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PubMed2004

Genetic components of vocal learning.

Vocal learning is a rare trait. Humans depend on vocal learning to acquire spoken language, but most species that communicate acoustically have an innate repertoire of sounds that they use for information exchange. Among the few non-human species that also rely on vocal learning, songbirds have provided by far the most information for understanding this process. This article concentrates on the genetic components of vocal learning in humans and birds. We summarize the existing evidence for a genetic predisposition towards acquiring the species-specific human and avian vocal repertoires. We describe the approaches used for finding genes involved in shaping the neural circuitry required for vocal learning or in mediating the learning process itself. Special attention is given to a particular gene, FOXP2, which has been implicated in a human speech and language disorder. We have studied FoxP2 in avian vocal learners and non-learners and review evidence that links both the molecule and its close homologue FoxP1 to the development of brain regions implicated in vocal learning and to their function. FoxP2 has a characteristic expression pattern in a brain structure uniquely associated with learned vocal communication, Area X in songbirds, or its analogue in parrots and hummingbirds. In both avian song learners and non-learners FoxP2 expression predominates in sensory and sensory-motor circuits. These latter regions also express FoxP2 in mammals and reptiles. We conclude that FoxP2 is important for the building and function of brain pathways including, but not limited to, those essential for learned vocal communication.

Animals↗
PubMed2002

New approach to pharmacophore mapping and QSAR analysis using inductive logic programming. Application to thermolysin inhibitors and glycogen phosphorylase B inhibitors.

A key problem in QSAR is the selection of appropriate descriptors to form accurate regression equations for the compounds under study. Inductive logic programming (ILP) algorithms are a class of machine-learning algorithms that have been successfully applied to a number of SAR problems. Unlike other QSAR methods, which use attributes to describe chemical structure, ILP uses relations. This gives ILP the advantages of not requiring explicit superimposition of individual compounds in a dataset, of dealing naturally with multiple conformations, and of using a language much closer to that used normally by chemists. We unify ILP and standard regression techniques to give a QSAR method that has the strength of ILP at describing steric structure with the familiarity and power of regression methods. Complex pharmacophores, correlating with activity, were identified and used as new indicator variables, along with the comparative molecular field analysis (CoMFA) prediction, to form predictive regression equations. We compared the formation of 3D-QSARs using standard CoMFA with the use of ILP on the well-studied thermolysin zinc protease inhibitor dataset and a glycogen phosphorylase inhibitor dataset. In each case the addition of ILP variables produced statistically better results (P < 0.01 for thermolysin and P < 0.05 for GP datasets) than the CoMFA analysis. Moreover, the new ILP variables were not found to increase the complexity of the final QSAR equations and gave possible insight into the binding mechanism of the ligand-protein complex under study.

Algorithms↗
PubMed2006

Feature-guided clustering of multi-dimensional flow cytometry datasets.

BACKGROUND: Flow cytometry produces large multi-dimensional datasets of the physical and molecular characteristics of individual cells. The objective of this study was to simplify the cytometry datasets by arranging or clustering "objects" (cells) into a smaller number of relatively homogeneous groups (clusters) on the basis of interobject similarities and dissimilarities. RESULTS: The algorithm was designed to be driven by histogram features; that is, the relevant single parameter histogram features were used to guide multidimensional k-means clustering without an a priori estimate of cluster number. To test this approach, we simulated cell-derived datasets using protein-coated microspheres (artificial "cells"). The microspheres were constructed to provide 119 populations in 40 samples. The feature-guided (FG) approach accurately identified 100% of the predetermined cluster combinations. In contrast, an approach based on the partition index (PI) cluster validity measure accurately identified 83.2% of the clusters. Direct comparisons of the two methods indicated that the FG method was significantly more accurate than PI in identifying both the number of clusters and the number of objects within the clusters (p<.0001). CONCLUSION: We conclude that parameter feature analysis can be used to effectively guide k-means clustering of flow cytometry datasets.

Algorithms↗
PubMed2004

Current and future therapy in muscular dystrophy; need for a common language between basic scientists and clinicians.

This paper reviews the current therapy of Duchenne dystrophy, with the only two effective means of prolonging ambulation being the provision of knee-ankle-foot orthoses, and administration of corticosteroids, and the prospects, for the future application in Duchenne dystrophy, of ongoing research in cell therapy, gene therapy, protein upregulation and pharmacological possibilities. A critical review is also provided on the inappropriate nomenclature currently used and the need for a common language between basic and clinical scientists. Amongst the major problems are equating the mdx mouse, with its mild clinical phenotype, and Duchenne dystrophy, with its clearly defined severe clinical phenotype; the use of inappropriate and often emotive terminology to describe the pathological changes, such as "rescue", "reversal", "prevention", in place of describing the actual changes in acceptable descriptive language; and the use of the term therapy, in place of experiments, both in the basic laboratory studies and also the clinical experiments of injection of cells or gene constructs into single small muscles. A missing link in the multidisciplinary efforts, in this field, is the almost total absence of mouse doctors, who can define, at a clinical level, the motor, respiratory and cardiac deficits in the dystrophic animal, and bridge the gap between the mouse scientists doing experimental studies in the laboratory and the clinicians and veterinarians involved in the care of humans and dogs with these disorders and speaking the same language in relation to the clinical aspects and the pathology.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Experimentally induced peri-implantitis: a review of different treatment methods described in the literature.

The aim of this article was to present the experimental peri-implantitis models described in the literature and to provide a review of currently used treatment methods. For this purpose, 29 English- and German-language studies published in internationally reviewed journals were examined for similarities and differences regarding animal models, types of implants, and methods used for inducing peri-implantitis. In almost all studies, the implants were located in the mandible, which suggests that peri-implantitis of the maxilla has been researched very little. While in most studies, peri-implantitis was induced by means of ligature and plaque accumulation, only 3 studies have been published that attempted to induce peri-implantitis by means of mechanical overload. Of the latter, only one author observed peri-implant bone resorption. Eleven studies reporting on ligature-induced peri-implantitis presented enough data to be subjected to further statistical data analyses. Meta-analysis revealed that the period of ligature application, and thus the duration of plaque accumulation, generally had no influence on the resultant depth of the bone defect. However, when screw-type and cylindric implants were analyzed separately, a weakly significant positive effect of the duration of ligature application on the resultant defect depth was determined for cylindric implants (P = .092). This could imply that smooth screw-type implants were less susceptible to ligature-induced peri-implant inflammation. Regenerative treatment methods included the membrane technique using non-resorbable membranes (guided bone regeneration), augmentation with autogenous bone, augmentation with bone substitute materials (hydroxyapatite or demineralized freeze-dried bone) or with recombinant human bone morphogenetic protein-2, and a combination of membrane and augmentation procedures. While all described methods resulted in acceptable bone gain, it seems to be difficult to achieve new osseointegration (reosseointegration) of treated implants. Of all tested treatment methods, the combination of guided bone regeneration and augmentation with demineralized freeze-dried bone resulted in the most favorable results regarding bone gain and reosseointegration.

Animals↗
PubMed2005

Visualization methods for statistical analysis of microarray clusters.

BACKGROUND: The most common method of identifying groups of functionally related genes in microarray data is to apply a clustering algorithm. However, it is impossible to determine which clustering algorithm is most appropriate to apply, and it is difficult to verify the results of any algorithm due to the lack of a gold-standard. Appropriate data visualization tools can aid this analysis process, but existing visualization methods do not specifically address this issue. RESULTS: We present several visualization techniques that incorporate meaningful statistics that are noise-robust for the purpose of analyzing the results of clustering algorithms on microarray data. This includes a rank-based visualization method that is more robust to noise, a difference display method to aid assessments of cluster quality and detection of outliers, and a projection of high dimensional data into a three dimensional space in order to examine relationships between clusters. Our methods are interactive and are dynamically linked together for comprehensive analysis. Further, our approach applies to both protein and gene expression microarrays, and our architecture is scalable for use on both desktop/laptop screens and large-scale display devices. This methodology is implemented in GeneVAnD (Genomic Visual ANalysis of Datasets) and is available at http://function.princeton.edu/GeneVAnD. CONCLUSION: Incorporating relevant statistical information into data visualizations is key for analysis of large biological datasets, particularly because of high levels of noise and the lack of a gold-standard for comparisons. We developed several new visualization techniques and demonstrated their effectiveness for evaluating cluster quality and relationships between clusters.

Algorithms↗
PubMed2005

Automatic assignment of biomedical categories: toward a generic approach.

MOTIVATION: We report on the development of a generic text categorization system designed to automatically assign biomedical categories to any input text. Unlike usual automatic text categorization systems, which rely on data-intensive models extracted from large sets of training data, our categorizer is largely data-independent. METHODS: In order to evaluate the robustness of our approach we test the system on two different biomedical terminologies: the Medical Subject Headings (MeSH) and the Gene Ontology (GO). Our lightweight categorizer, based on two ranking modules, combines a pattern matcher and a vector space retrieval engine, and uses both stems and linguistically-motivated indexing units. RESULTS AND CONCLUSION: Results show the effectiveness of phrase indexing for both GO and MeSH categorization, but we observe the categorization power of the tool depends on the controlled vocabulary: precision at high ranks ranges from above 90% for MeSH to <20% for GO, establishing a new baseline for categorizers based on retrieval methods.

Abstracting and Indexing↗
PubMed1996

The sodium-hydrogen exchange system in the heart: its role in ischemic and reperfusion injury and therapeutic implications.

OBJECTIVES: To review evidence supporting a role for sodium-hydrogen exchange (Na/H exchange) in mediating myocardial ischemic and reperfusion injury, and to outline clinical implications in terms of the development of novel cardioprotection strategies. DATA SOURCES: Various sources were used including MEDLINE and Reference Update. Only articles written in the English language were used. DATA EXTRACTION: A wide range of publications dealing with cardiac injury and particularly studies involving intracellular pH regulation and Na/H exchange activity. The vast majority of papers cited were published since 1986, with a large percentage appearing within the past five years. DATA SYNTHESIS: Na/H exchange is a major mechanism for restoration of intracellular pH after ischemia, although its activation during both ischemia and reperfusion has been shown to be involved in a paradoxical induction of cell injury. This likely reflects the fact that activation of the exchanger is closely coupled to sodium influx and, as a consequence, to elevation in intracellular calcium concentrations through sodium-calcium exchange. In addition to intracellular acidosis, other factors can stimulate the exchanger, including various autocrine and paracrine factors such as endothelin-1 and activation of alpha 1 adrenergic receptors, both of which likely act through signal transduction processes including activation of protein kinase C. Although at least 5 Na/H exchange isoforms have been identified, it appears that subtype 1, termed NHE-1, is the predominant isoform in the mammalian myocardium. Effective pharmacological inhibitors of Na/H exchange, including those that are NHE-1 specific, have been developed. These have been extensively demonstrated to protect the ischemic and reperfused myocardium, as shown by improved systolic and diastolic function, preservation of cellular ultrastructure and reduced incidence of arrhythmias. Moreover, the salutary effects of these agents have been demonstrated by a variety of experimental models and animal species, suggesting that the role of Na/H exchange in mediating injury is not species-specific. CONCLUSION: Na/H exchange is an important target for pharmacological intervention in attenuation of ischemia- and reperfusion-induced cardiac injury. Coupled with the low potential for toxicity by the agents, Na/H exchange inhibition could emerge as an effective therapeutic strategy in cardiac disorders, particularly involving conditions associated with ischemia and reperfusion.

Animals↗
PubMed2006

Mouse models of 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is caused by an interstitial chromosomal microdeletion that encompasses about 40 genes. It is the most common of the microdeletion syndromes. The clinical phenotype, which is complex and variable, includes specific congenital defects of the cardiovascular system, craniofacies, and immune system. In early childhood, patients manifest cognitive impairment, behavioral disorders, and delays in motor development and language acquisition. Adult patients have a high risk for developing serious psychiatric disorders, especially schizophrenia, schizoaffective disorder, and bipolar disorder. The great majority of patients have an identical or near identical chromosomal deletion, and genotype-phenotype correlations have not been established. Indeed, little progress was made toward resolving the complex clinical phenotype until the deletion was successfully modeled in the mouse. In recent years, through a variety of mouse mutants that carry multigene and single gene mutations, we have learned that mutation in a single gene, Tbx1, is responsible for most of the congenital defects seen in the mouse models and in patients. We now face a greater challenge as we attempt to use the mouse to address the pathogenesis of the behavioral and psychiatric disorders associated with 22q11DS. Significant progress has already been made, and recent studies in the mouse suggest that several genes from the deleted region affect behavior and might contribute to disease burden in patients.

Animals↗
PubMed2004

The HUPO PSI's molecular interaction format--a community standard for the representation of protein interaction data.

A major goal of proteomics is the complete description of the protein interaction network underlying cell physiology. A large number of small scale and, more recently, large-scale experiments have contributed to expanding our understanding of the nature of the interaction network. However, the necessary data integration across experiments is currently hampered by the fragmentation of publicly available protein interaction data, which exists in different formats in databases, on authors' websites or sometimes only in print publications. Here, we propose a community standard data model for the representation and exchange of protein interaction data. This data model has been jointly developed by members of the Proteomics Standards Initiative (PSI), a work group of the Human Proteome Organization (HUPO), and is supported by major protein interaction data providers, in particular the Biomolecular Interaction Network Database (BIND), Cellzome (Heidelberg, Germany), the Database of Interacting Proteins (DIP), Dana Farber Cancer Institute (Boston, MA, USA), the Human Protein Reference Database (HPRD), Hybrigenics (Paris, France), the European Bioinformatics Institute's (EMBL-EBI, Hinxton, UK) IntAct, the Molecular Interactions (MINT, Rome, Italy) database, the Protein-Protein Interaction Database (PPID, Edinburgh, UK) and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING, EMBL, Heidelberg, Germany).

Database Management Systems↗
PubMed1998

Approaches to the automatic discovery of patterns in biosequences.

This paper surveys approaches to the discovery of patterns in biosequences and places these approaches within a formal framework that systematises the types of patterns and the discovery algorithms. Patterns with expressive power in the class of regular languages are considered, and a classification of pattern languages in this class is developed, covering the patterns that are the most frequently used in molecular bioinformatics. A formulation is given of the problem of the automatic discovery of such patterns from a set of sequences, and an analysis is presented of the ways in which an assessment can be made of the significance of the discovered patterns. It is shown that the problem is related to problems studied in the field of machine learning. The major part of this paper comprises a review of a number of existing methods developed to solve the problem and how these relate to each other, focusing on the algorithms underlying the approaches. A comparison is given of the algorithms, and examples are given of patterns that have been discovered using the different methods.

Algorithms↗
PubMed2004

Inferring pathways from gene lists using a literature-derived network of biological relationships.

MOTIVATION: A number of omic technologies such as transcriptional profiling, proteomics, literature searches, genetic association, etc. help in the identification of sets of important genes. A subset of these genes may act in a coordinated manner, possibly because they are part of the same biological pathway. Interpreting such gene lists and relating them to pathways is a challenging task. Databases of biological relationships between thousands of mammalian genes can help in deciphering omics data. The relationships between genes can be assembled into a biological network with each protein as a node and each relationship as an edge between two proteins (or nodes). This network may then be searched for subnetworks consisting largely of interesting genes from the omics experiment. The subset of genes in the subnetwork along with the web of relationships between them helps to decipher the underlying pathways. Finding such subnetworks that maximally include all proteins from the query set but few others is the focus for this paper. RESULTS: We present a heuristic algorithm and a scoring function that work well both on simulated data and on data from known pathways. The scoring function is an extension of a previous study for a single biological experiment. We use a simple set of heuristics that provide a more efficient solution than the simulated annealing method. We find that our method works on reasonably complex curated networks containing approximately 9000 biological entities (genes and metabolites), and approximately 30,000 biological relationships. We also show that our method can pick up a pathway signal from a query list including a moderate number of genes unrelated to the pathway. In addition, we quantify the sensitivity and specificity of the technique.

Algorithms↗
PubMed2004

Bio-steps beyond Turing.

Are there 'biologically computing agents' capable to compute Turing uncomputable functions? It is perhaps tempting to dismiss this question with a negative answer. Quite the opposite, for the first time in the literature on molecular computing we contend that the answer is not theoretically negative. Our results will be formulated in the language of membrane computing (P systems). Some mathematical results presented here are interesting in themselves. In contrast with most speed-up methods which are based on non-determinism, our results rest upon some universality results proved for deterministic P systems. These results will be used for building "accelerated P systems". In contrast with the case of Turing machines, acceleration is a part of the hardware (not a quality of the environment) and it is realised either by decreasing the size of "reactors" or by speeding-up the communication channels. Consequently, two acceleration postulates of biological inspiration are introduced; each of them poses specific questions to biology. Finally, in a more speculative part of the paper, we will deal with Turing non-computability activity of the brain and possible forms of (extraterrestrial) intelligence.

Cell Membrane↗
PubMed2001

Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease.

The question of whether any non-human species displays episodic memory is controversial. Associative accounts of animal learning recognize that behaviour can change in response to single events but this does not imply that animals need or are later able to recall representations of unique events at a different time and place. The lack of language is also relevant, being the usual medium for communicating about the world, but whether it is critical for the capacity to represent and recall events is a separate matter. One reason for suspecting that certain animals possess an episodic-like memory system is that a variety of learning and memory tasks have been developed that, even though they do not meet the strict criteria required for episodic memory, have an 'episodic-like' character. These include certain one-trial learning tasks, scene-specific discrimination learning, multiple reversal learning, delayed matching and non-matching tasks and, most recently, tasks demanding recollection of 'what, where and when' an event happened. Another reason is that the neuronal architecture of brain areas thought to be involved in episodic memory (including the hippocampal formation) are substantially similar in mammals and, arguably, all vertebrates. Third, our developing understanding of activity-dependent synaptic plasticity (which is a candidate neuronal mechanism for encoding memory traces) suggests that its expression reflects certain physiological characteristics that are ideal components of a neuronal episodic memory system. These include the apparently digital character of synaptic change at individual terminals and the variable persistence of potentiation accounted for by the synaptic tag hypothesis. A further value of studying episodic-like memory in animals is the opportunity it affords to model certain kinds of neurodegenerative disease that, in humans, affect episodic memory. An example is recent work on a transgenic mouse that over-expresses a mutation of human amyloid precursor protein (APP) that occurs in familial Alzheimer's disease, under the control of platelet derived (PD) growth factor promoter (the PDAPP mouse). A striking age- and amyloid plaque-related deficit is seen using a task in which the mice have to keep changing their memory representation of the world rather than learn a single fact.

Alzheimer Disease↗
PubMed2005

Sex differences in the myocardial inflammatory response to acute injury.

Hemorrhage, trauma, ischemia/reperfusion, burn, and sepsis each lead to cardiac dysfunction. These insults lead to an inflammatory cascade, which plays an important role in this process. Gender has been shown to influence the inflammatory response, as well as outcomes after acute injury. The mechanisms by which gender affects the inflammatory response to and the outcome of acute injury are being actively investigated. We searched PubMed for articles in the English language by using the search words sex, gender, estrogen, testosterone, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, and elucidate the various mechanisms by which gender affects the myocardial response to acute injury.

Adenosine Triphosphate↗
PubMed2006

MASCOT HTML and XML parser: an implementation of a novel object model for protein identification data.

Protein identification using MS is an important technique in proteomics as well as a major generator of proteomics data. We have designed the protein identification data object model (PDOM) and developed a parser based on this model to facilitate the analysis and storage of these data. The parser works with HTML or XML files saved or exported from MASCOT MS/MS ions search in peptide summary report or MASCOT PMF search in protein summary report. The program creates PDOM objects, eliminates redundancy in the input file, and has the capability to output any PDOM object to a relational database. This program facilitates additional analysis of MASCOT search results and aids the storage of protein identification information. The implementation is extensible and can serve as a template to develop parsers for other search engines. The parser can be used as a stand-alone application or can be driven by other Java programs. It is currently being used as the front end for a system that loads HTML and XML result files of MASCOT searches into a relational database. The source code is freely available at http://www.ccbm.jhu.edu and the program uses only free and open-source Java libraries.

Databases, Protein↗
PubMed2001

Malignant melanoma.

CONTEXT: The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches. OBJECTIVES: To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches. METHODS: Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center. RESULTS: Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches. CONCLUSIONS: (1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.

Chromosome Aberrations↗
PubMed2006

Cognitive deficits in familial Alzheimer's disease associated with M239V mutation of presenilin 2.

The neuropsychological assessment of non-demented subjects with gene mutation of familial Alzheimer's disease (AD) provides a model for exploring the early cognitive features of the disease. We evaluated 1 patient and 6 non-demented subjects belonging to a family with AD with M239V mutation of the presenilin 2 gene, aiming to verify the contribution of specific cognitive patterns to the characterization of familial AD. One patient, 3 non-demented subjects with M239V mutation and 3 subjects without mutation from the same family underwent neuropsychological testing. The patient's cognitive profile was characterized by anosognosia, visuospatial agnosia, apraxia and fluent aphasia. Of the 3 non-demented subjects with mutation, 1 showed no deficits, another constructive apraxia and the third spatial perception and memory deficits. The 3 subjects without mutation showed normal abilities. The cognitive deficits of the non-demented subjects with mutations indicate focal dysfunction of the posterior cortical areas, resembling the more extended parieto-occipito-temporal dysfunction of the demented patient. Such grading of visuospatial, praxis, and language impairments highlights a distinctive pattern related to the M239V mutation of the presenilin 2 gene.

Aged↗