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PubMed1993

G-proteins in experimental hypertension: a study of spontaneously hypertensive rat myocardial and renal cortical plasma membranes.

OBJECTIVE: Spontaneously hypertensive rat (SHR) myocardium is known to exhibit reduced beta-adrenergic agonist-stimulated adenylyl cyclase activity. As G-proteins play a pivotal role in transducing information from the receptor to adenylyl cyclase, a study was undertaken to assess whether changes in G-protein expression and functioning could explain this. DESIGN: Studies were performed in plasma membrane homogenates from vascular tissue (myocardium) from 11-week-old SHR (weighing 255 g) and control rats from both Wistar-Kyoto (WKY) and Wistar strains. Similar studies were performed in non-vascular tissue (renal cortical plasma membranes) to assess whether any observed changes are part of a more widely distributed membrane defect. METHODS: G-protein function was inferred from studies of adenylyl cyclase activity and levels of G-protein subunits (Gs alpha, Gi alpha 1, Gi alpha 2, Gi alpha 3, Go alpha and beta) were assessed by immunoblotting. RESULTS: Differences in adenylyl cyclase activity were seen in SHR compared with WKY rat myocardium: in WKY rats adenylyl cyclase activity was greater than in SHR under forskolin-stimulated conditions and in the presence of fluoride and several ligands which couple to the catalytic unit of adenylyl cyclase via Gs, including the receptor-linked species prostaglandin E1, glucagon and isoproterenol. However, with the exception of forskolin-stimulated activity, which in SHR was greater than in Wistar rats, SHR myocardial adenylyl cyclase activities were similar to those in Wistar rat membranes. Immunoblotting studies showed similar levels of G-protein subunits in all three strains. Studies of renal cortical plasma membranes failed to identify any differences in adenylyl cyclase activity or in G-protein subunit levels. CONCLUSIONS: SHR, WKY rats and Wistar rats exhibit differences in myocardial adenylyl cyclase activity which are not seen in renal cortical plasma membranes. These are not related to hypertension or to differences in G-protein levels, and probably reflect strain differences in Gs function.

Adenylyl Cyclases↗
PubMed2005

Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics.

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Genetic polymorphisms for TPMT are a major factor responsible for large individual variations in thiopurine toxicity and therapeutic effect. The present study investigated the functional effects of human TPMT variant alleles that alter the encoded amino acid sequence of the enzyme, TPMT*2, *3A, *3B, *3C and *5 to *13. After expression in COS-1 cells and correction for transfection efficiency, allozymes encoded by these alleles displayed levels of activity that varied from virtually undetectable (*3A,*3B and *5) to 98% (*7) of that observed for the wild-type allele. Although some allozymes had significant elevations in apparent Km values for 6-mercaptopurine and S-adenosyl-L-methionine (i.e. the two cosubstrates for the reaction), the level of enzyme protein was the major factor responsible for variation in activity. Quantitative Western blot analysis demonstrated that the level of enzyme protein correlated closely with level of activity for all allozymes except TPMT*5. Furthermore, protein levels correlated with rates of TPMT degradation. TPMT amino acid sequences were then determined for 16 non-human mammalian species and those sequences (plus seven reported previously, including two nonmammalian vertebrate species) were used to determine amino acid sequence conservation. Most human TPMT variant allozymes had alterations of residues that were highly conserved during vertebrate evolution. Finally, a human TPMT homology structural model was created on the basis of a Pseudomonas structure (the only TPMT structure solved to this time), and the model was used to infer the functional consequences of variant allozyme amino acid sequence alterations. These studies indicate that a common mechanism responsible for alterations in the activity of variant TPMT allozymes involves alteration in the level of enzyme protein due, at least in part, to accelerated degradation.

Alleles↗
PubMed1984

Induction of category distributions: a framework for classification learning.

We present a framework for classification learning that assumes that learners use presented instances (whether labeled or unlabeled) to infer the density functions of category exemplars over a feature space and that subsequent classification decisions employ a relative likelihood decision rule based on these inferred density functions. A specific model based on this general framework, the category density model, was proposed to account for the induction of normally distributed categories either with or without error correction or provision of labeled instances. The model was implemented as a computer simulation. Results of five experiments indicated that people could learn category distributions not only without error correction, but without knowledge of the number of categories or even that there were categories to be learned. These and other findings dictated a more general learning model that integrated distributional representations based on both parametric descriptions and stored instances.

Decision Making↗
PubMed2002

Phosphoglucose isomerases of hagfish, zebrafish, gray mullet, toad, and snake, with reference to the evolution of the genes in vertebrates.

Phosphoglucose isomerase (PGI) is a protein with multiple functions. To infer its structure changes and evolution in vertebrates, we cloned cDNAs encoding PGI genes from hagfish (Paramyxine yangi), gray mullet (Mugil cephalus), zebrafish (Danio rerio), toad (Bufo melanosticus), and snake (Boiga kraepelini). Only one PGI gene was cloned in each of hagfish, toad, and snake, but two PGI genes were found in zebrafish and gray mullet, respectively. The PGI of hagfish encodes 554 amino acids, in contrast to the PGIs of bonyfishes, toad, and snake which encode 553 amino acids and the PGIs of mammals which encode 558 amino acids. Among 558 aligned amino acid sites, there are 314 sites (56.27%) totally conserved. To see if diversifying selection acts on PGI amino acids of vertebrates, we calculated the pairwise ratio of nonsynonymous versus synonymous substitution per site (Ka/Ks) and the ratio of radical amino acid changes versus conservative amino acid changes per sites (dR/dC) between PGI sequences. The average pairwise ratio between nonsynonymous substitutions per nucleotide (Ka) and synonymous substitutions per nucleotide (Ks) among vertebrate PGI sequences equals 0.047 +/- 0.019. The average pairwise ratio between radical amino acid changes and conservative amino acid changes (dR/dC) among the vertebrate PGIs equal 0.938 +/- 0.158 for charge changes, 0.558 +/- 0.085 for polarity changes, and 0.465 +/- 0.0714 when both polarity and volume are considered. There is no amino acid within the vertebrate PGIs under diversifying selection as analyzed by the method of Yang et al. (2000b). The results suggest that the present vertebrate PGIs are at evolutionary stasis and are being subjected to intense purifying selection. The purifying selection is to maintain polarity and volume of the protein but not the charge groups of amino acids. Phylogenetic analysis reveals that vertebrate PGIs can be classified into three major groups: the mammalian, amphibian-reptilian, and teleostean PGIs. The gene tree suggests that the gene duplication event of PGI in bonyfishes occurred before diversification of Acanthopterygii but after the split of bonyfishes and tetrapods. The evolution of multiple functions of PGI is discussed.

Amino Acid Sequence↗
PubMed2005

Computationally analyzing the possible biological function of YJL103C--an ORF potentially involved in the regulation of energy process in yeast.

Although the complete genomes of a number of organisms have been sequenced, the biological functions of many genes are still not known. Because experimentally studying the functions of those genes one by one requires tremendous time, it is vital to use published resources like microarray gene expression data for computational analysis of gene functions. One example is YJL103C, a yeast gene of unknown function in the Saccharomyces Genome Database (SGD). It is possible to quickly infer its biological function by computational analysis. In this study, we present an efficient model to explore the biological function of a novel gene using microarray data. We showed that the expression pattern of YJL103C is most similar to the genes in the energy group and respiratory chain subgroup. We further found that YJL103C contains a HAP2,3,4 box in its promoter region and a cytochrome C heme-binding signature in its protein sequence. Our findings define a potential role for YJL103C in the regulation of energy metabolism, specifically in the process of oxidative phosphorylation. Similar bioinformatics methods can be applied to infer the biological functions of other novel genes in organisms for which microarray data are available. In this work, we selected a single gene of unknown function as a case study. By focusing on the power of computer analysis and bioinformatics on the available microarray data, we have determined the likely biological function of YJL103C. Our study provides a method by which to explore the potential function of other genes currently annotated as having an unknown function in any organism for which global gene expression data are available.

Binding Sites↗
PubMed2006

Prior specification in Bayesian statistics: three cautionary tales.

One of the most important differences between Bayesian and traditional techniques is that the former combines information available beforehand-captured in the prior distribution and reflecting the subjective state of belief before an experiment is carried out-and what the data teach us, as expressed in the likelihood function. Bayesian inference is based on the combination of prior and current information which is reflected in the posterior distribution. The fast growing implementation of Bayesian analysis techniques can be attributed to the development of fast computers and the availability of easy to use software. It has long been established that the specification of prior distributions should receive a lot of attention. Unfortunately, flat distributions are often (inappropriately) used in an automatic fashion in a wide range of types of models. We reiterate that the specification of the prior distribution should be done with great care and support this through three examples. Even in the absence of strong prior information, prior specification should be done at the appropriate scale of biological interest. This often requires incorporation of (weak) prior information based on common biological sense. Very weak and uninformative priors at one scale of the model may result in relatively strong priors at other levels affecting the posterior distribution. We present three different examples intuïvely illustrating this phenomenon indicating that this bias can be substantial (especially in small samples) and is widely present. We argue that complete ignorance or absence of prior information may not exist. Because the central theme of the Bayesian paradigm is to combine prior information with current data, authors should be encouraged to publish their raw data such that every scientist is able to perform an analysis incorporating his/her own (subjective) prior distributions.

Animals↗
PubMed1997

Bayesian analysis for a single 2 x 2 table.

The simple comparison of two binomial populations is frequently of interest in epidemiology when the domains are large. For small domains, however, there are no exact methods except Fisher's exact test. A basic problem, therefore, is to compare two populations by assessing the difference between the proportions of individuals who possess a characteristic in the first and second populations. When there is prior information, we take the proportions to have independent conjugate beta distributions with known parameters, thereby facilitating a Bayesian analysis. We consider Bayesian inference on functions of the proportions, and the three most common scalar measures used in epidemiology and health services research, namely relative risk, odds ratio and attributable risk. We develop the highest density regions (both exact and approximate) for relative risk, odds ratio and attributable risk. In addition, we consider the Bayes factor for testing whether the model with a common proportion holds rather than one with distinct proportions. Using data from the population-based Worcester Heart Attack Study, we apply our methodology to study gender differences in the therapeutic management of patients with acute myocardial infarction (AMI) by selected demographic and clinical characteristics. The Bayes factor, the approximate and exact intervals generally suggest that there are no substantial differences in the pharmacologic management of males and females hospitalized with AMI.

Adult↗
PubMed1998

The fate of duplicated genes: loss or new function?

Gene duplication events are important sources of novel gene functions. However, more often than not, a duplicate gene may lose its function and become a pseudogene. What is the relative frequency of these two scenarios: functional divergence versus gene loss? Given that most non-neutral mutations are deleterious, gene loss should be far more frequent than divergence. However, a recent empirical study suggests that about 50% of all gene duplications will lead to functional divergence. The study infers the frequency of functional divergence from the size distribution of gene families produced by two successive genome duplications early in vertebrate evolution. Reasons for this unexpectedly high frequency of functional divergence are discussed.

Animals↗
PubMed1992

Positional behavior and body size of arboreal primates: a theoretical framework for field studies and an illustration of its application.

The rationale for most field studies of the positional behavior of arboreal primates has been the need to document natural behaviors quantitatively in order to infer the functional significance of morphological configurations. This focus on interactions of morphology with behavior is justifiable, but there exists another important level of biological relationships, that of the animal with its structural habitat, which it must negotiate to find food and avoid being preyed on. Recently it has become apparent that body size is likely to affect relationships of positional behavior with habitat structure, as well as with morphology. Here I offer a framework for research on functional relationships of positional behavior, body size, and habitat structure, with the ultimate objective of elucidating the aptive significance of the great diversity exhibited by arboreal primates. This approach specifies several distinct problems that animals solve, and indicates how research might be directed at revealing the relative effectiveness with which different primates solve them. A preliminary application of the framework examines sympatric north Sumatran primates.

Animals↗
PubMed2004

Optimizing physical energy functions for protein folding.

We optimize a physical energy function for proteins with the use of the available structural database and perform three benchmark tests of the performance: (1) recognition of native structures in the background of predefined decoy sets of Levitt, (2) de novo structure prediction using fragment assembly sampling, and (3) molecular dynamics simulations. The energy parameter optimization is based on the energy landscape theory and uses a Monte Carlo search to find a set of parameters that seeks the largest ratio deltaE(s)/DeltaE for all proteins in a training set simultaneously. Here, deltaE(s) is the stability gap between the native and the average in the denatured states and DeltaE is the energy fluctuation among these states. Some of the energy parameters optimized are found to show significant correlation with experimentally observed quantities: (1) In the recognition test, the optimized function assigns the lowest energy to either the native or a near-native structure among many decoy structures for all the proteins studied. (2) Structure prediction with the fragment assembly sampling gives structure models with root mean square deviation less than 6 A in one of the top five cluster centers for five of six proteins studied. (3) Structure prediction using molecular dynamics simulation gives poorer performance, implying the importance of having a more precise description of local structures. The physical energy function solely inferred from a structural database neither utilizes sequence information from the family of the target nor the outcome of the secondary structure prediction but can produce the correct native fold for many small proteins.

Algorithms↗
PubMed2006

Prediction of protein secondary structure content using amino acid composition and evolutionary information.

Knowing protein structure and inferring its function from the structure are one of the main issues of computational structural biology, and often the first step is studying protein secondary structure. There have been many attempts to predict protein secondary structure contents. Previous attempts assumed that the content of protein secondary structure can be predicted successfully using the information on the amino acid composition of a protein. Recent methods achieved remarkable prediction accuracy by using the expanded composition information. The overall average error of the most successful method is 3.4%. Here, we demonstrate that even if we only use the simple amino acid composition information alone, it is possible to improve the prediction accuracy significantly if the evolutionary information is included. The idea is motivated by the observation that evolutionarily related proteins share the similar structure. After calculating the homolog-averaged amino acid composition of a protein, which can be easily obtained from the multiple sequence alignment by running PSI-BLAST, those 20 numbers are learned by a multiple linear regression, an artificial neural network and a support vector regression. The overall average error of method by a support vector regression is 3.3%. It is remarkable that we obtain the comparable accuracy without utilizing the expanded composition information such as pair-coupled amino acid composition. This work again demonstrates that the amino acid composition is a fundamental characteristic of a protein. It is anticipated that our novel idea can be applied to many areas of protein bioinformatics where the amino acid composition information is utilized, such as subcellular localization prediction, enzyme subclass prediction, domain boundary prediction, signal sequence prediction, and prediction of unfolded segment in a protein sequence, to name a few.

Amino Acid Sequence↗
PubMed1998

Detection of protein three-dimensional side-chain patterns: new examples of convergent evolution.

Detection of recurring three-dimensional side-chain patterns is a potential means of inferring protein function. This paper presents a new method for detecting such patterns and discusses various implications. The method allows detection of side-chain patterns without any prior knowledge of function, requiring only protein structure data and associated multiple sequence alignments. A recursive, depth-first search algorithm finds all possible groups of identical amino acids common to two protein structures independent of sequence order. The search is highly constrained by distance constraints, and by ignoring amino acids unlikely to be involved in protein function. A weighted root-mean-square deviation (RMSD) between equivalenced groups of amino acids is used as a measure of similarity. The statistical significance of any RMSD is assigned by reference to a distribution fitted to simulated data. Searches with the Ser/His/Asp catalytic triad, a His/His porphyrin binding pattern, and the zinc-finger Cys/Cys/His/His pattern are performed to test the method on known examples. An all-against-all comparison of representatives from the structural classification of proteins (SCOP) is performed, revealing several new examples of evolutionary convergence to common patterns of side-chains within different tertiary folds and in different orders along the sequence. These include a di-zinc binding Asp/Asp/His/His/Ser pattern common to alkaline phosphatase/bacterial aminopeptidase, and an Asp/Glu/His/His/Asn/Asn pattern common to the active sites of DNase I and endocellulase E1. Implications for protein evolution, function prediction and the rational design of functional regulators are discussed.

Acetylglucosaminidase↗
PubMed2000

Three-dimensional view of the surface motif associated with the P-loop structure: cis and trans cases of convergent evolution.

Here we identify the determinants of the nucleotide-binding ability associated with the P-loop-containing proteins, inferring their functional importance from their structural convergence to a unique three- dimensional (3D) motif. (1) A new surface 3D pattern is identified for the P-loop nucleotide-binding region, which is more selective than the corresponding sequence pattern; (2) the signature displays one residue that we propose is the determinant for the guanine-binding ability (the residues aligned to ras D119; this residue is known to be important only in the G-proteins, we extend the prediction to all the other P-loop- containing proteins); and (3) two cases of convergent evolution at the molecular level are highlighted in the analysis of the active site: the positive charge aligned to ras K117 and the arginine residues aligned to the GAP arginine finger. The analysis of the residues conserved on protein surfaces allows one to identify new functional or evolutionary relationships among protein structures that would not be detectable by conventional sequence or structure comparison methods.

Adenosine Triphosphate↗
PubMed2001

Relative language proficiency modulates BOLD signal change when bilinguals perform semantic judgments. Blood oxygen level dependent.

The effect of relative language proficiency on the spatial distribution and magnitude of BOLD signal change was evaluated by studying two groups of right-handed English-Mandarin bilingual participants with contrasting language proficiencies as they made semantic judgments with words and characters. Greater language proficiency corresponded to shorter response times and greater accuracy in the semantic judgment task. Within the left prefrontal and parietal regions, the change in BOLD signal was smaller in a participant's more proficient language. The least proficient performance was associated with right, in addition to left, inferior frontal activation. The results highlight the importance of taking into consideration nature of task and relative language proficiency when drawing inferences from functional imaging studies of bilinguals.

Adult↗
PubMed1983

Motor representation in the rostral portion of the cat corpus callosum as evidenced by microstimulation.

In six chronic cats experiments were carried out to examine the motor effects elicited by microstimulation of the rostral portion of the corpus callosum (CC) which contains fibres interconnecting the motor cortices of the two hemispheres. Serial dorso-ventral penetrations were stereotaxically performed along the rostro-caudal extent of the CC at 0.25-0.5 mm intervals. Motor responses, consisting of very discrete contractions of shoulder, whisker and eyelid muscles, were obtained upon stimulation of about the most rostral 4 mm at intensities lower than 50 microA. At threshold the responses appeared in only one body region and were often unilateral. A light increase in current gave rise to symmetrical bilateral effects. Thresholds were the lowest in the middle of CC and gradually rose towards its dorsal and ventral surfaces. In the course of a penetration an effect once elicited persisted until either the threshold became higher than 50 microA or the ventral edge was reached. All motor effects had thresholds higher than 10 microA. Contractions of shoulder, whisker and eyelid muscles at a threshold lower than 20 microA were obtained in 62.7%, 25.7% and 54.3% of penetrations, respectively. Shoulder and eyelid muscles were represented in the rostral and caudal half of the effective zone, respectively, whereas the representation of whisker muscles overlapped with the other two in the rostral third or the middle part of the effective zone. Single fibres driven by palpation of muscles responding to microstimulation or by movements of the joint mobilized by microstimulation were found at the most rostral sites, whereas units responding to hair displacement over or around the affected muscles were isolated mainly at the most caudal sites. It was inferred that functionally homogeneous callosal fibres are clustered in bundles arranged in dorso-ventrally oriented laminae. The somatotopic representation of the motor effects elicited by microstimulation along the rostro-caudal extent of the effective zone should be the consequence of the serial arrangement of these partially overlapping laminae.

Animals↗
PubMed1999

Development and preliminary clinical tests of an impedance sensing VDD recording pacemaker for diagnosis and research.

Episodes of serious but infrequently occurring cardiac arrhythmias can be difficult to detect and analyse, even with modern Holter monitoring. A previous diagnostic pacemaker developed by this group provided VVI pacing therapy and recorded intracardiac ECG signals but had no atrial sensing or impedance measuring capability. A new external diagnostic pacemaker system is described that has been developed to assist in diagnosing intermittent arrhythmias by selectively recording intracardiac signals. Unlike other ambulatory monitors, in addition to recording ECG, the device combines VDD pacing therapy with the capability of monitoring and recording intracardiac impedance and pressure waveforms through a temporary intracardiac lead. A PCMCIA memory card allows storage of 48 arrhythmic events of 21 seconds each. Twelve seconds of waveform are retained before the event occurs and nine seconds after. Data retrieval and processing is performed with a PC which reconstructs each waveform for display. The ECG provides data on cardiac rhythm while cardiac function is inferred from the haemodynamic signals. During simulated trials, 14 event types were presented to the system. All events were successfully detected and recorded. During in vivo clinical tests 83 waveform recordings were made. Impedance fluctuations with typical peak-to-peak values of 64 ohms were successfully recorded.

Arrhythmias, Cardiac↗
PubMed2002

Using seed purity data to estimate an average pollen mediated gene flow from crops to wild relatives.

Gene flow from crops to wild related species has been recently under focus in risk-assessment studies of the ecological consequences of growing transgenic crops. However, experimental studies addressing this question are usually temporally or spatially limited. Indirect population-structure approaches can provide more global estimates of gene flow, but their assumptions appear inappropriate in an agricultural context. In an attempt to help the committees providing advice on the release of transgenic crops, we present a new method to estimate the quantity of genes migrating from crops to populations of related wild plants by way of pollen dispersal. This method provides an average estimate at a landscape level. Its originality is based on the measure of the inverse gene flow, i.e. gene flow from the wild plants to the crop. Such gene flow results in an observed level of impurities from wild plants in crop seeds. This level of impurity is usually known by the seed producers and, in any case, its measure is easier than a direct screen of wild populations because crop seeds are abundant and their genetic profile is known. By assuming that wild and cultivated plants have a similar individual pollen dispersal function, we infer the level of pollen-mediated gene flow from a crop to the surrounding wild populations from this observed level of impurity. We present an example for sugar beet data. Results suggest that under conditions of seed production in France (isolation distance of 1,000 m) wild beets produce high numbers of seeds fathered by cultivated plants.

Journal Article↗