inference had the merit to evaluate the degree of disturbance by the center of gravity of the resulting membership function. Therefore by combining neural network and fuzzy inference, CH, SF, and LC could be differentiated to the degree 77%, 80%, and 100%, respectively.

Chronic Disease↗

PubMed2005

Fold independent structural comparisons of protein-ligand binding sites for exploring functional relationships.

The rapid growth in protein structural data and the emergence of structural genomics projects have increased the need for automatic structure analysis and tools for function prediction. Small molecule recognition is critical to the function of many proteins; therefore, determination of ligand binding site similarity is important for understanding ligand interactions and may allow their functional classification. Here, we present a binding sites database (SitesBase) that given a known protein-ligand binding site allows rapid retrieval of other binding sites with similar structure independent of overall sequence or fold similarity. However, each match is also annotated with sequence similarity and fold information to aid interpretation of structure and functional similarity. Similarity in ligand binding sites can indicate common binding modes and recognition of similar molecules, allowing potential inference of function for an uncharacterised protein or providing additional evidence of common function where sequence or fold similarity is already known. Alternatively, the resource can provide valuable information for detailed studies of molecular recognition including structure-based ligand design and in understanding ligand cross-reactivity. Here, we show examples of atomic similarity between superfamily or more distant fold relatives as well as between seemingly unrelated proteins. Assignment of unclassified proteins to structural superfamiles is also undertaken and in most cases substantiates assignments made using sequence similarity. Correct assignment is also possible where sequence similarity fails to find significant matches, illustrating the potential use of binding site comparisons for newly determined proteins.

Animals↗

PubMed2002

Proteins with class alpha/beta fold have high-level participation in fusion events.

Now that complete genome sequences are available for a variety of organisms, the elucidation of potential gene products function is a central goal in the post-genome era. Domain fusion analysis has been proposed recently to infer the functional association of the component proteins. Here, we took a new approach to the analysis of the structural features of the proteins involved in fusion events. An exhaustive survey of fusion events within 30 completely sequenced genomes and subsequent structure annotations to the component proteins at a SCOP superfamily level with hidden Markov models was carried out. A domain fusion map was then constructed. The results revealed that proteins with the class alpha/beta fold are frequently involved in fusion events, around 86% of the total 676 assigned single-domain fusion pairs including at least one component protein belonging to the alpha/beta fold class. Moreover, the domain fusion map in our work may offer an attractive framework for designing chimeric enzymes following Nature's lead, and may give useful hints for exploring the evolutionary history of proteins. (c) 2002 Elsevier Science Ltd.

Archaeal Proteins↗

PubMed2003

Predicting protein function from protein/protein interaction data: a probabilistic approach.

MOTIVATION: The development of experimental methods for genome scale analysis of molecular interaction networks has made possible new approaches to inferring protein function. This paper describes a method of assigning functions based on a probabilistic analysis of graph neighborhoods in a protein-protein interaction network. The method exploits the fact that graph neighbors are more likely to share functions than nodes which are not neighbors. A binomial model of local neighbor function labeling probability is combined with a Markov random field propagation algorithm to assign function probabilities for proteins in the network. RESULTS: We applied the method to a protein-protein interaction dataset for the yeast Saccharomyces cerevisiae using the Gene Ontology (GO) terms as function labels. The method reconstructed known GO term assignments with high precision, and produced putative GO assignments to 320 proteins that currently lack GO annotation, which represents about 10% of the unlabeled proteins in S. cerevisiae.

Algorithms↗

PubMed2006

Prediction of protein subcellular localization.

Because the protein's function is usually related to its subcellular localization, the ability to predict subcellular localization directly from protein sequences will be useful for inferring protein functions. Recent years have seen a surging interest in the development of novel computational tools to predict subcellular localization. At present, these approaches, based on a wide range of algorithms, have achieved varying degrees of success for specific organisms and for certain localization categories. A number of authors have noticed that sequence similarity is useful in predicting subcellular localization. For example, Nair and Rost (Protein Sci 2002;11:2836-2847) have carried out extensive analysis of the relation between sequence similarity and identity in subcellular localization, and have found a close relationship between them above a certain similarity threshold. However, many existing benchmark data sets used for the prediction accuracy assessment contain highly homologous sequences-some data sets comprising sequences up to 80-90% sequence identity. Using these benchmark test data will surely lead to overestimation of the performance of the methods considered. Here, we develop an approach based on a two-level support vector machine (SVM) system: the first level comprises a number of SVM classifiers, each based on a specific type of feature vectors derived from sequences; the second level SVM classifier functions as the jury machine to generate the probability distribution of decisions for possible localizations. We compare our approach with a global sequence alignment approach and other existing approaches for two benchmark data sets-one comprising prokaryotic sequences and the other eukaryotic sequences. Furthermore, we carried out all-against-all sequence alignment for several data sets to investigate the relationship between sequence homology and subcellular localization. Our results, which are consistent with previous studies, indicate that the homology search approach performs well down to 30% sequence identity, although its performance deteriorates considerably for sequences sharing lower sequence identity. A data set of high homology levels will undoubtedly lead to biased assessment of the performances of the predictive approaches-especially those relying on homology search or sequence annotations. Our two-level classification system based on SVM does not rely on homology search; therefore, its performance remains relatively unaffected by sequence homology. When compared with other approaches, our approach performed significantly better. Furthermore, we also develop a practical hybrid method, which combines the two-level SVM classifier and the homology search method, as a general tool for the sequence annotation of subcellular localization.

Algorithms↗

PubMed1985

Correspondence between immunological and functional domains in the transforming protein of Fujinami sarcoma virus.

Monoclonal antibodies reactive with either gag or fps portions of the wild-type Fujinami sarcoma virus transforming protein have been used to probe the structure of proteins encoded by mutant genomes constructed in vitro. The pattern of immunoreactivity suggests that the functional domain defined in genetic studies (Stone et al., Cell 37:549-558, 1984) corresponds to a discrete immunological domain in the native, wild-type Fujinami sarcoma virus protein. At least one mutation affecting both the structure and function of the proposed NH2-terminal fps-specific domain encodes a product with high specific activities in kinase assays. Furthermore, a cell line expressing high levels of this mutant protein is only moderately transformed. The striking correspondence between the immunological domain defined here and the functional domain inferred from the results of transfection experiments suggests that this non-kinase-specifying region constitutes a discrete structural as well as functional component of the viral protein.

Animals↗

PubMed1986

Mediation of intracellular calcium: variances on a common theme.

The discovery of troponin C and calmodulin set the tenor for understanding the intracellular mechanism of action of calcium. These proteins represent cellular receptors and distinct mediators of calcium. More recently, additional calcium-binding proteins have been identified. Immunological and sequence data suggest that these proteins represent a novel family of calcium mediators. The precise pathways in which these proteins are involved are not known. However, function by inference, the mediation of intracellular calcium, provides new avenues in which to better understand the complex cellular role calcium plays in regulating cell function.

Animals↗

PubMed2006

Titrametric characterization of pH-induced phase transitions in functionalized microgels.

The chain and radial functional group distributions in carboxylic acid-functionalized poly(N-isopropylacrylamide)-based microgels have significant impacts on the types of swelling responses exhibited by the microgels upon the application of a temperature and/or pH stimulus. Potentiometric, conductometric, and calorimetric titration approaches are used in this work to characterize the chain distributions of -COOH groups in five microgels prepared using different -COOH-functionalized monomers. A direct correlation is observed between the kinetically predicted formation of functional monomer blocks within the microgel, the excess Gibbs free energy of ionization, and the apparent pK(a) versus degree of ionization profiles generated from potentiometric titration. Isothermal titration calorimetry (ITC) can be used to quantify the relative number of functional groups present in microgels prepared with the same functional monomer and/or identify differences between microgels with the same bulk -COOH content but different chain distributions. In particular, microgels prepared with diacid-functionalized monomers exhibit a characteristic two-step ITC profile. For microgels with the same bulk -COOH content, the heat of ionization measured via ITC increases systematically with the overall change in both the pK(a) and the excess Gibbs free energy for microgels prepared with monoacid-functionalized monomers. Diacid monomer-functionalized microgels have lower ionization enthalpies attributable to the break-up of hydrogen-bonded intramolecular ring complexes upon carboxylic acid ionization. The inferred chain functional group distributions can be used to understand differences in microgel swelling across the pH-induced phase transition.

Acrylamides↗

PubMed1998

Control of bone formation and resorption: biological and clinical perspective.

Bone is subject to continuous breakdown (resorption) by osteoclasts and rebuilding (formation) by osteoblasts in order to fulfill its functions. Most bone diseases including osteoporosis are due to excessive bone resorption relative to formation. Recent research has generated new insights into the regulation of osteoclast and osteoblast differentiation and function and the interaction between the two cell types. There is increased awareness of the role of mechanical stimuli in bone homeostasis and by inference the function of bone cells. This information can lead to new therapeutic modalities for maintaining a healthy skeleton into old age.

Animals↗

PubMed2003

A device for cooling localized regions of human cerebral cortex. Technical note.

Neurosurgeons use invasive mapping methods during surgery to understand the functional neuroanatomy of patients. Electrical stimulation methods are used routinely for the temporary disruption of focal regions of cerebral cortex so that the surgeon may infer the functional role of the brain site being stimulated. Although it is an efficient and useful method, modes of electrical stimulation mapping have significant limitations. Neuroscientists use focal cooling to effect a more controlled disruption of cortical functions in experimental animals, and in this report, the authors describe their experience using a device to achieve this same objective in patients undergoing neurosurgery. The cooling probe consists of a stainless steel chamber with thermocouples and electroencephalography (EEG) recording contacts. Active cooling is achieved by infusing chilled saline into the chamber when the cooling probe is positioned on the pial surface. Experiments were performed in 18 patients. Temperature gradient measurements indicate that the entire thickness of gray matter under the probe is cooled to temperatures that disrupt local synaptic activity. Statistically significant changes in spontaneous and stimulus-evoked EEG activity were consistently observed during cooling, providing clear evidence of reversible disruption of physiological functions. Preliminary findings during functional mapping of the Broca area demonstrated qualitative differences between the temporary neurological deficits induced by cooling and those caused by electrical stimulation. These findings indicate the safety and utility of the cooling probe as a neurosurgical research tool. Additional rigorously designed studies should be undertaken to correlate the effects of cooling, electrical stimulation, and focal lesioning.

Brain Mapping↗

PubMed2002

Community structure and function in prokaryotic marine plankton.

Molecular biodiversity studies of microbial communities have provided invaluable information on the existence of heretofore unknown organisms and on community composition. Cloning and 'fingerprinting' techniques have been used many times to study prokaryote community composition of marine plankton. There are still many opportunities for new discoveries in this area, but the results have also opened new questions about the activities of these organisms and their function, going beyond just listing taxa or counting organisms. Rarely can the broad function be inferred from phylogenetic position alone (e.g. cyanobacteria). The recent discovery of abundant non-cyanobacterial marine phototrophs points to our inability to link phylogenetic position with function in a detailed way. One approach we have found fruitful is to combine fluorescence in situ hybridization with microautoradiography, a technique dubbed STARFISH. A recent application has shown that ubiquitous archaea from the deep sea, phylogenetically related to extreme thermophiles, are active in the uptake of amino acids from ambient (nanomolar) concentrations. This suggests the group is at least partly heterotrophic and able to compete successfully with bacteria for nutrients. Other as-yet uncultivated groups are also amenable to similar studies.

Animals↗

PubMed2026

Dynamic Protein Structure Paradox: An Integrative Framework for Endpoint-Conditioned Evidentiary Sufficiency in Structure-to-Function Claims.

Accurate coordinates for a represented protein state do not, by themselves, establish activity or any other condition-specific function. This article defines the Dynamic Protein Structure Paradox (DPSP) as the apparent conflict between structural accuracy and functional underdetermination and develops it as an integrative evidentiary assessment framework rather than a new theory or paradigm. The underlying problem has been longstanding, since structural genomics, function annotation, allostery, and disorder research each established that fold does not determine function and that function does not determine fold. DPSP consolidates those results into one endpoint-conditioned rule. Once a measurable endpoint is defined, it assesses four coupled dimensions: relevant-state completeness, context completeness, ensemble or kinetic dependence, and chemical dependence. A rubric rates each dimension as adequate, uncertain, or missing, and a materiality test determines which gaps influence the stated decision. The outcome is one of three mutually exclusive modes of utilization: geometry-led, conditional, or function-measured. The deliverable is a concise evidence statement delineating what the structure supports, which decisive variable remains unmeasured, and what corroboration is necessary. DPSP complements, rather than replaces, existing structural, ensemble, and computational approaches. The framework remains unvalidated, its thresholds are provisional, and the studies necessary to confirm or refute it are specified.

Proteins↗

PubMed2004

Evolutionary and functional relationships within the DJ1 superfamily.

BACKGROUND: Inferences about protein function are often made based on sequence homology to other gene products of known activities. This approach is valuable for small families of conserved proteins but can be difficult to apply to large superfamilies of proteins with diverse function. In this study we looked at sequence homology between members of the DJ-1/ThiJ/PfpI superfamily, which includes a human protein of unclear function, DJ-1, associated with inherited Parkinson's disease. RESULTS: DJ-1 orthologs in a variety of eukaryotic species cluster together in a single group. The most closely related group is the bacterial ThiJ genes. These are kinases involved in the biosynthesis of thiamine, a function that has been dispensed with evolutionarily in most eukaryotes where thiamine is an essential nutrient. The similarity with other characterized members of the superfamily, including proteases, is more remote. This is congruent with the recently solved crystal structures that fail to demonstrate the presence of a catalytic triad required for protease activity. CONCLUSION: DJ-1 may have evolved from the bacterial gene encoding ThiJ kinase. However, as this function has been dispensed with in eukaryotes it appears that the gene has been co-opted for another function.

Amino Acid Sequence↗

PubMed2005

Microarray annotation and biological information on function.

OBJECTIVES: Many methods for statistical analysis of gene expression studies by DNA microarrays produce lists of genes as output. To understand gene lists in terms of traditional biology, e.g. which pathways may be affected, it is necessary to get appropriate annotations for the probes on an array. METHODS: Problems arise with the different sources that have been used by manufacturers to design microarray probes, and their association to biological entities like genes, transcripts and proteins. Function annotation is of crucial importance, and systems like Gene Ontology can be used for this purpose. It arranges annotation terms in a hierarchical manner and thus makes annotations in a gene list amenable to automated analysis. RESULTS: Several methods for analyses of gene function are described. The hierarchical nature of systems like Gene Ontology particularly suggests using methods from graph theory. CONCLUSIONS: The main problem in annotating microarray probes and inferring affected functional modules is the incompleteness and degree of error in current biological databases. Initial approaches to make use of functional annotation exist, but have to be extended, in particular with respect to estimating the statistical significance of results.

Computational Biology↗

PubMed1989

Methodology for measuring health-state preferences--I: Measurement strategies.

Values play a critical part in decision making at both the individual and policy levels. Numerous methodologies for determining the preferences of individuals and groups have been proposed, but agreement has not been reached regarding their scientific adequacy and feasibility. This is the first of a four-part series of papers that analyzes and critiques the state-of-the-art in measuring preferences, particularly the measurement of health-state preferences. In this first paper we discuss the selection of relevant attributes to comprise the health-state descriptions, and the relative merits of three measurement strategies: holistic, explicitly decomposed, and statistically inferred decomposed. The functional measurement approach, a statistically inferred decomposed strategy, is recommended because it simultaneously validates the process by which judges combine attributes, the scale values they assign to health states, and the interval property of the scale.

Attitude to Health↗

PubMed1986

Neuropsychological performance in dementia of the Alzheimer type and multi-infarct dementia.

Neuropsychological performance was examined in patients with dementia of the Alzheimer type (DAT) and in age- and education-matched patients with multi-infarct dementia (MID). Significant differences were observed for FSIQ, VIQ, and Picture Completion. This contrasts to no difference in verbal memory, visual-spatial skills, and sustained attention/concentration. This report illustrates that neuropsychological testing of elderly patients is unable to aid in the differential diagnosis between clinically similar forms of dementia, and should be employed to establish the level of cognitive function to make inferences regarding the patient's functional independence.

Journal Article↗

PubMed1995

The utriculo-endolymphatic valve in pediatric temporal bones.

The utriculo-endolymphatic valve (UEV) is located in the posterior wall of the utricle at its junction with the utricular duct and was first described in a human fetus by Bast in 1928. Although different theories about its normal position and function have been postulated, the function of the UEV remains unclear. In the present investigation we studied 118 temporal bones from 70 children to determine whether there were differences in the position of the valve and by inference, its function between children and adults. Premortem ages ranged from newborn to 10 years (mean age, 11.6 months). All temporal bones were fixed in 10% formalin, decalcified and processed by the celloidin technique. Specimens were sectioned in a horizontal plane at a thickness of 20 microns. Every tenth section was stained with hematoxylin-eosin and studied by light microscopy. The position of the UEV was then classified as closed or open. Valves damaged by preparation or having an uncertain position were classified as artifact. The chi-square test was used to determine a correlation between the position of the valve and the status of the rest of the endolymphatic system and whether or not endolymphatic hydrops was present in the cochlear and vestibular systems. The UEV was closed in 39 temporal bones (33.1%) and open in 13 (11.0%). Artifacts were found in 66 bones (55.9%). In the group of patients with a collapsed ductus reuniens the UEV was closed in 38% of the specimens, suggesting that the UEV prevented loss of endolymph from the pars superior, but these findings were not statistically significant.

Artifacts↗