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PubMed2006

Management of medicines information for patient safety.

Ensuring patient safety in the management of medicines requires the efficient collection, administration, analysis and distribution of huge amounts of data from different sources. This requires the development of generic methods and tools for tasks such as: (1) data mining and semantics-based inference; (2) integration of heterogeneous scientific information databases relating to drugs and diseases; (3) terminology and coding issues; (4) adverse drug events and signal detection; and (5) networking and security. Collaborative research and development will be required to develop coordinated health care information services. Easy access to high-quality information will provide better health care and increased cost efficiency.

Consumer Product Safety↗
PubMed2003

Greedily building protein networks with confidence.

MOTIVATION: With genome sequences complete for human and model organisms, it is essential to understand how individual genes and proteins are organized into biological networks. Much of the organization is revealed by proteomics experiments that now generate torrents of data. Extracting relevant complexes and pathways from high-throughput proteomics data sets has posed a challenge, however, and new methods to identify and extract networks are essential. We focus on the problem of building pathways starting from known proteins of interest. RESULTS: We have developed an efficient, greedy algorithm, SEEDY, that extracts biologically relevant biological networks from protein-protein interaction data, building out from selected seed proteins. The algorithm relies on our previous study establishing statistical confidence levels for interactions generated by two-hybrid screens and inferred from mass spectrometric identification of protein complexes. We demonstrate the ability to extract known yeast complexes from high-throughput protein interaction data with a tunable parameter that governs the trade-off between sensitivity and selectivity. DNA damage repair pathways are presented as a detailed example. We highlight the ability to join heterogeneous data sets, in this case protein-protein interactions and genetic interactions, and the appearance of cross-talk between pathways caused by re-use of shared components. SIGNIFICANCE AND COMPARISON: The significance of the SEEDY algorithm is that it is fast, running time O[(E + V) log V] for V proteins and E interactions, a single adjustable parameter controls the size of the pathways that are generated, and an associated P-value indicates the statistical confidence that the pathways are enriched for proteins with a coherent function. Previous approaches have focused on extracting sub-networks by identifying motifs enriched in known biological networks. SEEDY provides the complementary ability to perform a directed search based on proteins of interest. AVAILABILITY: SEEDY software (Perl source), data tables and confidence score models (R source) are freely available from the author.

Algorithms↗
PubMed2002

On the number of experiments required to find the causal structure of complex systems.

The need to capture the complexity of biological systems in a simpler formalism is the underlying impetus of biological sciences. Understanding the function of many biological complex systems, such as genetic networks or molecular signalling pathways, requires precise identification of the interactions between their individual components. A number of questions in the study of complex systems are then important-in particular, what can be inferred about the interactions in a complex system from an arbitrary set of experiments, and, what is the minimum number of experiments required to characterize the system? This paper shows that the problem of finding the minimal causal structure of a system based on a set of observations is computationally intractable for even moderately sized systems (it is NP-hard), but a reasonable approximation can be found in a relatively short (polynomial) time. Next, it is shown that the number of experiments required to characterize a complex system grows exponentially with the upper bound on the number of immediate upstream influences of each element, but only logarithmically with the number of elements in the system. This makes it possible to study biological systems with extremely large number of interacting elements and relatively sparse interconnections, such as gene regulatory and cell signalling networks. Finally, the construction of a randomized experimental sequence which achieves this bound is discussed.

Animals↗
PubMed1990

Conditions for versatile learning, Helmholtz's unconscious inference, and the task of perception.

It is a mistake to consider perception and learning separately because what one learns is strongly constrained by what one perceives, and what one perceives depends on what one has experienced. I shall propose the hypothesis that perception is the computation of a representation that enables us to make reliable and versatile inferences about associations occurring in the world around us--that is, perception prepares the ground for learning. The statistical problem in learning is to determine whether a compound event such as "C followed by U" is a random co-occurrence or a significant association, for if it is the former it would be a mistake to pay any particular attention to C, whereas if it is the latter C is a conditional stimulus for U and a useful predictor for it. Now you cannot decide whether the association is random or not without knowledge of the prior probabilities of C and U: hence on my hypothesis when you perceive an object or event the representation must not only signal "it's there" or "it's happened", but must also make evident (or rapidly accessible) the prior probability of what has been signalled. Furthermore it must do this for all the objects or events that can act as conditional stimuli, and this implies that the representative elements should be statistically independent (or approximately so) in the normal environment. Forms of coding that would do this, and the relationship with Helmholtz's unconscious inference, will be discussed. These considerations imply that the task performed in perception has been overlooked both by learning theorists and by connectionists working on associative and adaptive networks. Coding for independence may be particularly important in understanding the developmental processes during the sensitive period: it may be the operation that leads ontogenetically-timed, activity-dependent, connections to imprint appropriate codes if the animal has experience, but inappropriate codes without experience.

Adaptation, Physiological↗
PubMed2000

Gene diversity of chimpanzee ABO blood group genes elucidated from exon 7 sequences.

Human and non-human primate ABO blood group genes show relatively large numbers of nucleotide differences. In this study, we determined exon 7 sequences for 10 individuals of common chimpanzee and for four individuals of bonobo to estimate nucleotide diversities among them. Sequence data showed the existence of chimpanzee specific 9-base deletion in the beginning of the exon 7 coding region. From a phylogenetic network of exon 7 sequences of ABO blood group genes for human, common chimpanzee, bonobo and gorilla, effects of parallel substitutions and/or some kinds of convergent events are inferred in the chimpanzee lineage. We also estimated nucleotide diversities for common chimpanzee and bonobo ABO blood group genes, and these values were 0.4% and 0.2%, respectively. These values are higher than that of most human genes.

ABO Blood-Group System↗
PubMed2004

Dynamic gene expression profiling using a microfabricated living cell array.

We describe the development of a microfluidic platform for continuous monitoring of gene expression in live cells. This optically transparent microfluidic device integrates high-throughput molecular stimulation with nondestructive monitoring of expression events in individual living cells, hence, a living cell array (LCA). Several concentrations of a soluble molecular stimulus are generated in an upstream microfluidic network and used to stimulate downstream reporter cells, each containing a green fluorescence reporter plasmid for a gene of interest. Cellular fluorescence is continuously monitored and quantified to infer the expression dynamics of the gene being studied. We demonstrate this approach by profiling the activation of the transcription factor NF-kappaB in HeLa S3 cells in response to varying doses of the inflammatory cytokine TNF-alpha. The LCA platform offers a unique opportunity to simultaneously control dynamic inputs and measure dynamic outputs from adherent mammalian cells in a high-throughput fashion. This approach to profiling expression dynamics, in conjunction with complementary techniques such as DNA microarrays, will help provide a more complete picture of the dynamic cellular response to diverse soluble stimuli.

Gene Expression Profiling↗
PubMed1999

Neurobiological bases of behavioral development in the second year.

We discuss selected psychological competences that develop and become noticeable between one and two years of age and are temporally correlated to structural, biochemical and physiological changes in the brain. The psychological competences are: Language development, a sense of "right" and "wrong", self-awareness, and the ability to make inferences. The accompanying changes in the brain involve the prefrontal cortex, language-related cortical areas, hippocampus, cerebellum, basal ganglia and an increase in the connectivity of the network. Of special interest are the maturational changes in layers III-IV of the prefrontal cortex. Layer III is the origin and target of callosal and commissural axons linking the two hemispheres and the target of associational axons linking ipsilateral areas within each hemisphere. Layer IV, the target for axons from the mediodorsal nucleus of the thalamus, conveys information from other associational cortices, cerebellum, basal ganglia, and the reticular and limbic systems. In the second year, intensive dendritic growth and synaptogenesis in these layers increase the linking of these two layers and form a neural basis for a more efficient convergence and integration of information from the two hemispheres, which are functionally asymmetric. It is our hypothesis that these changes, together with the maturational changes in the cortico-subcortical network, are a basis for the observed emergence of the psychological competences. We are aware that temporal correlations cannot prove firm causal relationships. However, knowledge of these correlations is useful in generating specific hypotheses that can be tested directly.

Axons↗
PubMed2001

NMR studies of protein surface accessibility.

Characterization of protein surface accessibility represents a new frontier of structural biology. A surface accessibility investigation for two structurally well-defined proteins, tendamistat and bovine pancreatic trypsin inhibitor, is performed here by a combined analysis of water-protein Overhauser effects and paramagnetic perturbation profiles induced by the soluble spin-label 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl on NMR spectra. This approach seems to be reliable not only for distinguishing between buried and exposed residues but also for finding molecular locations where a network of more ordered waters covers the protein surface. From the presented set of data, an overall picture of the surface accessibility of the two proteins can be inferred. Detailed knowledge of protein accessibility can form the basis for successful design of mutants with increased activity and/or greater specificity.

Aprotinin↗
PubMed2006

Population genetic structure and demographic history of the endemic Formosan lesser horseshoe bat (Rhinolophus monoceros).

Intraspecific phylogenies can provide useful insights into how populations have been shaped by historical and contemporary processes. Taiwan formed around 5 million years ago from tectonic uplift, and has been connected to mainland Asia several times since its emergence. A central mountain range runs north to south, bisecting the island, and potentially impedes gene flow along an east-west axis. The Formosan lesser horseshoe bat (Rhinolophus monoceros) is endemic to Taiwan, where it is found mainly at low altitude. To determine the population structure and the demographic and colonization history of this species, we examined variation in the mitochondrial DNA control region in 203 bats sampled at 26 sites. We found very high haplotype and nucleotide diversity, which decreased from the centre to the south and north. Population differentiation followed a pattern of isolation by distance, though most regional genetic variance was attributable to differences between the relatively isolated southern population and those from other regions. A haplotype network was consistent with these findings and also suggested a southward colonization, followed by subsequent secondary contact between the south and other regions. Mismatch distributions were used to infer a past population expansion predating the last glacial maximum, and a neighbour-joining tree showed that R. monoceros formed a monophyletic grouping with respect to its sister taxa. Taken together, our results suggest that this taxon arose from a single period of colonization, and that demographic growth followed in the late Pleistocene. Current genetic structure reflects limited gene flow, probably coupled with stepwise colonization in the past. We consider explanations for the persistence of the species through multiple glacial maxima.

Animals↗
PubMed2002

Micromechanical studies of mitotic chromosomes.

We review micromechanical experiments on mitotic chromosomes. We focus on work where chromosomes were extracted from prometaphase amphibian cells, and then studied by micromanipulation and microfluidic biochemical techniques. These experiments reveal that chromosomes have well-behaved elastic response over a fivefold range of stretching, with an elastic modulus similar to that of a loosely tethered polymer network. Perturbation by microfluidic 'spraying' of various ions reveals that the mitotic chromosome can be rapidly and reversibly decondensed or overcondensed, i.e. that the native state is not maximally compacted. Finally, we discuss microspraying experiments of DNA-cutting enzymes which reveal that the element which gives mitotic chromosomes their mechanical integrity is DNA itself. These experiments indicate that chromatin-condensing proteins are not organized into a mechanically contiguous 'scaffold', but instead that the mitotic chromosome is best thought of as a cross-linked network of chromatin. Preliminary results from restriction-enzyme digestion experiments indicate a spacing between chromatin 'cross-links' of roughly 15 kb, a size similar to that inferred from classical chromatin-loop-isolation studies. We compare our results to similar experiments done by Houchmandzadeh and Dimitrov (J Cell Biol 145: 215-213 (1999)) on chromatids reconstituted using Xenopus egg extracts. Remarkably, while the stretching elastic response of the reconstituted chromosomes is similar to that observed for chromosomes from cells, the reconstituted chromosomes are far more easily bent. This result suggests that reconstituted chromatids have a large-scale structure which is quite different from chromosomes in somatic cells. More generally our results suggest a strategy for the use of micromanipulation methods for the study of chromosome structure.

Animals↗
PubMed1987

Temporal and social contexts of heroin-using populations. An illustration of the snowball sampling technique.

Snowball sampling is a method that has been used in the social sciences to study sensitive topics, rare traits, personal networks, and social relationships. The method involves the selection of samples utilizing "insider" knowledge and referral chains among subjects who possess common traits that are of research interest. It is especially useful in generating samples for which clinical sampling frames may be difficult to obtain or are biased in some way. In this paper, snowball samples of heroin users in two Dutch cities have been analyzed for the purpose of providing descriptions and limited inferences about the temporal and social contexts of their lifestyles. Two distinct heroin-using populations have been discovered who are distinguished by their life cycle stage. Significant contextual explanations have been found involving the passage from adolescent peer group to criminal occupation, the functioning of network "knots" and "outcroppings," and the frequency of social contact. It is suggested that the snowball sampling method may have utility in studying the temporal and social contexts of other populations of clinical interest.

Activities of Daily Living↗
PubMed2004

Inferring a system model of subcellular topoisomerase II beta localization dynamics.

Measuring the mobility of proteins in living cells has become critical to many studies in cell biology and forms the basis for discussion on sub-cellular dynamics. Increasingly localization networks are being put together into compartment models to represent the exchange of molecules, represented mathematically as ordinary differential equations (ODE). The set-up is based on published literature, the "knowledge" of the investigator and 3D visualization of the data. Here we demonstrate this method on the example of a simple distribution model of the molecule Topoisomerase II beta (Topo II beta), nuclear protein that modifies DNA topology. It is found in high concentration in the nucleolus and diffuse in the nucleoplasm, demonstrating a non-membranous inhomogeneity in its distribution. We expand on the simple model by adding additional components to fit fluorescence recovery after photobleaching (FRAP) experiments for protein (GFP) labeled Topo II beta to measure its mobility. This model is then validated by comparing it with alternative scenarios and shown to have predictive power.

Animals↗
PubMed1994

Crystal structure of the catalytic domain of the beta-1,4-glycanase cex from Cellulomonas fimi.

beta-1,4-Glycanases, principally cellulases and xylanases, are responsible for the hydrolysis of plant biomass. The bifunctional beta-1,4-xylanase/glucanase Cex from the bacterium Cellulomonas fimi, one of a large family of cellulases/xylanases, depolymerizes oligosaccharides and releases a disaccharide unit from the substrate nonreducing end. Hydrolysis occurs with net retention of the anomeric configuration of the sugar through a double-displacement mechanism involving a covalent glycosyl-enzyme intermediate. The active site nucleophile, Glu233, has been unambiguously identified by trapping of such an intermediate [Tull et al. (1991) J. Biol. Chem. 266, 15621-15625] and the acid/base catalyst, Glu127, by detailed kinetic analysis of mutants [MacLeod et al. (1994) Biochemistry 33, 6371-6376]. However, little is known about the enzyme's overall folding and its active site architecture. We report here the high-resolution crystal structure of the catalytic domain of Cex. The atomic structure refinement results in a model that includes 2400 protein atoms and 45 water molecules, with an R-factor of 0.217 for data extending to 1.8-A resolution. The protein forms an eight-parallel-stranded alpha/beta-barrel, which is a novel folding pattern for a microbial beta-glycanase. The active site, inferred from the location of Glu233, Glu127, and other conserved residues, is an open cleft on the carboxy-terminal end of the alpha/beta-barrel. An extensive hydrogen-bonding network stabilizes the ionization states of the key residues; in particular, the Asp235-His205-Glu233 hydrogen-bonding network may play a role in modulating the ionization state of Glu233 and in controlling local charge balance during the reaction.

Binding Sites↗
PubMed2026

Identifying causal genetic variants for high-altitude adaptation through blood eQTL analysis in plateau populations.

A substantial number of genetic variants have been associated with high-altitude adaptation (HAA), yet most of them are located in non-coding genomic regions, leaving their specific functions and underlying mechanisms largely unknown. In this study, we analyze whole-genome and transcriptome sequencing data from a self-established cohort comprising 61 native highlanders (NHs) and 164 acclimatized newcomers (ANs), identifying 6,586 cis- and 34,203 trans-expression quantitative trait loci (eQTLs), along with 130 cell type-specific eQTLs. By further combining these data with a large East Asia (~30% Tibetan) genome-wide association study (GWAS) cohort, we employ colocalization and causal inference analyses to prioritize 85 cis-eQTLs associated with HAA and identify several novel candidate causal genes, including EXOC8, which is experimentally confirmed to regulate erythroid differentiation. Additionally, network analysis of these causal genes uncovers multiple regulatory pathways, mainly involving energy metabolism, autophagy, ubiquitination and inflammation. Our study offers a comprehensive eQTL map and reveals causal chains of "variant-gene-phenotype" for HAA-related traits, which provides new insights into potential regulatory mechanisms and targets for prevention and treatment of altitude sickness.

Quantitative Trait Loci↗
PubMed2006

Dynamics of prefrontal and cingulate activity during a reward-based logical deduction task.

We used behavioral and functional magnetic resonance imaging (fMRI) methods to probe the cerebral organization of a simple logical deduction process. Subjects were engaged in a motor trial-and-error learning task, in which they had to infer the identity of an unknown 4-key code. The design of the task allowed subjects to base their inferences not only on the feedback they received but also on the internal deductions that it afforded (autoevaluation). fMRI analysis revealed a large bilateral parietal, prefrontal, cingulate, and striatal network that activated suddenly during search periods and collapsed during ensuing periods of sequence repetition. Fine-grained analyses of the temporal dynamics of this search network indicated that it operates according to near-optimal rules that include 1) computation of the difference between expected and obtained rewards and 2) anticipatory deductions that predate the actual reception of positive reward. In summary, the dynamics of effortful mental deduction can be tracked with fMRI and relate to a distributed network engaging prefrontal cortex and its interconnected cortical and subcortical regions.

Adult↗
PubMed2005

Foot-and-mouth disease virus replication sites form next to the nucleus and close to the Golgi apparatus, but exclude marker proteins associated with host membrane compartments.

Picornavirus infection of cells generally results in the production of membranous vesicles containing the viral proteins necessary for viral RNA synthesis. To determine whether foot-and-mouth disease virus (FMDV) infection induced similar structures, and which cellular components were involved, the subcellular distribution of FMDV proteins was compared with protein markers of cellular membrane compartments. Using immunofluorescence analysis and digital deconvolution, it was shown that FMDV structural and non-structural proteins co-localize to punctate structures in juxtanuclear virus assembly sites close to the Golgi complex. Significantly, viral protein 2C did not co-localize with marker proteins of the cis- or medial-Golgi compartments or trans-Golgi network. Furthermore, incubation of infected cells with brefeldin A caused a redistribution of Golgi proteins to the endoplasmic reticulum, but did not affect the distribution of 2C and, by inference, the integrity of the virus assembly site. Taken with the observation that 2C was membrane-associated, but failed to fractionate with Golgi markers on density gradients, it was possible to conclude that Golgi membranes were not a source of structures containing 2C. Further immunofluorescence analysis showed that 2C was also separate from marker proteins of the endoplasmic reticulum, endoplasmic reticulum intermediate compartment, endosomes and lysosomes. The results suggest that the membranes generated at FMDV assembly sites are able to exclude organelle-specific marker proteins, or that FMDV uses an alternative source of membranes as a platform for assembly and replication.

Animals↗
PubMed2005

Analysis of angiogenesis using in vitro experiments and stochastic growth models.

The global properties of vascular networks grown with an in vitro angiogenesis assay are compared quantitatively, using automated image analysis, with the global properties of networks obtained with discrete, stochastic growth models. The model classes that are investigated are invasion percolation and diffusion limited aggregation. By matching global properties to experimental data, one can infer which model classes and parameters are most reflective of angiogenesis in experimental cells. This sheds light on large-scale emergent properties of angiogenesis from a systems perspective. It is found that invasion percolation is better than diffusion limited aggregation at matching experimental data. We also present evidence that the distribution of the lengths of real tubule complexes follows a power law.

Animals↗