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PubMed1999

Analysis of site-specific phosphorylation of the retinoblastoma protein during cell cycle progression.

Differential phosphorylation of the retinoblastoma protein plays a pivotal role in cell cycle regulation. The retinoblastoma protein is specifically phosphorylated during the cell cycle by cyclin-dependent kinase complexes which intersect with many cellular signaling networks. Since the loss of the retinoblastoma signaling pathways occurs in a wide variety of human tumors, understanding the significance of site-specific phosphorylation can clarify the role of selected cyclin-dependent kinase complexes during cell cycle progression. Here we describe the phosphospecificity and cellular characterization of a panel of polyclonal antibodies that recognize unique phosphorylation sites within the retinoblastoma protein. These reagents were used to validate authentic cellular retinoblastoma phosphorylation sites at amino acids 780, 795, and 807/811 correlating with the G1-S transition.

Animals↗

PubMed1993

Localization of ribosomal DNA in Rhagoletis pomonella (Diptera: Tephritidae) by in situ hybridization.

The ribosomal DNA (rDNA) of Rhagoletis pomonella was localized within both salivary gland polytene chromosomes and somatic cell mitotic chromosomes by in situ hybridization using the heterospecific Drosophila melanogaster rDNA clone, Dm238. In situ hybridization analysis of polytene nuclei showed that R. pomonella rDNA is located in the nucleolus and adjacent granular network of chromosome 1. The site of origin of rDNA is within this isomorphic granular network. The preservation of nucleolar ultrastructure in some polytene chromosome preparations allowed light microscope localization of R. pomonella rDNA to the apparent periphery of fibrillar centres within fibrillar complexes. In somatic cell nuclei, DM238 hybridized to the nucleolus organizing region (NOR) located on chromosome 1 at the site of the secondary constriction. The frequency distribution of heteromorphisms for rDNA content, differential appearance of secondary constrictions, non-pairing of the NOR and differences in homologue lengths suggests that the structural differentiation of this region in chromosome 1 is sex linked. This the first published description of the salivary gland polytene chromosomes from R. pomonella, and we include a tentative karyotype description, polytene chromosome maps and comments on their suitability for banding and molecular analysis.

Animals↗

PubMed1997

Probabilistic independence networks for hidden Markov probability models.

Graphical techniques for modeling the dependencies of random variables have been explored in a variety of different areas, including statistics, statistical physics, artificial intelligence, speech recognition, image processing, and genetics. Formalisms for manipulating these models have been developed relatively independently in these research communities. In this paper we explore hidden Markov models (HMMs) and related structures within the general framework of probabilistic independence networks (PINs). The paper presents a self-contained review of the basic principles of PINs. It is shown that the well-known forward-backward (F-B) and Viterbi algorithms for HMMs are special cases of more general inference algorithms for arbitrary PINs. Furthermore, the existence of inference and estimation algorithms for more general graphical models provides a set of analysis tools for HMM practitioners who wish to explore a richer class of HMM structures. Examples of relatively complex models to handle sensor fusion and coarticulation in speech recognition are introduced and treated within the graphical model framework to illustrate the advantages of the general approach.

Algorithms↗

PubMed1995

Artificial neural networks for decision support in clinical medicine.

Connectionist models such as neural networks are alternatives to linear, parametric statistical methods. Neural networks are computer-based pattern recognition methods with loose similarities with the nervous system. Individual variables of the network, usually called 'neurones', can receive inhibitory and excitatory inputs from other neurones. The networks can define relationships among input data that are not apparent when using other approaches, and they can use these relationships to improve accuracy. Thus, neural nets have substantial power to recognize patterns even in complex datasets. Neural network methodology has outperformed classical statistical methods in cases where the input variables are interrelated. Because clinical measurements usually derive from multiple interrelated systems it is evident that neural networks might be more accurate than classical methods in multivariate analysis of clinical data. This paper reviews the use of neural networks in medical decision support. A short introduction to the basics of neural networks is given, and some practical issues in applying the networks are highlighted. The current use of neural networks in image analysis, signal processing and laboratory medicine is reviewed. It is concluded that neural networks have an important role in image analysis and in signal processing. However, further studies are needed to determine the value of neural networks in the analysis of laboratory data.

Clinical Medicine↗

PubMed1998

Feed forward neural networks for the analysis of censored survival data: a partial logistic regression approach.

Flexible modelling in survival analysis can be useful both for exploratory and predictive purposes. Feed forward neural networks were recently considered for flexible non-linear modelling of censored survival data through the generalization of both discrete and continuous time models. We show that by treating the time interval as an input variable in a standard feed forward network with logistic activation and entropy error function, it is possible to estimate smoothed discrete hazards as conditional probabilities of failure. We considered an easily implementable approach with a fast selection criteria of the best configurations. Examples on data sets from two clinical trials are provided. The proposed artificial neural network (ANN) approach can be applied for the estimation of the functional relationships between covariates and time in survival data to improve model predictivity in the presence of complex prognostic relationships.

Clinical Trials as Topic↗

PubMed1978

The Slovak-American "swaddling ethos": homeostat for family dynamics and cultural continuity.

This paper explores the systemic relationships among cultural ethos, family dynamics, personality configuration, and child-rearing patterns among multigeneration Slovak-Americans. The "swaddling ethos" is posited to serve as a homeostat whose regulatory function can be discerned through the analysis of family structure and process, in particular through the explication of values, affective patterns, roles, boundaries, and structural units within the family. The core of the ethos is a dependency-security complex that attaches the individual to an extended family network of obligation, indebtedness, and reciprocity (ethnic, Slovak); induces rebellion against such attachment (mainstream American); and undermines efforts toward separation-individuation, resulting in the perpetuation of an ethnic tradition.

Attitude↗

PubMed1993

Application of artificial neural networks for reduction of false-positive detections in digital chest radiographs.

A methodology based on the fuzzy set theory and the convolution neural network (CNN) architecture is proposed to tackle the problem of reducing false-positive rate in automatic lung nodule detection. The CNN which simulates human visual mechanism was trained by a supervised back-propagation algorithm based on fuzzy membership functions. The training and testing database consists of image blocks (each 32 x 32 pixels) of suspected lung nodule areas (nodule candidates) which were generated from our pre-scanning program [1]. A linguistic label was assigned to each nodule candidate of the training set, then the label was converted to a membership value through a pre-defined membership function and used as teaching signal (desired outputs) during the network learning. Before the nodule candidate was fed to the network input, it was pre-processed to reduce the complex background noise and the contrast discrepancy resulted from film development. During the network testing phase, a defuzzification process was applied to decipher the trained network's output triggered by the nodule candidate in the testing set. Finally, a Receiver Operating Characteristic (ROC) analysis was used to evaluate the CNN's performance based on the defuzzified output of the testing database. Preliminary results showed an average Az (the performance index) of 0.84 which is equivalent to 0.80 true-positive detection (sensitivity) with an average 2-3 false-positive detections per chest image.

Computer Simulation↗

PubMed1998

Matrix-assisted laser desorption/ionization time of flight mass spectrometric analysis of the pattern of peptide expression in single neurons resulting from alternative mRNA splicing of the FMRFamide gene.

MALDI-ToF MS (matrix-assisted laser desorption/ionization time of flight mass spectrometry) has become a fast, reliable and sensitive technique for the identification of neuropeptides in biological tissues. Here, we applied this technique to identified neurons of the cardioregulatory network in the snail Lymnaea that express the FMRFamide gene. This enabled us to study the complex processing of the FMRFamide gene at the level of single identified neurons. In the CNS of Lymnaea, FMRFamide-like and additional peptides are encoded by a common, multiexon gene. Alternate mRNA splicing of the FMRFamide gene leads to the production of two different mRNAs. Type 1 mRNA (exon II) encodes for the tetrapeptides (FLRF/FMRFamide), whereas Type 2 (exons III-V) encodes for the heptapeptides (SDPFLRFamide/GDPFLRFamide). Previous in situ hybridization and immunocytochemical studies indicated that these two transcripts are expressed in the CNS neurons of Lymnaea in a differential and mutually exclusive manner. Two single identified neurons of the cardiorespiratory network, the Ehe neuron and the visceral white interneuron (VWI), were known to express the FMRFamide gene (Ehe, type 1 mRNA; VWI, type 2 mRNA). MALDI-ToF MS analysis of these neurons and other neurons expressing the FMRFamide gene confirmed the mutually exclusive expression of the distinct sets of peptides encoded on the two transcripts and revealed the pattern of post-translational processing of both protein precursors. From the gene sequence it was predicted that 16 final peptide products from the two precursor proteins could possibly exist. We showed that most of these peptides were indeed present in the identified neurons (13) while others were not (three), suggesting that not all of the potential cleavage sites within the two precursors are utilized. In this way, the neuronal expression of the full range of the peptide products resulting from alternative mRNA splicing was revealed for the first time.

Alternative Splicing↗

PubMed2026

A Computational Workflow for Prioritizing Microbial Metabolite-Associated Host Genes in Constipation-Predominant Irritable Bowel Syndrome.

No standardized computational pipeline exists for systematically prioritizing microbial metabolite-associated host genes and protein-ligand complexes from publicly available chemical, genomic, and structural databases. This article describes an eight-stage workflow that accepts a user-defined set of gut microbiota-derived metabolites and produces a ranked shortlist of candidate metabolite-associated host genes, enriched biological pathways, and structurally prioritized protein-ligand complexes for experimental follow-up. The pipeline integrates (i) chemoinformatic metabolite profiling; (ii) multi-database candidate target prediction using protein-chemical interaction and ligand-based target-prediction tool and a molecular docking program; (iii) differential gene expression analysis of publicly available transcriptomic data; (iv) target-differentially expressed gene overlap; (v) protein-protein interaction network construction and pathway enrichment; (vi) molecular docking with a molecular docking program; (vii) 200 ns molecular dynamics simulation using a molecular dynamics engine with a protein force field used for molecular dynamics simulations; and (viii) MM-PBSA binding free-energy estimation. As a worked example, nine gut microbiota-derived or microbiota-modified metabolites representing short-chain fatty acids, bile acids, tryptophan-derived metabolites, and urolithin A were processed using the public IBS-C rectal mucosal transcriptomic dataset GSE36701. The workflow ranked 17 unique predicted metabolite-associated genes that were differentially expressed in this dataset. Docking, molecular dynamics simulation, and MM-PBSA analyses structurally prioritized five metabolite-protein complexes: lithocholic acid-VDR, lithocholic acid-NR1H4/FXR, ursodeoxycholic acid-NR1H4/FXR, tryptamine-HTR2A (simulated in an explicit 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer), and urolithin A-CASP3. The protocol is designed to be adaptable to other metabolite sets, disease transcriptomic datasets, and target classes; all outputs are hypothesis-generating computational predictions that require independent transcriptomic replication, protein-level validation, and functional ligand-response assays before causal or therapeutic conclusions can be drawn.

Irritable Bowel Syndrome↗

PubMed2026

Comprehensive Analysis of Differentially Expressed Genes and Immune Infiltration in Burn Injury: Key Biomarkers and Pathways.

BACKGROUND: Burn injuries trigger complex immune responses and gene expression changes, impacting wound healing and systemic inflammation. Understanding these changes is crucial for identifying biomarkers and therapeutic targets. METHODS: We analyzed two gene expression omnibus datasets (wound tissue [GSE8056] and blood [GSE37069]) to identify differentially expressed genes (DEGs) in burn injury samples versus controls. Immune cell proportions were assessed using CIBERSORT. Functional enrichment analyses (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) and protein-protein interaction networks were constructed to identify key genes and pathways. RESULTS: We identified 1170 upregulated and 1227 downregulated DEGs. Gene Ontology analysis revealed enrichment in neutrophil activation, inflammatory response, and extracellular matrix organization. Kyoto Encyclopedia of Genes and Genomes analysis highlighted cytokine-cytokine receptor interaction, TNF, and IL-17 signaling pathways. Immune infiltration analysis showed significant changes in neutrophils, macrophages (M1/M2), and T-cell subsets. Protein-protein interaction network analysis identified five hub genes: JUN, STAT1, Bcl2, MMP9, and TLR2. CONCLUSIONS: This study provides a comprehensive bioinformatic analysis of gene expression and immune responses in burn injuries. The identified DEGs, hub genes, and pathways offer insights into the immune response mechanisms and suggest potential targets for diagnostic and therapeutic interventions in burn injury management.

Burns↗

PubMed1991

Subregional topography of capillaries in the dorsal vagal complex of rats: I. Morphometric properties.

Cytoarchitectonic and neurochemical studies of the dorsal vagal complex in the caudal medulla oblongata of rats indicate the existence of distinct anatomical and functional compartments within its components. We applied morphometric methods to discern whether capillary networks differed quantitatively between subregions and zones of area postrema, nucleus tractus solitarii (NTS), and dorsal motor nucleus of the vagus nerve (DMN) of rats. Analysis of 11 subdivisions of area postrema identified both "true" (range in luminal diameter of 3-7.5 microns) and sinusoidal (luminal diameter greater than 7.5 microns) capillaries that, together, made the capillary density for most of area postrema 75% greater than that found in NTS and DMN (526/mm2 vs about 300/mm2). The rank order of true capillary density in area postrema along its rostracaudal axis was caudal greater than central greater than rostral, whereas the reverse order was true for sinusoidal capillaries. Dorsal (periventricular) and medial zones of area postrema throughout its rostrocaudal axis tended to have higher values for capillary density, volume, surface area, luminal diameter, and pericapillary space volume than lateral or ventral zones bordering NTS. Within 200 microns of obex, the ventral zone of rostral area postrema was distinct, having a relatively sparse capillary density that may indicate morphological specializations limiting blood-tissue communication in this subregion. There were no quantitative differences in capillary dimensions between DMN and three subnuclei of NTS. These studies add to extant evidence that the dorsal vagal complex is differentiated for specific functions. Area postrema, especially, has topographical diversity in its capillary organization that likely corresponds to complex roles in neuroendocrine, autonomic, and chemosensory mechanisms.

Animals↗

PubMed1997

Using hypertext and the Internet for structure and management of observational studies.

The evolution of computer and communications systems in the past decade brings new opportunities for increased efficiency and accuracy of observational studies. In ongoing, large scale research studies, the problem of bridging organizational and analytical methods of the past to modern methods of data structure and control can consume considerable effort. A model for information flow in an observational study is sketched, and the flow is found inherently complex. This complexity and corresponding managerial demands are compounded by database file proliferation and by evolution of system hardware and software. Interactive, network-based database mapping and documentation tools are described as currently implemented in an SAS-based system for the management and analysis of several large epidemiologic studies.

Computer Communication Networks↗

PubMed1974

Dynamic single unit simulation of a realistic cerebellar network model. II. Purkinje cell activity within the basic circuit and modified by inhibitory systems.

In continuation of earlier computer simulation studies 15 of the feedback inhibition exercised by the Golgi cells of the cerebellum, an attempt is made at modeling the behavior of Purkinje and basket cells under somewhat more complex functional circumstances. The simulation study is based on a realistic network model (with respect to numerical and metrical parameters, and consisting of more than 3 X 10(4) units) of the cat cerebellar cortex, derived from a recent quantitative histological and stereological analysis 9-12. As an input two identical pairs of foci of incoming mossy fiber activity are applied, separated from one another both spatially and temporally. The stimulation results showed that the assumption of a rigidly preaddressed wiring in the parallel fiber--Purkinje cell synaptic system (i.e. that parallel fibers would systematically select for contact Purkinje cells standing in register) would hardly be realistic because such a solution would offer no advantage whatever over a randomly connected synaptic system. The results would favor the contention that dendritic geometry of the Purkinje cells has a crucial significance in the sense of the concepts developed by W. Rall. The stimulation gives some important hints for the ways in which the specific inhibitory interneuron systems (Golgi and basket cells) add refinement to the operations of the network, particularly in securing integration of the influences of parallel fibers thrown into action by mossy input to spatially and temporally separated foci, especially at the level of Purkinje cells positioned in interfocal areas. Reducing the length of the parallel fibers to one-half of what was suggested by the stereological studies causes a serious breakdown of interfocal neighborhood interactions.

Action Potentials↗

PubMed1995

Neural network classification of infrared spectra of control and Alzheimer's diseased tissue.

Artificial neural network classification methods were applied to infrared spectra of histopathologically confirmed Alzheimer's diseased and control brain tissue. Principal component analysis was used as a preprocessing technique for some of these artificial neural networks while others were trained using the original spectra. The leave-one-out method was used for cross-validation and linear discriminant analysis was used as a performance benchmark. In the cases where principal components were used, the artificial neural networks consistently outperformed their linear discriminant counterparts; 100% versus 98% correct classifications, respectively, for the two class problem, and 90% versus 81% for a more complex five class problem. Using the original spectra, only one of the three selected artificial neural network architectures (a variation of the back-propagation algorithm using fuzzy encoding) produced results comparable to the best corresponding principal component cases: 98% and 85% correct classifications for the two and five class problems, respectively.

Alzheimer Disease↗

PubMed1993

Evidence of multiple memory systems in the human brain. A [18F]FDG PET metabolic study.

Patients with global amnesia of different aetiologies (n = 11), and patients with probable Alzheimer's disease of recent onset and mild to moderate severity (n = 18) underwent extensive neuropsychological examination, which included the evaluation of multiple components of memory, and a measurement of regional cerebral glucose metabolism with [18F]fluoro-deoxyglucose ([18F]FDG) and PET. In the neuropsychological tests, both global amnesia and Alzheimer's disease patients had impaired episodic long-term memory, while deficits of short-term, semantic and implicit memory were present only in Alzheimer's disease. When local metabolic rates for glucose were compared with values from age- and education-matched normal controls, a common pattern of bilateral hypometabolism was present in the hippocampus, cingulate and frontal basal cortex of both global amnesia and Alzheimer's disease patients. On the other hand, significant hypometabolism was found in the thalamus in only global amnesia, and in the frontal, parietal and temporal associative cortex in only Alzheimer's disease. The results of a multivariate regression analysis of test scores with metabolic data indicated that different clusters of cerebral areas were associated with each of the main components of memory function. These data are in agreement with 'neural network' models of the neural basis of cognition, according to which complex functions are subserved by multiple interconnected cortical and subcortical structures.

Aged↗

PubMed1998

Targeting of active sialyltransferase to the plant Golgi apparatus.

Glycosyltransferases in the Golgi apparatus synthesize cell wall polysaccharides and elaborate the complex glycans of glycoproteins. To investigate the targeting of this type of enzyme to plant Golgi compartments, we generated transgenic Arabidopsis plants expressing alpha-2,6-sialyltransferase, a glycosyltransferase of the mammalian trans-Golgi cisternae and the trans-Golgi network. Biochemical analysis as well as immunolight and immunoelectron microscopy of these plants indicate that the protein is targeted specifically to the Golgi apparatus. Moreover, the protein is predominantly localized to the cisternae and membranes of the trans side of the organelle. When supplied with the appropriate substrates, the enzyme has significant alpha-2,6-sialyltransferase activity. These results indicate a conservation of glycosyltransferase targeting mechanisms between plant and mammalian cells and also demonstrate that glycosyltransferases can be subcompartmentalized to specific cisternae of the plant Golgi apparatus.

Animals↗

PubMed1997

Cloning, tissue expression, and chromosomal localization of the mouse IRS-3 gene.

Insulin receptor substrate (IRS) proteins are key regulators of basic functions such as cellular growth and metabolism. They provide an interface between multiple receptors and a complex network of intracellular signaling molecules. Two members of this family (IRS-1 and IRS-2) have been identified previously. In this investigation, we analyzed a mouse expressed sequence tag clone that proved to be a new member of the IRS family. Sequence analysis of this clone and comparison with the sequences deposited in GenBank demonstrates this protein may be the murine homolog of rat IRS-3, recently purified and cloned from rat adipocytes. Accordingly, we have named our protein mouse IRS-3. The expressed sequence tag clone contains the complete coding sequence of 1485 bp, encoding a protein of 495 amino acids. Sequence alignment with the other members of the IRS family shows that this protein contains pleckstrin homology and phosphotyrosine-binding domains that are highly conserved. In addition, there is conservation of many tyrosine phosphorylation motifs responsible for interactions with downstream signaling molecules containing SH2 domains. The murine IRS-3 messenger RNA (2.4 kilobases in length) is expressed in many tissues, with highest levels in liver and lung. Mouse IRS-3 is highly expressed in the first part of the embryonic life, when IRS-1 messenger RNA is barely detectable. Unlike the genes encoding IRS-1 and IRS-2, the IRS-3 gene contains an intron (344 bp in length) in the region between the pleckstrin homology and the phosphotyrosine-binding domains. Fluorescent in situ hybridization localized the mouse IRS-3 gene on the telomeric region of chromosome 5G2. Cloning of the murine IRS-3 gene will make it possible to apply genetic approaches to elucidate the physiological role of this new member of the IRS family of proteins.

Amino Acid Sequence↗

PubMed1993

Role of Tyr201 and Tyr385 in substrate activation by p-hydroxybenzoate hydroxylase from Pseudomonas fluorescens.

The crystal structure of the enzyme-substrate complex of p-hydroxybenzoate hydroxylase from Pseudomonas fluorescens shows that the hydroxyl group of 4-hydroxybenzoate interacts with the side chain of Tyr201, which is in close contact with the side chain of Tyr385. The role of this hydrogen bonding network in substrate activation was studied by kinetic and spectral analysis of Tyr-->Phe mutant enzymes. The catalytic properties of the enzymes with Tyr201 or Tyr385 replaced by Phe (Tyr201-->Phe and Tyr385-->Phe) with the physiological substrate are comparable with those of the corresponding mutant proteins of p-hydroxybenzoate hydroxylase from P. aeruginosa [Entsch, B., Palfey, B. A., Ballou, D. P. & Massey, V. (1991) J. Biol. Chem. 266, 17341-17349]. Enzyme Tyr201-->Phe has a high Km for NADPH and produces only 5% of 3,4-dihydroxybenzoate/catalytic cycle. Unlike the wild-type enzyme, the Tyr201-->Phe mutant does not stabilize the phenolate form of 4-hydroxybenzoate. With enzyme Tyr385-->Phe, flavin reduction is rate-limiting and the turnover rate is only 2% of wild type. Despite rather efficient hydroxylation, and deviating from the description of the corresponding P. aeruginosa enzyme, mutant Tyr385-->Phe prefers the binding of the phenolic form of 4-hydroxybenzoate. Studies with substrate analogs show that both tyrosines are important for the fine tuning of the effector specificity. Binding of 4-fluorobenzoate differentially stimulates the stabilization of the 4 alpha-hydroperoxyflavin intermediate. Unlike wild type, both Tyr mutants produce 3,4,5-trihydroxybenzoate from 3,4-dihydroxybenzoate. The affinity of enzyme Tyr201-->Phe for the dianionic substrate 2,3,5,6-tetrafluoro-4-hydroxybenzoate is very low, probably because of repulsion of the substrate phenolate in a more nonpolar microenvironment. In contrast to data reported for p-hydroxybenzoate hydroxylase from P. aeruginosa, binding of the inhibitor 4-hydroxycinnamate to wild-type and mutant proteins is not simply described by binary complex formation. A binding model is presented, including secondary binding of the inhibitor. Enzyme Tyr201-->Phe does not stabilize the phenolate form of the inhibitor. In enzyme Tyr385-->Phe, the phenolic pKa of bound 4-hydroxycinnamate is increased with respect to wild type. It is proposed that Tyr385-->Phe is involved in substrate activation by facilitating the deprotonation of Tyr201.

4-Hydroxybenzoate-3-Monooxygenase↗