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PubMed2000

The new architectonics: an invitation to structural biology.

The philosophy of art might offer an epistemological basis for talking about the complexity of biological molecules in a meaningful way. The analysis of artistic compositions requires the resolution of intrinsic tensions between disparate sensory categories-color, line and form-not unlike those encountered in looking at the surfaces of protein molecules, where charge, polarity, hydrophobicity, and shape compete for our attentions. Complex living systems exhibit behaviors such as contraction waves moving along muscle fibers, or shivers passing through the growth cones of migrating neurons, that are easy to describe with common words, but difficult to explain in terms of the language of chemistry. The problem follows from a lack of everyday experience with processes that move towards equilibrium by switching between crystalline order and chain-like disorder, a commonplace occurrence in the submicroscopic world of proteins. Since most of what is understood about protein function comes from studies of isolated macromolecules in solution, a serious gap exists between what we know and what we would like to know about organized biological systems. Closing this gap can be achieved by recognizing that protein molecules reside in gradients of Gibbs free energy, where local forces and movements can be large compared with Brownian motion. Architectonics, a term borrowed from the philosophical literature, symbolizes the eventual union of the structure of theories-how our minds construct the world-with the theory of structures-or how stability is maintained in the chaotic world of microsystems.

History, 20th Century↗

PubMed2006

ArrayCluster: an analytic tool for clustering, data visualization and module finder on gene expression profiles.

SUMMARY: One of the significant challenges in gene expression analysis is to find unknown subtypes of several diseases at the molecular levels. This task can be addressed by grouping gene expression patterns of the collected samples on the basis of a large number of genes. Application of commonly used clustering methods to such a dataset however are likely to fail owing to over-learning, because the number of samples to be grouped is much smaller than the data dimension which is equal to the number of genes involved in the dataset. To overcome such difficulty, we developed a novel model-based clustering method, referred to as the mixed factors analysis. The ArrayCluster is a freely available software to perform the mixed factors analysis. It provides us some analytic tools for clustering DNA microarray experiments, data visualization and an automatic detector for module transcriptional of genes that are relevant to the calibrated molecular subtypes and so on.

Bayes Theorem↗

PubMed2004

Automatic parsing of parental verbal input.

To evaluate theoretical proposals regarding the course of child language acquisition, researchers often need to rely on the processing of large numbers of syntactically parsed utterances, both from children and from their parents. Because it is so difficult to do this by hand, there are currently no parsed corpora of child language input data. To automate this process, we developed a system that combined the MOR tagger, a rule-based parser, and statistical disambiguation techniques. The resultant system obtained nearly 80% correct parses for the sentences spoken to children. To achieve this level, we had to construct a particular processing sequence that minimizes problems caused by the coverage/ambiguity tradeoff in parser design. These procedures are particularly appropriate for use with the CHILDES database, an international corpus of transcripts. The data and programs are now freely available over the Internet.

Adult↗

PubMed2005

A new empirical angle on the variability debate: quantitative neurosyntactic analyses of a large data set from Broca's aphasia.

Behavioral variation in Broca's aphasia has been characterized as boundless, calling into question the validity of the syndrome-based schema and related diagnostic methods of acquired language disorders. More generally, this putative variability has cast serious doubts on the feasibility of localizing linguistic operations in cortex. We present a new approach to the quantitative analysis of deficient linguistic performance, and apply it to a large data set, constructed from the published literature: Comprehension data of 69 carefully selected Broca's aphasic patients, tested on nearly 6000 stimulus sentences, were partitioned in different ways, and subjected to a series of analyses. While a certain amount of variability is indeed evident in the data, our quantitative analyses reveal a highly robust selective impairment pattern for the group: the patients' ability to analyze syntactic movement is severely compromised, in line with the Trace-Deletion Hypothesis. Further analyses suggest that patients' performance on no-movement sentence types exhibits less variation than on sentences that contain movement. We discuss the clinical and theoretical implications of our results.

Aphasia, Broca↗

PubMed2006

Learning phonetic categories by tracking movements.

We explore in this study how infants may derive phonetic categories from adult input that are highly variable. Neural networks in the form of self-organizing maps (SOMs; ) were used to simulate unsupervised learning of Mandarin tones. In Simulation 1, we trained the SOMs with syllable-sized continuous F(0) contours, produced by multiple speakers in connected speech, and with the corresponding velocity profiles (D1). No attempt was made to reduce the large amount of variability in the input or to add to the input any abstract features such as height and slope of the F(0) contours. In the testing phase, reasonably high categorization rate was achieved with F(0) profiles, but D1 profiles yielded almost perfect categorization of the four tones. Close inspection of the learned prototypical D1 profile clusters revealed that they had effectively eliminated surface variability and directly reflected articulatory movements toward the underlying targets of the four tones as proposed by . Additional simulations indicated that a further learning step was possible through which D1 prototypes with one-to-one correspondence to the tones were derived from the prototype clusters learned in Simulation 1. Implications of these findings for theories of language acquisition, speech perception and speech production are discussed.

Humans↗

PubMed2003

Evolutionary algorithms for the selection of single nucleotide polymorphisms.

BACKGROUND: Large databases of single nucleotide polymorphisms (SNPs) are available for use in genomics studies. Typically, investigators must choose a subset of SNPs from these databases to employ in their studies. The choice of subset is influenced by many factors, including estimated or known reliability of the SNP, biochemical factors, intellectual property, cost, and effectiveness of the subset for mapping genes or identifying disease loci. We present an evolutionary algorithm for multiobjective SNP selection. RESULTS: We implemented a modified version of the Strength-Pareto Evolutionary Algorithm (SPEA2) in Java. Our implementation, Multiobjective Analyzer for Genetic Marker Acquisition (MAGMA), approximates the set of optimal trade-off solutions for large problems in minutes. This set is very useful for the design of large studies, including those oriented towards disease identification, genetic mapping, population studies, and haplotype-block elucidation. CONCLUSION: Evolutionary algorithms are particularly suited for optimization problems that involve multiple objectives and a complex search space on which exact methods such as exhaustive enumeration cannot be applied. They provide flexibility with respect to the problem formulation if a problem description evolves or changes. Results are produced as a trade-off front, allowing the user to make informed decisions when prioritizing factors. MAGMA is open source and available at http://snp-magma.sourceforge.net. Evolutionary algorithms are well suited for many other applications in genomics.

Algorithms↗

PubMed2005

OntoDiagram: automatic diagram generation for congenital heart defects in pediatric cardiology.

In pediatric cardiology as well as many other medical specialties, the accurate portrayal of a large volume of patient information is crucial to providing good patient care. Our research aims at utilizing clinical and spatial ontologies representing the human heart, to automatically generate a Mullins-like diagram based on a patient's information in the cardiology databases. Our ontology allows an intuitive way of modeling congenital defects with the structure of the human heart. A prototype system has been implemented using Protege and the Java Advanced Imaging package , and is currently under testing at the Children's Mercy Hospitals and Clinics. A pilot study showed the diagrammatical representation and characterization of congenital heart defects can be used to facilitate a better understanding of a complex congenital heart defects.

Anatomy, Cross-Sectional↗

PubMed1986

Neural dynamics of speech and language coding: developmental programs, perceptual grouping, and competition for short-term memory.

A computational theory of how an observer parses a speech stream into context-sensitive language representations is described. It is shown how temporal lists of events can be chunked into unitized representations, how perceptual groupings of past item sublists can be reorganized due to information carried by newly occurring items, and how item information and temporal order information are bound together into context-sensitive codes. These language units are emergent properties due to intercellular interactions among large numbers of nerve cells. The controlling neural networks can arise through simple rules of neuronal development: random growth of connections along spatial gradients, activity-dependent self-similar cell growth, and competition for conserved synaptic sites. Within these networks, a spatial frequency analysis of temporally evolving activity patterns leads to competitive masking of inappropriate list encodings in short term memory. The neurons obey membrane equations undergoing shunting recurrent on-center off-surround interactions. Several design principles are embodied by the networks, such as the sequence masking principle, the long-term memory invariance principle, and the principle of self-similar growth.

Auditory Pathways↗

PubMed2026

Fractional laser therapy versus microneedling for non-acne scars and scar-like dermal fibrotic lesions.

BACKGROUND: Scarring caused by trauma, burns, surgery, and other dermal fibrotic conditions can lead to functional limitation and cosmetic distress. The comparative effectiveness of fractional laser therapy and microneedling for non-acne scars remains uncertain. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing fractional laser therapy with microneedling for non-acne scars and scar-like dermal fibrotic lesions. Following a PROSPERO-registered protocol and PRISMA guidelines, we searched PubMed, EMBASE, Web of Science, Cochrane Library, and CNKI from inception to May 2026 without language restrictions. Parallel-group and split-body randomized trials were eligible. Random-effects models were used to calculate standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes. RESULTS: Nine randomized controlled trials were included. Fractional laser therapy showed a statistically significant advantage over microneedling in scar scores (SMD = -0.99, 95% CI [-1.83, -0.15], P = 0.02) and collagen fiber regeneration (SMD = -2.14, 95% CI [-3.57, -0.72], P = 0.03). No statistically significant differences were found between the two interventions for elastic fiber improvement, epidermal thickness, or adverse events. Subgroup analyses did not show clear or consistent significant differences according to laser type, including comparisons between traditional and non-traditional fractional lasers and between CO₂ and non-CO₂ fractional laser systems. Substantial heterogeneity was observed across several outcomes, indicating considerable between-study variability. CONCLUSION: Based on currently available randomized evidence, fractional laser therapy may provide superior improvement in overall scar severity and collagen fiber regeneration compared with microneedling for non-acne scars and scar-like dermal fibrotic lesions. However, no clear differences were observed for elastic fiber improvement, epidermal thickness, or adverse-event incidence. Given the substantial heterogeneity, limited sample sizes, and possible reporting bias, these findings should be interpreted cautiously. Further large, standardized trials with longer follow-up are needed.

Humans↗

PubMed2003

Precaution, uncertainty and causation in environmental decisions.

What measures of uncertainty and what causal analysis can improve the management of potentially severe, irreversible or dreaded environmental outcomes? Environmental choices show that policies intended to be precautionary (such as adding MTBE to petrol) can cause unanticipated harm (by mobilizing benzene, a known leukemogen, in the ground water). Many environmental law principles set the boundaries of what should be done but do not provide an operational construct to answer this question. Those principles, ranging from the precautionary principle to protecting human health from a significant risk of material health impairment, do not explain how to make environmental management choices when incomplete, inconsistent and complex scientific evidence characterizes potentially adverse environmental outcomes. Rather, they pass the task to lower jurisdictions such as agencies or authorities. To achieve the goals of the principle, those who draft it must deal with scientific casual conjectures, partial knowledge and variable data. In this paper we specifically deal with the qualitative and quantitative aspects of the European Union's (EU) explanation of consistency and on the examination of scientific developments relevant to variability and uncertain data and causation. Managing hazards under the precautionary principle requires inductive, empirical methods of assessment. However, acting on a scientific conjecture can also be socially unfair, costly, and detrimental when applied to complex environmental choices. We describe a constructive framework rationally to meet the command of the precautionary principle using alternative measures of uncertainty and recent statistical methods of causal analysis. These measures and methods can bridge the gap between conjectured future irreversible or severe harm and scant scientific evidence, thus leading to more confident and resilient social choices. We review two sets of measures and computational systems to deal with uncertainty and link them to causation through inductive empirical methods such as Bayesian Networks. We conclude that primary legislation concerned with large uncertainties and potential severe or dreaded environmental outcomes can produce accurate and efficient choices. To do so, primary legislation should specifically indicate what measures can represent uncertainty and how to deal with uncertain causation thus providing guidance to an agency's rulemaking or to an authority's writing secondary legislation. A corollary conclusion with legal, scientific and probabilistic implications concerns how to update past information when the state of information increases because a failure to update can result in regretting past choices. Elected legislators have the democratic mandate to formulate precautionary principles and are accountable. To preserve that mandate, imbedding formal methods to represent uncertainty in the statutory language of the precautionary principle enhances subsequent judicial review of legislative actions. The framework that we propose also reduces the Balkanized views and interpretations of probabilities, possibilities, likelihood and uncertainty that exists in environmental decision-making.

Bayes Theorem↗

PubMed2005

Naming our concerns about neuroscience: a review of Bennett and Hacker's philosophical foundations of neuroscience.

Bennett and Hacker use conceptual analysis to appraise the theoretical language of modern cognitive neuroscientists, and conclude that neuroscientific theory is largely dualistic despite the fact that neuroscientists equate mind with the operations of the brain. The central error of cognitive neuroscientists is to commit the mereological fallacy, the tendency to ascribe to the brain psychological concepts that only make sense when ascribed to whole animals. The authors review how the mereological fallacy is committed in theories of memory, perception, thinking, imagery, belief, consciousness, and other psychological processes studied by neuroscientists, and the consequences that fallacious reasoning have for our understanding of how the brain participates in cognition and behavior. Several behavior-analytic concepts may themselves be nonsense based on thorough conceptual analyses in which the criteria for sense and nonsense are found in the ways the concepts are used in ordinary language. Nevertheless, the authors' nondualistic approach and their consistent focus on behavioral criteria for the application of psychological concepts make Philosophical Foundations of Neuroscience an important contribution to cognitive neuroscience.

Animals↗

PubMed2007

FLAME, a novel fuzzy clustering method for the analysis of DNA microarray data.

BACKGROUND: Data clustering analysis has been extensively applied to extract information from gene expression profiles obtained with DNA microarrays. To this aim, existing clustering approaches, mainly developed in computer science, have been adapted to microarray data analysis. However, previous studies revealed that microarray datasets have very diverse structures, some of which may not be correctly captured by current clustering methods. We therefore approached the problem from a new starting point, and developed a clustering algorithm designed to capture dataset-specific structures at the beginning of the process. RESULTS: The clustering algorithm is named Fuzzy clustering by Local Approximation of MEmbership (FLAME). Distinctive elements of FLAME are: (i) definition of the neighborhood of each object (gene or sample) and identification of objects with "archetypal" features named Cluster Supporting Objects, around which to construct the clusters; (ii) assignment to each object of a fuzzy membership vector approximated from the memberships of its neighboring objects, by an iterative converging process in which membership spreads from the Cluster Supporting Objects through their neighbors. Comparative analysis with K-means, hierarchical, fuzzy C-means and fuzzy self-organizing maps (SOM) showed that data partitions generated by FLAME are not superimposable to those of other methods and, although different types of datasets are better partitioned by different algorithms, FLAME displays the best overall performance. FLAME is implemented, together with all the above-mentioned algorithms, in a C++ software with graphical interface for Linux and Windows, capable of handling very large datasets, named Gene Expression Data Analysis Studio (GEDAS), freely available under GNU General Public License. CONCLUSION: The FLAME algorithm has intrinsic advantages, such as the ability to capture non-linear relationships and non-globular clusters, the automated definition of the number of clusters, and the identification of cluster outliers, i.e. genes that are not assigned to any cluster. As a result, clusters are more internally homogeneous and more diverse from each other, and provide better partitioning of biological functions. The clustering algorithm can be easily extended to applications different from gene expression analysis.

Algorithms↗

PubMed1998

Cognitive substrates of thought disorder, I: the semantic system.

OBJECTIVE: Few studies have explored in detail the relation of cognitive deficits in attention, working memory, and semantics to thought disorder. The authors sought to determine whether thought disorder resides in the semantic system or elsewhere. METHOD: Twenty-three normal comparison subjects and 23 patients with schizophrenia participated in the study. All subjects received tests of executive function and working memory, including the Wisconsin Card Sorting Test and the Letter-Number Span test; a test of deployment of attentional resources; and tests of semantic processing and language comprehension, including the Peabody Picture Vocabulary Test, the Speed and Capacity of Language-Processing Test, the Boston Naming Test, and tests of semantic verbal fluency and phonologic verbal fluency, from which was derived a difference score. All patients were also administered the Scale for the Assessment of Thought, Language, and Communication to assess thought disorder. RESULTS: The normal subjects were compared with the schizophrenic patients who were rated as having mild thought disorder (N=13) or moderate to severe thought disorder (N=10). While differences between the schizophrenic subgroups and the comparison subjects were observed on nearly all tests, a large difference in effect size between the two schizophrenic subgroups was apparent only in the verbal fluency difference score. In a series of multiple regression analyses, two variables made significant contributions to the prediction of positive thought disorder: the verbal fluency difference score and the Peabody Picture Vocabulary Test score. CONCLUSIONS: These results suggest that clinically rated thought disorder is associated with and may result from semantic processing abnormalities. In particular, patients with more severe thought disorder may have difficulty accessing semantic items because of disorganization of the semantic systems and, to a more limited degree, may also lack a semantic or conceptual knowledge base.

Adult↗

PubMed2006

PDA: Pooled DNA analyzer.

BACKGROUND: Association mapping using abundant single nucleotide polymorphisms is a powerful tool for identifying disease susceptibility genes for complex traits and exploring possible genetic diversity. Genotyping large numbers of SNPs individually is performed routinely but is cost prohibitive for large-scale genetic studies. DNA pooling is a reliable and cost-saving alternative genotyping method. However, no software has been developed for complete pooled-DNA analyses, including data standardization, allele frequency estimation, and single/multipoint DNA pooling association tests. This motivated the development of the software, 'PDA' (Pooled DNA Analyzer), to analyze pooled DNA data. RESULTS: We develop the software, PDA, for the analysis of pooled-DNA data. PDA is originally implemented with the MATLAB language, but it can also be executed on a Windows system without installing the MATLAB. PDA provides estimates of the coefficient of preferential amplification and allele frequency. PDA considers an extended single-point association test, which can compare allele frequencies between two DNA pools constructed under different experimental conditions. Moreover, PDA also provides novel chromosome-wide multipoint association tests based on p-value combinations and a sliding-window concept. This new multipoint testing procedure overcomes a computational bottleneck of conventional haplotype-oriented multipoint methods in DNA pooling analyses and can handle data sets having a large pool size and/or large numbers of polymorphic markers. All of the PDA functions are illustrated in the four bona fide examples. CONCLUSION: PDA is simple to operate and does not require that users have a strong statistical background. The software is available at http://www.ibms.sinica.edu.tw/%7Ecsjfann/first%20flow/pda.htm.

Algorithms↗

PubMed2003

The relationship between the characteristics of speech and velopharyngeal gap size.

OBJECTIVE: The purpose of this study was to examine the relationship between perceptual characteristics of hypernasality, nasal emission and nasal rustle, and size of the velopharyngeal gap. DESIGN: A retrospective medical chart review. SETTING: Cincinnati Children's Hospital Medical Center. SUBJECTS: Subjects were patients of the Craniofacial Anomaly Team. All were between ages 3 and 12 years and diagnosed with velopharyngeal dysfunction secondary to cleft palate +/- cleft lip. A total of 173 charts were reviewed. OUTCOME MEASURES: Speech characteristics were assessed perceptually by an experienced speech-language pathologist. Following that assessment, velopharyngeal closure was evaluated using videofluoroscopy, nasopharyngoscopy, or both. RESULTS: Based on the perceptual ratings alone, 21 subjects were diagnosed with nasal rustle only, 27 had hypernasality with nasal rustle, 89 had hypernasality with nasal emission without nasal rustle, and 36 had hypernasality with no audible nasal emission. An ordinal logit regression was conducted and showed that moderate and severe hypernasality contributed significantly to the prediction of a large gap size; nasal rustle contributed significantly to prediction of a small gap size. Perceptual characteristics of speech correctly predicted gap size for 121 of the 173 subjects (70%). CONCLUSIONS: This investigation revealed that some information regarding velopharyngeal gap size may be predicted from the speech assessment alone. Confidence in the prediction is strongest if the patient has nasal rustle, suggesting a small gap, or if the patient has moderate to severe hypernasality, which is more commonly associated with a large opening.

Child↗

PubMed2006

Font tuning associated with expertise in letter perception.

Font tuning (FT) occurs when observers recognize a sequence of letters presented in the same font faster than in different fonts (Sanocki 1987, 1988 Journal of Experimental Psychology. Human Perception and Performance 13 267-278; 14 472-480). Here, we test the hypothesis that FT is associated with expertise with a specific writing system. We developed a systematic search task allowing the measurement of FT over a large number of letters and generalized the finding of FT from English readers viewing Roman letters to Chinese readers viewing Chinese characters. Non-Chinese readers did not show evidence of FT for Chinese characters in this search task. We also used a simpler 3-letter identification task to directly compare novice and expert readers, and to explore FT for different aspects of font such as fill, slant, and aspect ratio. We found that experts tune to aspect ratio but not to the other font changes. These findings reveal that letters are not processed visually in the same manner as shapes, and suggest an explanation for the cortical specialization obtained in the visual system for letters.

Humans↗

PubMed2003

Bacterial otitis media: current vaccine development strategies.

Otitis media is the most common reason for children less than 5 years of age to visit a medical practitioner. Whilst the disease rarely results in death, there is significant associated morbidity. The most common complication is loss of hearing at a critical stage of the development of speech, language and cognitive abilities in children. The cause and pathogenesis of otitis media is multifactorial. Among the contributing factors, the single most important are viral and bacterial infections. Infection with respiratory syncytial virus, influenza viruses, para-influenza viruses, enteroviruses and adenovirus are most commonly associated with acute and chronic otitis media. Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis are the most commonly isolated bacteria from the middle ears of children with otitis media. Treatment of otitis media has largely relied on the administration of antimicrobials and surgical intervention. However, attention has recently focused on the development of a vaccine. For a vaccine to be effective against bacterial otitis media, it must, at the very least, contain antigens that induce a protective immune response in the middle ear against the three most common infecting bacteria. Whilst over the past decade there has been significant progress in the development of vaccines against invasive S. pneumoniae disease, these vaccines are less efficacious for otitis media. The search for candidate vaccine antigens for non-typeable H. influenzae are well advanced whilst less progress has been made for M. catarrhalis. No human studies have been conducted for non-typeable H. influenzae or M. catarrhalis and the concept of a tribacterial vaccine remains to be tested in animal models. Only when vaccine antigens are determined and an understanding of the immune responses induced in the middle ear by infection and immunization is gained will the formulation of a tribacterial vaccine against otitis media be possible.

Animals↗

PubMed2006

Genetic Parallel Programming: design and implementation.

This paper presents a novel Genetic Parallel Programming (GPP) paradigm for evolving parallel programs running on a Multi-Arithmetic-Logic-Unit (Multi-ALU) Processor (MAP). The MAP is a Multiple Instruction-streams, Multiple Data-streams (MIMD), general-purpose register machine that can be implemented on modern Very Large-Scale Integrated Circuits (VLSIs) in order to evaluate genetic programs at high speed. For human programmers, writing parallel programs is more difficult than writing sequential programs. However, experimental results show that GPP evolves parallel programs with less computational effort than that of their sequential counterparts. It creates a new approach to evolving a feasible problem solution in parallel program form and then serializes it into a sequential program if required. The effectiveness and efficiency of GPP are investigated using a suite of 14 well-studied benchmark problems. Experimental results show that GPP speeds up evolution substantially.

Algorithms↗