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PubMed2007

The reinfection threshold regulates pathogen diversity: the case of influenza.

The awareness that pathogens can adapt and evolve over relatively short time-scales is changing our view of infectious disease epidemiology and control. Research on the transmission dynamics of antigenically diverse pathogens is progressing and there is increasing recognition for the need of new concepts and theories. Mathematical models have been developed considering the modelling unit in two extreme scales: either diversity is not explicitly represented or diversity is represented at the finest scale of single variants. Here, we use an intermediate approach and construct a model at the scale of clusters of variants. The model captures essential properties of more detailed systems and is much more amenable to mathematical treatment. Specificities of pathogen clusters and the overall potential for transmission determine the reinfection rates. These are, in turn, important regulators of cluster dynamics. Ultimately, we detect a reinfection threshold (RT) that separates different behaviours along the transmissibility axis: below RT, levels of infection are low and cluster substitutions are probable; while above RT, levels of infection are high and multiple cluster coexistence is the most probable outcome.

Animals↗
PubMed2003

Tests for gene clustering.

Comparing chromosomal gene order in two or more related species is an important approach to studying the forces that guide genome organization and evolution. Linked clusters of similar genes found in related genomes are often used to support arguments of evolutionary relatedness or functional selection. However, as the gene order and the gene complement of sister genomes diverge progressively due to large scale rearrangements, horizontal gene transfer, gene duplication and gene loss, it becomes increasingly difficult to determine whether observed similarities in local genomic structure are indeed remnants of common ancestral gene order, or are merely coincidences. A rigorous comparative genomics requires principled methods for distinguishing chance commonalities, within or between genomes, from genuine historical or functional relationships. In this paper, we construct tests for significant groupings against null hypotheses of random gene order, taking incomplete clusters, multiple genomes, and gene families into account. We consider both the significance of individual clusters of prespecified genes and the overall degree of clustering in whole genomes.

Algorithms↗
PubMed2000

Prevalence and genetic diversity of human caliciviruses (HuCVs) in Mexican children.

Human caliciviruses (HuCVs) contain two genera: "Norwalk-like viruses" (NLVs) and "Sapporo-like viruses" (SLVs). The importance of the two genera as a cause of acute gastroenteritis of infants and children remains unknown. Beginning in 1989, a birth cohort of children in Mexico was enrolled and monitored for acute gastroenteritis. A subset of 115 diarrhea stool specimens from 76 children and 66 non-diarrhea stool specimens from 64 children was examined for HuCVs by RT-PCR by using a primer pair (p289/290) that detects both NLVs and SLVs. Twenty-two (19%) of the 115 diarrhea stool specimens and 5 (7%) of 66 non-diarrhea stool specimens produced RT-PCR products of expected size (319 bp for NLVs and 331 bp for SLVs). Twenty of the twenty-seven strains were cloned and sequenced. Pairwise sequence analysis showed that 9 (60%) and 6 (40%) of the 15 strains from the diarrhea stools were NLVs and SLVs, respectively. The same proportions of NLVs (60%) and SLVs (40%) were observed in the non-diarrhea stools. Strains in the NLV genus could be further divided into four clusters: Lordsdale, MxV, and HV and one potentially new cluster. Strains in the SLV genus could be divided into three clusters: Sapporo/82, Lon/92, and a potentially new cluster. Strains from the Lordsdale cluster were the most common among these children. The findings of both genera and multiple clusters of HuCVs co-circulating and the identification of new strains of HuCVs in the population justify the need for future studies of HuCVs in infants and children.

Caliciviridae↗
PubMed1978

Functional organization of receptive fields in the cat somatosensory cortex. I: Integration within the coronal region.

The receptive fields (RF) of the neurons in the coronal region of the first somatosensory cortex (SI) were studied in a preparation of unanesthetized paralyzed cats. The majority of units responded to simple light mechanical stimuli to the hairy or glabrous skin. There were units with slightly larger RFs and more complex properties, such as those preferentially responding to the moving skin stimuli with directional selectivity. The receptive fields tend to be larger in the more rostral (area 3a) or medial coronal (area 3b) region than in the caudal region (area 3b). The largest RFs intermingled among focal ones included other smaller RFs in the vicinity. Their configurations were different at different loci in the coronal region. It is suggested that the coronal SI region is organized in terms of multiple clusterings of units, each with particular receptive field characteristics. The representation of a single peripheral locus on the forepaw can thus be multiple, if it appeared in more than one of such clusterings of receptive fields.

Animals↗
PubMed1998

N-cadherin/catenin-mediated morphoregulation of somite formation.

Somitogenesis during early stages in the chick and mouse embryo was examined in relation to N-cadherin-mediated adhesion. Previous studies indicated that N-cadherin localizes to the somite regions during their formation. Those observations were extended to include a spatiotemporal immunohistochemical analyses of beta-catenin and alpha-catenin, as well as a more detailed study of N-cadherin, during segmentation, compaction, and compartmentalization of the somite. N-cadherin and the catenins appear early within the segmental plate and are expressed as small patch-like foci throughout this tissue. The small foci of immunostaining coalesce into larger clusters of N-cadherin/catenin-expressing regions. The clusters subsequently coalesce into a region of centrally localized cells that express N-cadherin/catenins at their apical surfaces. The multiple clusters are spaced wide apart in the anterior segmental plates that form the first 6 somite pairs, as contrasted to segmental plates that form somites 7 and beyond. To examine the functional significance of N-cadherin, segmental plates were exposed to antibodies that perturb N-cadherin-mediated adhesion in the chick embryo. The multiple, anomalous somites that result in these experiments indicate that each N-cadherin/catenin-expressing cluster can give rise to a somitic structure. beta-Catenin involvement in somitogenesis suggests a role for Wnt-mediated signaling. Embryos treated with LiCl also show induction of similar anomalous somites indicating further the possibility that Wnt-mediated signaling may be involved in the clustering event. It is suggested that beta-catenin serves to initiate the adhesion process which is spread then by N-cadherin. Later during compartmentalization, N-cadherin/catenins remain expressed by the myotome compartment. Taken together, these results suggest that the Ca2+-dependent cell adhesion molecule N-cadherin and the intracellular catenins are important in segmentation and formation of the somite and myotome compartment. It is proposed that the N-cadherin-mediated adhesion process may serve as a common, evolutionarily conserved, link in the differentiation pathways of skeletal and cardiac muscle.

Animals↗
PubMed2005

A new algorithm for comparing and visualizing relationships between hierarchical and flat gene expression data clusterings.

MOTIVATION: Clustering is one of the most widely used methods in unsupervised gene expression data analysis. The use of different clustering algorithms or different parameters often produces rather different results on the same data. Biological interpretation of multiple clustering results requires understanding how different clusters relate to each other. It is particularly non-trivial to compare the results of a hierarchical and a flat, e.g. k-means, clustering. RESULTS: We present a new method for comparing and visualizing relationships between different clustering results, either flat versus flat, or flat versus hierarchical. When comparing a flat clustering to a hierarchical clustering, the algorithm cuts different branches in the hierarchical tree at different levels to optimize the correspondence between the clusters. The optimization function is based on graph layout aesthetics or on mutual information. The clusters are displayed using a bipartite graph where the edges are weighted proportionally to the number of common elements in the respective clusters and the weighted number of crossings is minimized. The performance of the algorithm is tested using simulated and real gene expression data. The algorithm is implemented in the online gene expression data analysis tool Expression Profiler. AVAILABILITY: http://www.ebi.ac.uk/expressionprofiler

Algorithms↗
PubMed2006

The mental health impact of 9/11 on inner-city high school students 20 miles north of Ground Zero.

PURPOSE: To determine the rate of post-traumatic stress disorder (PTSD) after 9/11 in a sample of New York City high school students and associations among personal exposure, loss of psychosocial resources, prior mental health treatment, and PTSD. METHODS: A total of 1214 students (grades 9 through 12) attending a large community high school in Bronx County, 20 miles north of "Ground Zero," completed a 45-item questionnaire during gym class on one day eight months after 9/11. Students were primarily Hispanic (62%) and African American (29%) and lived in the surrounding neighborhood. The questionnaire included the PCL-T, a 17-item PTSD checklist supplied by the Office of Behavioral and Social Science Research of the National Institutes of Health (NIH). The PCL-T was scored following the DSM-IV criteria for PTSD requiring endorsement of at least one repeating symptom, two hyperarousal symptoms, and three avoidance symptoms. Bivariate analysis comparing PTSD with personal exposure, loss of psychosocial resources, and mental health variables was done and multiple logistic regression was used to identify significant associations. RESULTS: There were 7.4 % of students with the PTSD symptom cluster. Bivariate analysis showed a trend for females to have higher rates of PTSD (males [6%] vs. females [9%], p = .06] with no overall ethnic differences. Five of the six personal exposure variables, and both of the loss of psychosocial resources and mental health variables were significantly associated with PTSD symptom cluster. Multiple logistic regression analysis found one personal exposure variable (having financial difficulties after 9/11, odds ratio [OR] = 5.27; 95% confidence interval [CI] 2.9-9.7); both the loss of psychosocial resources variables (currently feeling less safe, OR = 3.58; 95% CI 1.9-6.8) and currently feeling less protected by the government, (OR = 4.04; 95% CI 2.1-7.7); and one mental health variable (use of psychotropic medication before 9/11, OR = 3.95; 95% CI 1.2-13.0) were significantly associated with PTSD symptom cluster. CONCLUSIONS: We found a rate of PTSD in Bronx students after 9/11 that was much higher than other large studies of PTSD in adolescents done before 9/11. Adolescents living in inner cities with high poverty and violence rates may be at high risk for PTSD after a terrorist attack. Students who still felt vulnerable and less safe eight months later and those with prior mental health treatment were four times more likely to have PTSD than those without such characteristics, highlighting the influence of personality and mental health on development of PTSD after a traumatic event.

Adolescent↗
PubMed1984

Single cell studies of the primate putamen. I. Functional organization.

In order to clarify the functional organization of the putamen and the nature of sensory inputs to this structure we studied the relation of single cell activity to active movements and somatosensory stimulation in the awake primate. Neurons (N = 707) were categorized on the basis of their relation to active movements or responses to sensory stimulation of individual body parts. 38% of neurons studied were related to the arm, 9% to the leg, 11% to the mouth or face, and 3% to axial portions of the body. The remaining neurons exhibited non-specific activation which could not be confidently localized to an individual body part (12%) or did not respond during the examination (26%). The high proportion of arm neurons was due to the focus of this study on cells related to arm movements. A large proportion (41%; N = 270) of the "arm" neurons was responsive to somatosensory stimulation. For these neurons the most effective stimulus (82%) was passive joint rotation. Six (5%) of the arm neurons responded to cutaneous stimulation. The putamen was found to be somatotopically organized. Neurons related to different body parts (leg, arm, and face) were segregated, and each body part was represented over a long anteroposterior extent of the nucleus. Clusters of 2-5 neurons with similar relations to active movements or responsive to passive movements of a single joint were often encountered over a 100-500 mu distance. Clusters of neurons with sensory driving were organized by joints. Rather than a single elbow or shoulder area, multiple clusters of neurons related to each joint were widely distributed over a long anteroposterior extent of the nucleus and were adjacent to clusters of neurons related to other joints of the arm. These clusters of neurons with similar functional properties may correspond to the subunits of the striatum which have been revealed by anatomic and morphologic studies. We propose that these clusters of neurons with similar functional properties represent the basic functional units of the striatum in a manner analogous to the functional columns of the neocortex.

Animals↗
PubMed2004

The predictive power of Horney's psychoanalytic approach: an empirical study.

This study investigated the construct validity of a measure of Karen Horney's (1945) psychoanalytic theory that postulated three neurotic trends: compliant, aggressive, and detached. Her theory was operationalized by the Horney-Coolidge Type Indicator (HCTI). One hundred seventy-two adults completed the HCTI and the short form of the Coolidge Axis II Inventory, a measure of the three DSM-IV personality disorder clusters. Multiple regression and canonical correlation analyses revealed significant and differential patterns of the three HCTI dimensions with the three clusters. Because Paris (1994) has noted that Horney's neurotic trends may today be conceived of as personality disorders, one implication of the present findings is that Horney's dynamic theory can be valid and useful in the general understanding of personality disorders from a cluster perspective.

Adolescent↗
PubMed2005

Comments about Joint Modeling of Cluster Size and Binary and Continuous Subunit-Specific Outcomes.

In longitudinal studies and in clustered situations often binary and continuous response variables are observed and need to be modeled together. In a recent publication Dunson, Chen, and Harry (2003, Biometrics 59, 521-530) (DCH) propose a Bayesian approach for joint modeling of cluster size and binary and continuous subunit-specific outcomes and illustrate this approach with a developmental toxicity data example. In this note we demonstrate how standard software (PROC NLMIXED in SAS) can be used to obtain maximum likelihood estimates in an alternative parameterization of the model with a single cluster-level factor considered by DCH for that example. We also suggest that a more general model with additional cluster-level random effects provides a better fit to the data set. An apparent discrepancy between the estimates obtained by DCH and the estimates obtained earlier by Catalano and Ryan (1992, Journal of the American Statistical Association 87, 651-658) is also resolved. The issue of bias in inferences concerning the dose effect when cluster size is ignored is discussed. The maximum-likelihood approach considered herein is applicable to general situations with multiple clustered or longitudinally measured outcomes of different type and does not require prior specification and extensive programming.

Animals↗
PubMed2001

[Genetic determination of smell].

The recent study of olfactory receptor genes sheds new light on the significance of this receptor not only for smell recognition but also in human embryogenesis. In this work current data concerning the role of olfactory receptors in human as well as their genetic determination are presented. Olfactory receptors are encoding approximately by 1000 hOR genes. The hOR gene family is most likely the largest in human genome. Among 1000 hOR genes, 347 are functional, the rest 70% being pseudogenes are not expressed. HOR genes reside at 25 locations in human genome in multiple clusters on all human chromosomes, except 2, 4, 18, 20, 21, and Y. Each receptor recognizes single as well as multiple odorant, and each odorant binds to multiple receptors to generate specific activation patterns for each of a great number of distinct smells. There is more and more evidence showing close correlation between HLA complex and smell recognition, which influence mating behavior in animals, consequently leading to increase immune response to various pathogens. The last investigations showed hOR expression in germinal cells and in developing embryo, suggest that hOR may play functional role in cell recognition in organogenesis.

Animals↗
PubMed1996

A negative tyrosine aminotransferase gene element that blocks glucocorticoid modulatory element-regulated modulation of glucocorticoid-induced gene expression.

Tyrosine aminotransferase (TAT) is the prototypic steroid-inducible gene. Recently, we have found that the modulation of TAT induction properties is reproduced by a novel cis-acting TAT gene element, the glucocorticoid modulatory element (GME). This GME lies about 1 kb upstream of the glucocorticoid response elements (GREs) of the TAT gene and binds a heterooligomer of two recently defined proteins. We now report the existence of an additional TAT gene element between the GME and the GREs that blocks the action of the GME and thus prevents the left shift in the glucocorticoid dose-response curve caused by the GME. This negative element has the properties of a silencer because its activity is relatively position- and orientation-independent. The interaction appears to be stoichiometric in that the effects of a single negative element can be overcome by a second GME. This negative element also has an intrinsic inhibitory activity in the absence of the GME. The majority of the negative element activity could be elicited by a 56-bp sequence between -3105 and -3050 bp of the TAT gene. Multiple, clustered mutations of this sequence reduced, but did not eliminate, the negative activity. Further efforts to restrict the negative element were unsuccessful, suggesting that multiple sequences are required for full activity. High affinity, sequence-specific binding of a trans-acting factor(s) was observed in gel shift assays. This binding was half-maximally competed by a 4.4-fold excess of nonradioactive probe and was very stable once formed (delta H [symbol: see text] dissoc. = 32 kcal/mol), suggesting that low concentrations of a high affinity binding protein(s) exist in nuclear extracts. Further support for this conclusion came from the observation that cotransfection of a plasmid containing multiple copies of the 56-bp negative element was able to relieve the negation of GME activity in a GME-56-bp-GRE reporter construct. These data directly support the role of a trans-acting factor(s) in binding to the 56-bp negative element and blocking GME activity. Collectively, these data suggest that glucocorticoid induction of TAT gene expression is subject to multiple levels of control by several new cis-acting elements and thus is much more complex than previously appreciated.

Base Sequence↗
PubMed2003

Multicontext fuzzy clustering for separation of brain tissues in magnetic resonance images.

A local image model is proposed to eliminate the adverse impact of both artificial and inherent intensity inhomogeneities in magnetic resonance imaging on intensity-based image segmentation methods. The estimation and correction procedures for intensity inhomogeneities are no longer indispensable because the highly convoluted spatial distribution of different tissues in the brain is taken into consideration. On the basis of the local image model, multicontext fuzzy clustering (MCFC) is proposed for classifying 2D and 3D MR data into tissues of white matter, gray matter, and cerebral spinal fluid automatically. In MCFC, multiple clustering contexts are generated for each pixel, and fuzzy clustering is independently performed in each context to calculate the degree of membership of a pixel to each tissue class. To maintain the statistical reliability and spatial continuity of membership distributions, a fusion strategy is adopted to integrate the clustering outcomes from different contexts. The fusion result is taken as the final membership value of the pixel. Experimental results on both real MR images and simulated volumetric MR data show that MCFC outperforms the classic fuzzy c-means (FCM) as well as other segmentation methods that deal with intensity inhomogeneities.

Artifacts↗
PubMed2001

Percolation clustering: a novel approach to the clustering of gene expression patterns in Dictyostelium development.

We present a novel approach to the clustering of gene expression patterns based on the mutual connectivity of the patterns. Unlike certain widely used methods (e.g., self-organizing maps and K-means) which essentially force gene expression data into a fixed number of predetermined clustering structures, our approach aims to reveal the natural tendency of the data to cluster, in analogy to the physical phenomenon of percolation. The approach is probabilistic in nature, and as such accommodates the possibility that one gene participates in multiple clusters. The result is cast in terms of the connectivity of each gene to a certain number of (significant) clusters. A computationally efficient algorithm is developed to implement our approach. Performance of the method is illustrated by clustering both constructed data and gene expression data obtained from Dictyostelium development.

Algorithms↗
PubMed2005

cluML: A markup language for clustering and cluster validity assessment of microarray data.

cluML is a new markup language for microarray data clustering and cluster validity assessment. The XML-based format has been designed to address some of the limitations observed in traditional formats, such as inability to store multiple clustering (including biclustering) and validation results within a dataset. cluML is an effective tool to support biomedical knowledge representation in gene expression data analysis. Although cluML was developed for DNA microarray analysis applications, it can be effectively used for the representation of clustering and for the validation of other biomedical and physical data that has no limitations.

Algorithms↗
PubMed1990

Activity of identified wrist-related pallidal neurons during step and ramp wrist movements in the monkey.

1. The activity of globus pallidus (GP) neurons (n = 1,117) was studied in two monkeys to reexamine the relation of neuronal activity to movement type (slow vs. fast) while they performed both a visually guided step and ramp wrist tracking task. To select neurons specifically related to wrist movements, we employed both a somatosensory examination of individual body parts and a statistical analysis of the strength of temporal coupling of neuronal discharges to active wrist movement. 2. Neuronal responses to somatosensory stimulation were studied in 1,000 high-frequency GP neurons, of which 686 exhibited clear responses to manipulation of body parts. Of the latter, 336 responded to passive manipulation of forelimb joints and 58 selectively to passive flexion or extension of the wrist. 3. In the external segment of GP (GPe), most neurons responding to passive wrist movement were found to be clustered in four to five adjacent, closely positioned (separated by 200 microns) tracks in single coronal planes. The clusters were irregular in shape with a maximal width of 800-1,000 microns. Separate clusters of neurons responsive to passive wrist movement were identified in planes 3 mm apart in one monkey and in planes 500 microns apart in the other. Multiple clusters of neurons were also found for neurons responsive to joints other than the wrist. These findings suggest a more discrete and complex representation of individual joints in the primate GP than previously conceived. 4. During the performance of the wrist flexion and extension task, 92 neurons showed clear and consistent changes in activity. For these neurons we measured, with a statistical method on a trial-by-trial basis, the strength of temporal coupling between the onset of active wrist movement and the onset of change in neuronal discharge rate. Fifteen neurons showed changes in activity time-locked to the onset of active wrist movement. 5. Twelve pallidal neurons were classified as "wrist-related" based on their movement-locked changes in discharge during task performance and their clear responses to passive wrist joint rotation on examination. All of these neurons exhibited statistically significant modulation of their discharge rate during both fast (peak velocity 97-205 degrees/s) and slow (peak velocity 20-62 degrees/s) wrist movements in the task. The amplitudes of modulation were larger during fast wrist movement than slow movement. These results suggest that the basal ganglia motor circuit plays a similar, rather than an exclusive, role in the control of slow and fast limb movements.

Animals↗
PubMed2004

Multiple sequence alignment in parallel on a workstation cluster.

SUMMARY: Multiple sequence alignment is the NP-hard problem of aligning three or more DNA or amino acid sequences in an optimal way so as to match as many characters as possible from the set of sequences. The popular sequence alignment program ClustalW uses the classical method of approximating a sequence alignment, by first computing a distance matrix and then constructing a guide tree to show the evolutionary relationship of the sequences. We show that parallelizing the ClustalW algorithm can result in significant speedup. We used a cluster of workstations using C and message passing interface for our implementation. Experimental results show that speedup of over 5.5 on six processors is obtainable for most inputs. AVAILABILITY: The software is available upon request from the second author.

Algorithms↗
PubMed2000

Rat somatosensory cerebropontocerebellar pathways: spatial relationships of the somatotopic map of the primary somatosensory cortex are preserved in a three-dimensional clustered pontine map.

In the primary somatosensory cortex (SI), the body surface is mapped in a relatively continuous fashion, with adjacent body regions represented in adjacent cortical domains. In contrast, somatosensory maps found in regions of the cerebellar hemispheres, which are influenced by the SI through a monosynaptic link in the pontine nuclei, are discontinuous ("fractured") in organization. To elucidate this map transformation, the authors studied the organization of the first link in the SI-cerebellar pathway, the SI-pontine projection. After injecting anterograde axonal tracers into electrophysiologically defined parts of the SI, three-dimensional reconstruction and computer-graphic visualization techniques were used to analyze the spatial distribution of labeled fibers. Several target regions in the pontine nuclei were identified for each major body representation. The labeled axons formed sharply delineated clusters that were distributed in an inside-out, shell-like fashion. Upper lip and other perioral representations were located in a central core, whereas extremity and trunk representations were found more externally. The multiple clusters suggest that the pontine nuclei contain several representations of the SI map. Within each representation, the spatial relationships of the SI map are largely preserved. This corticopontine projection pattern is compatible with recently proposed principles for the establishment of subcortical topographic patterns during development. The largely preserved spatial relationships in the pontine somatotopic map also suggest that the transformation from an organized topography in SI to a fractured map in the cerebellum takes place primarily in the mossy fiber pontocerebellar projection.

Animals↗