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PubMed2003

Inference and computation with population codes.

In the vertebrate nervous system, sensory stimuli are typically encoded through the concerted activity of large populations of neurons. Classically, these patterns of activity have been treated as encoding the value of the stimulus (e.g., the orientation of a contour), and computation has been formalized in terms of function approximation. More recently, there have been several suggestions that neural computation is akin to a Bayesian inference process, with population activity patterns representing uncertainty about stimuli in the form of probability distributions (e.g., the probability density function over the orientation of a contour). This paper reviews both approaches, with a particular emphasis on the latter, which we see as a very promising framework for future modeling and experimental work.

Animals↗

PubMed2006

ProFace: a server for the analysis of the physicochemical features of protein-protein interfaces.

BACKGROUND: Molecular recognition is all pervasive in biology. Protein molecules are involved in enzyme regulation, immune response, signal transduction, oligomer assembly, etc. Delineation of physical and chemical features of the interface formed by protein-protein association would allow us to better understand protein interaction networks on one hand, and to design molecules that can engage a given interface and thereby control protein function on the other hand. RESULTS: ProFace is a suite of programs that uses a file, containing atomic coordinates of a multi-chain molecule, as input and analyzes the interface between any two or more subunits. The interface residues are shown segregated into spatial patches (if such a clustering is possible based on an input threshold distance) and/or core and rim regions. A number of physicochemical parameters defining the interface is tabulated. Among the different output files, one contains the list of interacting residues across the interface. Results can be used to infer if a particular interface belongs to a homodimeric molecule. CONCLUSION: A web-server, ProFace (available at http://www.boseinst.ernet.in/resources/bioinfo/stag.html) has been developed for dissecting protein-protein interfaces and deriving various physicochemical parameters.

Amino Acid Sequence↗

PubMed2000

Structural requirements for catalysis and dimerization of human methionine adenosyltransferase I/III.

We have used site-directed mutagenesis to probe the structural requirements for catalysis and dimerization of human hepatic methionine adenosyltransferase (hMAT). We built a homology model of the dimeric hMAT III inferred by the crystal structure of the highly homologous Escherichia coli MAT dimer. The active sites of both enzymes comprise the same amino acids and are located in the inter-subunit interface. All of the amino acids predicted to be in the hMAT III active site were mutated, as well as residues in a conserved ATP binding region. All of the mutations except one severely affected catalytic activity. On the other hand, dimerization was affected only by single mutations of three different residues, all on one monomer. The homology model suggested that the side chains of these residues stabilized the monomer and participated in a bridge between subunits consisting of a network of metal and phosphate ions. In agreement with this observation, we demonstrated that dimerization cannot occur in the absence of phosphate.

Amino Acid Sequence↗

PubMed2025

Species-wide gene editing of a flowering regulator reveals hidden phenotypic variation.

Genes do not act in isolation, and the effects of a specific variant at one locus can often be greatly modified by polymorphic variants at other loci. A good example is FLOWERING LOCUS C (FLC), which has been inferred to explain much of the flowering time variation in Arabidopsis thaliana. We use a set of 62 flc species-wide mutants to document pleiotropic, genotype-dependent effects for FLC on flowering as well as several other traits. Time to flowering was greatly reduced in all mutants, with the remaining variation explained mainly by allelic variation at the FLC target FT. Analysis of FT sequence variation suggested that extremely early combinations of FLC and FT alleles should exist in the wild, which we confirmed by targeted collections. Our study provides a proof of concept on how pan-genetic analysis of hub genes can reveal the true extent of genetic networks in a species.

Gene Editing↗

PubMed2003

Rule-base derivation for intensive care ventilator control using ANFIS.

In recent years, much research has been done on the use of fuzzy systems in medicine. The fuzzy rule-bases have usually been derived after extensive discussion with the clinical experts. This takes a lot of time from the clinical experts and the knowledge engineers. This paper presents the use of the adaptive neuro-fuzzy inference system (ANFIS) in rule-base derivation for ventilator control. The change of the inspired fraction of oxygen (FiO(2)) advised by eight clinical experts responding to 71 clinical scenarios was recorded. ANFIS and a multilayer perceptron (MLP) were then used to model the relationship between the inputs (the arterial oxygen tension (PaO(2)), FiO(2) and the positive end-expiratory pressure (PEEP) level) and the change in FiO(2) suggested. Compared to a previous fuzzy advisor (FAVeM), both the ANFIS and the MLP were found to correlate with the clinicians' decision better (correlation coefficient of 0.694 and 0.701, respectively compared to 0.630). A formerly developed model-based radial basis network advisor (RBN-MB) was used for comparison. Closed-loop simulations showed that the ANFIS, MLP and the RBN-MB's performance were comparable to the clinicians' performance (correlation coefficients of 0.852, 0.962 and 0.787, respectively). The FAVeM's performance differed from the clinicians' performance (correlation coefficient of 0.332) but the resulting PaO(2) was still within safety limits.

Computer Simulation↗

PubMed2002

Absence of direct delivery for single transmembrane apical proteins or their "Secretory" forms in polarized hepatic cells.

The absence of a direct route to the apical plasma membrane (PM) for single transmembrane domain (TMD) proteins in polarized hepatic cells has been inferred but never directly demonstrated. The genes encoding three pairs of apical PM proteins, whose extracellular domains are targeted exclusively to the apical milieu in Madin-Darby canine kidney cells, were packaged into recombinant adenovirus and delivered to WIF-B cells in vitro and liver hepatocytes in vivo. By immunofluorescence and pulse-chase metabolic labeling, we found that the soluble constructs were overwhelmingly secreted into the basolateral milieu, which in vivo is the blood and in vitro is the culture medium. The full-length proteins were first delivered to the basolateral surface but then concentrated in the apical PM. Our results imply that hepatic cells lack trans-Golgi network (TGN)-based machinery for directly sorting single transmembrane domain apical proteins and raise interesting questions about current models of PM protein sorting in polarized and nonpolarized cells.

Adenoviridae↗

PubMed2006

Extracting gene networks for low-dose radiation using graph theoretical algorithms.

Genes with common functions often exhibit correlated expression levels, which can be used to identify sets of interacting genes from microarray data. Microarrays typically measure expression across genomic space, creating a massive matrix of co-expression that must be mined to extract only the most relevant gene interactions. We describe a graph theoretical approach to extracting co-expressed sets of genes, based on the computation of cliques. Unlike the results of traditional clustering algorithms, cliques are not disjoint and allow genes to be assigned to multiple sets of interacting partners, consistent with biological reality. A graph is created by thresholding the correlation matrix to include only the correlations most likely to signify functional relationships. Cliques computed from the graph correspond to sets of genes for which significant edges are present between all members of the set, representing potential members of common or interacting pathways. Clique membership can be used to infer function about poorly annotated genes, based on the known functions of better-annotated genes with which they share clique membership (i.e., "guilt-by-association"). We illustrate our method by applying it to microarray data collected from the spleens of mice exposed to low-dose ionizing radiation. Differential analysis is used to identify sets of genes whose interactions are impacted by radiation exposure. The correlation graph is also queried independently of clique to extract edges that are impacted by radiation. We present several examples of multiple gene interactions that are altered by radiation exposure and thus represent potential molecular pathways that mediate the radiation response.

Algorithms↗

PubMed2006

In silico ADME modelling 2: computational models to predict human serum albumin binding affinity using ant colony systems.

Modelling of in vitro human serum albumin (HSA) binding data of 94 diverse drugs and drug-like compounds is performed to develop global predictive models that are applicable to the whole medicinal chemistry space. For this aim, ant colony systems, a stochastic method along with multiple linear regression (MLR), is employed to exhaustively search and select multivariate linear equations, from a pool of 327 molecular descriptors. This methodology helped us to derive optimal quantitative structure-property relationship (QSPR) models based on five and six descriptors with excellent predictive power. The best five-descriptor model is based on Kier and Hall valence connectivity index--Order 5 (path), Auto-correlation descriptor (Broto-Moreau) weighted by atomic masses--Order 4, Auto-correlation descriptor (Broto-Moreau) weighted by atomic polarizabilities--Order 5, AlogP98, SklogS (calculated buffer water solubility) [R=0.8942, Q=0.86790, F=62.24 and SE=0.2626]; the best six-variable model is based on Kier and Hall valence connectivity index of Order 3 (cluster), Auto-correlation descriptor (Broto-Moreau) weighted by atomic masses--Order 4, Auto-correlation descriptor (Broto-Moreau) weighted by atomic polarizabilities--Order 5, Atomic-Level-Based AI topological descriptors--AIdsCH, AlogP98, SklogS (calculated buffer water solubility) [R=0.9128, Q=0.89220, F=64.09 and SE=0.2411]. From the analysis of the physical meaning of the selected descriptors, it is inferred that the binding affinity of small organic compounds to human serum albumin is principally dependent on the following fundamental properties: (1) hydrophobic interactions, (2) solubility, (3) size and (4) shape. Finally, as the models reported herein are based on computed properties, they appear to be a valuable tool in virtual screening, where selection and prioritisation of candidates is required.

Algorithms↗

PubMed2001

Medical applications of enhanced rule-based expert systems.

The paper describes several types of efficiency enhancements of 'classical' rule-based diagnostic expert systems. The blackboard control structure enables to explore more knowledge bases of the same syntax in parallel, the taxonomy structures make fast zooming of attention possible and provide additional inference mechanism based on inheritance principles. The applicability of the enhancing techniques is documented by four case studies exploring the extended FEL-EXPERT shell in different tasks of medical decision-making. The authors consider the enhancing techniques as useful steps on the way from 'classical' diagnostic expert systems towards more complex multi-agent decision tools.

Classification↗

PubMed2006

Why are proteins charged? Networks of charge-charge interactions in proteins measured by charge ladders and capillary electrophoresis.

Almost all proteins contain charged amino acids. While the function in catalysis or binding of individual charges in the active site can often be identified, it is less clear how to assign function to charges beyond this region. Are they necessary for solubility? For reasons other than solubility? Can manipulating these charges change the properties of proteins? A combination of capillary electrophoresis (CE) and protein charge ladders makes it possible to study the roles of charged residues on the surface of proteins outside the active site. This method involves chemical modification of those residues to generate a large number of derivatives of the protein that differ in charge. CE separates those derivatives into groups with the same number of modified charged groups. By studying the influence of charge on the properties of proteins using charge ladders, it is possible to estimate the net charge and hydrodynamic radius and to infer the role of charged residues in ligand binding and protein folding.

Amino Acids↗

PubMed1996

Temporal reasoning for diagnosis in a causal probabilistic knowledge base.

We have added temporal reasoning to the Heart Disease Program (HDP) to take advantage of the temporal constraints inherent in cardiovascular reasoning. Some processes take place over minutes while others take place over months or years and a strictly probabilistic formalism can generate hypotheses that are impossible given the temporal relationships involved. The HDP has temporal constraints on the causal relations specified in the knowledge base and temporal properties on the patient input provided by the user. These are used in two ways. First, they are used to constrain the generation of the pre-computed causal pathways through the model that speed the generation of hypotheses. Second, they are used to generate time intervals for the instantiated nodes in the hypotheses, which are matched and adjusted as nodes are added to each evolving hypothesis. This domain offers a number of challenges for temporal reasoning. Since the nature of diagnostic reasoning is inferring a causal explanation from the evidence, many of the temporal intervals have few constraints and the reasoning has to make maximum use of those that exist. Thus, the HDP uses a temporal interval representation that includes the earliest and latest beginning and ending specified by the constraints. Some of the disease states can be corrected but some of the manifestations may remain. For example, a valve disease such as aortic stenosis produces hypertrophy that remains long after the valve has been replaced. This requires multiple time intervals to account for the existing findings. This paper discusses the issues and solutions that have been developed for temporal reasoning integrated with a pseudo-Bayesian probabilistic network in this challenging domain for diagnosis.

Artificial Intelligence↗

PubMed2005

Neural mechanism for judging the appropriateness of facial affect.

Questions regarding the appropriateness of facial expressions in particular situations arise ubiquitously in everyday social interactions. To determine the appropriateness of facial affect, first of all, we should represent our own or the other's emotional state as induced by the social situation. Then, based on these representations, we should infer the possible affective response of the other person. In this study, we identified the brain mechanism mediating special types of social evaluative judgments of facial affect in which the internal reference is related to theory of mind (ToM) processing. Many previous ToM studies have used non-emotional stimuli, but, because so much valuable social information is conveyed through nonverbal emotional channels, this investigation used emotionally salient visual materials to tap ToM. Fourteen right-handed healthy subjects volunteered for our study. We used functional magnetic resonance imaging to examine brain activation during the judgmental task for the appropriateness of facial affects as opposed to gender matching tasks. We identified activation of a brain network, which includes both medial frontal cortex, left temporal pole, left inferior frontal gyrus, and left thalamus during the judgmental task for appropriateness of facial affect compared to the gender matching task. The results of this study suggest that the brain system involved in ToM plays a key role in judging the appropriateness of facial affect in an emotionally laden situation. In addition, our result supports that common neural substrates are involved in performing diverse kinds of ToM tasks irrespective of perceptual modalities and the emotional salience of test materials.

Adult↗

PubMed2002

Frontal and parietal lobe activation during transitive inference in humans.

Cortical areas engaged in knowledge manipulation during reasoning were identified with functional magnetic resonance imaging (MRI) while participants performed transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B < C, then A < C). Initially, participants learned a list of arbitrarily ordered visual shapes. Learning occurred by exposure to pairs of list items that were adjacent in the sequence. Subsequently, functional MR images were acquired as participants performed TI on non-adjacent sequence items. Control tasks consisted of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task with the HT task identified activation resulting from TI, termed 'reasoning', while controlling for rule application, decision processes, perception, and movement, collectively termed 'support processes'. The HT-VIS comparison revealed activation related to support processes. The TI reasoning network included bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA), premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By contrast, cortical regions activated by support processes included the bilateral supplementary motor area (SMA), primary motor cortex (M1), somatic sensory cortices, and right PMA. These results emphasize the role of a prefrontal-parietal network in manipulating information to form new knowledge based on familiar facts. The findings also demonstrate PFC activation beyond short-term memory to include mental operations associated with reasoning.

Adult↗

PubMed2002

Genetic analysis of incident HIV-1 strains among injection drug users in Bangkok: evidence for multiple transmission clusters during a period of high incidence.

During 1995-1996, 1,209 HIV-1-negative injection drug users (IDUs) attending methadone treatment clinics operated by the Bangkok Metropolitan Administration in Bangkok, Thailand, were enrolled in a prospective cohort study. Through 1998, 133 of these IDUs had seroconverted to HIV-1; 130 of these seroconverters were included in this study. HIV-1 CRF01_AE and subtype B strains accounted for 79% and 21% of the incident infections, respectively. To examine phylogenetic relationships among these incident HIV-1 strains, we used several phylogenetic inference methodologies to analyze the env (C2-V4) sequences in blood samples collected soon after seroconversion. These analyses consistently revealed eight phylogenetic clusters comprising 21 incident strains (bootstrap method, >80%; six CRF01_AE and two subtype B clusters). Two factors were found to be associated with the eight clusters. The first factor was temporal: seven of the eight clusters comprised 17 sequences from IDUs whose estimated dates of seroconversion were within a period of high incidence from July 1996 through January 1997. The second factor was a possible geographic association: four clusters were observed among IDUs who had attended the same methadone treatment clinics. These phylogenetic clusters likely represent subgroups within larger HIV transmission networks among IDUs in Bangkok. Despite prevention efforts, the incidence of HIV-1 infection among the Bangkok IDU population continues to be high. A better understanding of transmission networks and factors associated with such networks can help guide prevention efforts.

Adult↗

PubMed2005

Investigations into resting-state connectivity using independent component analysis.

Inferring resting-state connectivity patterns from functional magnetic resonance imaging (fMRI) data is a challenging task for any analytical technique. In this paper, we review a probabilistic independent component analysis (PICA) approach, optimized for the analysis of fMRI data, and discuss the role which this exploratory technique can take in scientific investigations into the structure of these effects. We apply PICA to fMRI data acquired at rest, in order to characterize the spatio-temporal structure of such data, and demonstrate that this is an effective and robust tool for the identification of low-frequency resting-state patterns from data acquired at various different spatial and temporal resolutions. We show that these networks exhibit high spatial consistency across subjects and closely resemble discrete cortical functional networks such as visual cortical areas or sensory-motor cortex.

Brain↗

PubMed2002

Risperidone in children with autism and serious behavioral problems.

BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.

Adolescent↗

PubMed2004

Measuring functional connectivity during distinct stages of a cognitive task.

The inherently multivariate nature of functional brain imaging data affords the unique opportunity to explore how anatomically disparate brain areas interact during cognitive tasks. We introduce a new method for characterizing inter-regional interactions using event-related functional magnetic resonance imaging (fMRI) data. This method's principle advantage over existing analytical techniques is its ability to model the functional connectivity between brain regions during distinct stages of a cognitive task. The method is implemented by using separate covariates to model the activity evoked during each stage of each individual trial in the context of the general linear model (GLM). The resulting parameter estimates (beta values) are sorted according to the stage from which they were derived to form a set of stage-specific beta series. Regions whose beta series are correlated during a given stage are inferred to be functionally interacting during that stage. To validate the assumption that correlated fluctuations in trial-to-trial beta values imply functional connectivity, we applied the method to an event-related fMRI data set in which subjects performed two sequence-tapping tasks. In concordance with previous electrophysiological and fMRI coherence studies, we found that the task requiring greater bimanual coordination induced stronger correlations between motor regions of the two hemispheres. The method was then applied to an event-related fMRI data set in which subjects performed a delayed recognition task. Distinct functional connectivity maps were generated during the component stages of this task, illustrating how important and novel observations of neural networks within the isolated stages of a cognitive task can be obtained.

Adult↗

PubMed2005

Genetic structure and history of populations of the deep-sea fish Helicolenus dactylopterus (Delaroche, 1809) inferred from mtDNA sequence analysis.

Helicolenus dactylopterus is an Atlantic benthopelagic fish species inhabiting high-energy habitats on continental slopes, seamounts and islands. Partial sequences of the mitochondrial control region (D-loop) and cytochrome b (cyt b) were used to test the hypothesis that H. dactylopterus disperses between continental margin, island and seamount habitats on intraregional, regional and oceanic scales in the North Atlantic. Individuals were collected from five different geographical areas: Azores, Madeira, Portugal (Peniche), Cape Verde and the northwest Atlantic. D-loop (415 bp) and cyt b (423 bp) regions were partially sequenced for 208 and 212 individuals, respectively. Analysis of variation among mitochondrial DNA sequences based on pairwise F-statistics and AMOVA demonstrated marked genetic differentiation between populations in different geographical regions specifically the Mid-Atlantic Ridge (Azores)/northeast Atlantic (Portugal, Madeira) compared to populations around the Cape Verde Islands and in the northwest Atlantic. Some evidence of intraregional genetic differentiation between populations was found. Minimum-spanning network analysis revealed star-shaped patterns suggesting that populations had undergone expansion following bottlenecks and/or they have been colonized by jump dispersal events across large geographical distances along pathways of major ocean currents. Mismatch distribution analysis indicated that Azores and northwest Atlantic populations fitted a model of historical population expansion following a bottleneck/founder event estimated to be between 0.64 and 1.2 million years ago (Ma).

Analysis of Variance↗