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PubMed1993

Role of tumor necrosis factor-alpha in disease states and inflammation.

OBJECTIVE: To review the animal and human data defining the role of tumor necrosis factor (TNF) in the pathogenesis of the septic shock syndrome, the systemic inflammatory response syndrome, and related pathologic states. DATA SOURCES: The international English language literature from 1975 to present formed the basis for this review. MEDLINE was used to identify pertinent animal and human studies. STUDY SELECTION: Those animal and human studies that focused on the mechanisms of action of TNF, its role in the inflammatory cytokine network, and the potential uses of anti-TNF therapies were emphasized. DATA EXTRACTION: Animal studies were selected based on the relevance of the model to the pathogenesis of the human systemic inflammatory response syndrome. Where they provided supportive evidence, human studies were selected on the basis of study design. DATA SYNTHESIS: TNF plays a major role in systemic inflammatory response syndrome secondary to infection, burns, trauma or hemorrhagic shock, and pancreatitis. TNF influences the outcome of other infectious processes, including allograft rejection, ischemia-reperfusion injury, delayed-type hypersensitivity, and granuloma development. The administration of anti-TNF antibodies, soluble TNF receptors, and related fusion proteins may limit organ damage and decrease mortality rate. CONCLUSIONS: Although the regulated release of TNF may exert normal physiologic effects, the uncontrolled production of TNF may lead to organ dysfunction and death. TNF mediates a variety of other physiologic processes that are unrelated to sepsis syndrome. New anti-TNF therapies appear to attenuate the injurious actions of TNF.

Animals↗
PubMed1988

Informational parameters and randomness of mitochondrial DNA.

The informational content of genomes of nuclear and mitochondrial origin is examined. By using the parameters of Shannon's information theory the language of mitochondrial DNA is shown to be more similar to the language of bacterial DNA than to that of nuclear DNA in more evolutionarily advanced animals. Moreover, using the parameters of Kolmogorov's theory on randomness, genes of different organisms (Neurospora crassa and Saccharomyces cerevisiae) coding for the same protein (subunit 9 of ATPase) are shown to have, if both of mitochondrial origin, a similar degree of randomness, whereas genes coding for the same protein, both belonging to the same organisms, exhibit a quite different degree of randomness when one is of mitochondrial origin and the other of nuclear origin. These results are in favor of the symbiotic origin of mitochondria.

Adenosine Triphosphatases↗
PubMed2005

Application of a generalized MWC model for the mathematical simulation of metabolic pathways regulated by allosteric enzymes.

In our effort to elucidate the systems biology of the model organism, Escherichia coli, we have developed a mathematical model that simulates the allosteric regulation for threonine biosynthesis pathway starting from aspartate. To achieve this goal, we used kMech, a Cellerator language extension that describes enzyme mechanisms for the mathematical modeling of metabolic pathways. These mechanisms are converted by Cellerator into ordinary differential equations (ODEs) solvable by Mathematica. In this paper, we describe a more flexible model in Cellerator, which generalizes the Monod, Wyman, Changeux (MWC) model for enzyme allosteric regulation to allow for multiple substrate, activator and inhibitor binding sites. Furthermore, we have developed a model that describes the behavior of the bifunctional allosteric enzyme aspartate Kinase I-Homoserine Dehydrogenase I (AKI-HDHI). This model predicts the partition of enzyme activities in the steady state which paves a way for a more generalized prediction of the behavior of bifunctional enzymes.

Algorithms↗
PubMed2003

Predicting bacterial transcription units using sequence and expression data.

MOTIVATION: A key aspect of elucidating gene regulation in bacterial genomes is identifying the basic units of transcription. We present a method, based on probabilistic language models, that we apply to predict operons, promoters and terminators in the genome of Escherichia coli K-12. Our approach has two key properties: (i) it provides a coherent set of predictions for related regulatory elements of various types and (ii) it takes advantage of both DNA sequence and gene expression data, including expression measurements from inter-genic probes. RESULTS: Our experimental results show that we are able to predict operons and localize promoters and terminators with high accuracy. Moreover, our models that use both sequence and expression data are more accurate than those that use only one of these two data sources.

Algorithms↗
PubMed2006

Mechanisms of disease: neurogenetics of MeCP2 deficiency.

Rett syndrome (RTT) is unique among genetic, chromosomal and other developmental disorders because of its extreme female gender bias, early normal development, and subsequent developmental regression with loss of motor and language skills. RTT is caused by heterozygosity for mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2. MeCP2 is a multifunctional protein that can act as an architectural chromatin-binding protein, a function that is unrelated to its ability to bind methyl-CpG and to attract chromatin modification complexes. Inactivating mutations that cause RTT in females are not prenatally lethal in males, but lead to profound congenital encephalopathy. Molecular diagnoses of RTT, through demonstration of a MECP2 mutation, made at an early stage of the disorder, usually confirm the sporadic nature and very low recurrence risk of the condition. A positive DNA test result, however, also predicts the inevitable clinical course, given the lack of effective intervention. Initial hypotheses indicating that the MeCP2 protein acts as a genome-wide transcriptional repressor were not confirmed by global gene expression studies in various tissues of individuals with RTT and mouse models of MeCP2 deficiency. Rather, recent evidence points to low-magnitude effects of a small number of genes--including the brain--derived neurotrophic factor pathway and glucocorticoid response genes-that might affect formation and maturation of synapses or synaptic function in postmitotic neurons.

Animals↗
PubMed2003

Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum.

Many members of the forkhead/winged helix transcriptional factors are known to be regulators of embryogenesis. Mutations of the Fox gene family have been implicated in a range of human developmental disorders. Foxp2, a member of the Fox gene family, has recently been identified as the first gene that is linked to an inherited form of language and speech disorder. To elucidate the anatomical basis of language processing in the brain, we have examined the expression pattern of Foxp2 gene and its homologous gene, Foxp1, in the rat brain through development. Expression of Foxp2 mRNA was detected in the ventral telencephalon as early as embryonic day 13. Foxp2 mRNA was expressed primarily in differentiated cells of the lateral ganglionic eminence (striatal primordium). Of particular interest was that the developmental expression of Foxp2 followed a compartmental order in the striatum. Patches containing high levels of Foxp2 were aligned with patches enriched in mu-opoid receptor, a marker for striosomal cells, in the striatum through postnatal development. Conversely, Foxp2-positive patches were devoid of calbindin-D28k, a maker for striatal matrix cells. Therefore, Foxp2 was preferentially expressed in striosomal compartment in the striatum during development. In the mature striatum, Foxp2 expression was maintained in striosomes, although its expression level was reduced. In contrast to Foxp2, Foxp1 was expressed in both the striosomal and matrix compartments in the striatum through development. The striatum is known to be involved in the process of procedural memory, and mutation of Foxp2 results in neurological disorders of language and speech. Given the preferential expression of Foxp2 in the striosomal compartment, the striatum, particularly the striosomal system, may participate in neural information processing for language and speech. Our suggestion is consistent with the declarative/procedural model proposed by Ullman and colleagues (Ullman et al. [1997] J. Cogn. Neurosci. 9:266-276; Ullman [2001] Nat. Rev. Neurosci. 2:717-726), in which the procedural memory-dependent mental grammar is rooted in the basal ganglia and the frontal cortex and the declarative memory-dependent mental lexicon is rooted in the temporal lobe.

Age Factors↗
PubMed2005

Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2.

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.

Animals↗
PubMed1982

In search of more complex genetic codes--can linguistics be a guide?

Striking similarities have been pointed out between the structures of the human language and the genetic code. The primary genetic code utilizes the principle of linear representation much like e.g. the Indo-European languages do. There are numerous indications that more complex secondary and tertiary structural elements in DNA direct highly specific interactions with proteins. Thus, more complex genetic codes might exist which might be superimposed on DNA sequences coding for polypeptides or might be extended to "non-coding" DNA sequences. Structural features of highly complex languages, like Chinese or Egyptian hieroglyphics using conceptual expression patterns have been compared to the more complex ways of encoding. It is proposed that the application of linguistic principles may be helpful in the computer analyses of known DNA sequences. There is considerable evidence for the innate specification at least for the basic structural elements of human languages. This innate specification may be the cause for language university. Based on the striking structural similarities between language and genetic code, the question is raised to what extent and in what way DNA sequences might be related to the innate specification of human languages.

Computers↗
PubMed2006

Application of a generalized MWC model for the mathematical simulation of metabolic pathways regulated by allosteric enzymes.

In our effort to elucidate the systems biology of the model organism, Escherichia coli, we have developed a mathematical model that simulates the allosteric regulation for threonine biosynthesis pathway starting from aspartate. To achieve this goal, we used kMech, a Cellerator language extension that describes enzyme mechanisms for the mathematical modeling of metabolic pathways. These mechanisms are converted by Cellerator into ordinary differential equations (ODEs) solvable by Mathematica. In this paper, we describe a more flexible model in Cellerator, which generalizes the Monod, Wyman, Changeux (MWC) model for enzyme allosteric regulation to allow for multiple substrate, activator and inhibitor binding sites. Furthermore, we have developed a model that describes the behavior of the bifunctional allosteric enzyme aspartate kinase I-homoserine dehydrogenase I (AKI-HDHI). This model predicts the partition of enzyme activities in the steady state which paves the way for a more generalized prediction of the behavior of bifunctional enzymes.

Algorithms↗
PubMedDate not supplied

Insulin-like growth factors as determinants of follicular fate.

OBJECTIVE: To review the English-language literature as it relates to the rat intraovarian insulin-like growth factor (IGF) system, special emphasis being placed on the hypotheses under study. METHODS: A thorough literature review of the English-language literature. RESULTS: Current data support the view that intraovarian IGF-I may act as an amplifier of gonadotropin hormonal action. The role of IGF-I as a determinant of follicular fate remains a matter of study. CONCLUSIONS: The intraovarian IGF-I system may play a central role in ovarian physiology by amplifying gonadotropin hormonal action and, possibly, by playing a role in determining follicular fate.

Animals↗
PubMedDate not supplied

Unlimited capacity and processibility of sequence information: prerequisites for a system of biological chains.

Both genetic chains in a cell and phonological chains in a human phonological working memory simultaneously store and process sequence information. Unlimited capacity and processibility of sequence information are two prerequisites for such a system of biological chains. It is demonstrated that information chains (I-chains) and conformation chains (C-chains) satisfy these two prerequisites. Namely, in both kinds of chains constant efficiency and precision of intra- and inter-sequence interactions are guaranteed irrespective of the chain length. Nucleic acids and proteins are I-chains and C-chains of genetic chains, respectively. A 'molecular' model of a phonological chain is formulated based on the properties of phonological working memory. It is proposed that prose and verse are I-chains and C-chains of phonological chains, respectively. The correspondence between a system of genetic chains and a system of phonological chains is explored in detail. A critical difference between systems of biological chains and artificial information-processing systems is attributed to the existence of C-chains.

Humans↗
PubMed1993

Tumor necrosis factor in the pathogenesis of infectious diseases.

OBJECTIVES: To review the immunologic role of the cytokines and the specific role that tumor necrosis factor (TNF) plays in response to infection. The influence of bacterial lipopolysaccharide on TNF, the cytokine cascade, and resultant pathologies are also reviewed. DATA SOURCES: A MEDLINE search of the international English language literature from 1960 to the present was reviewed, but data from the past 5 yrs primarily formed the basis for this review. STUDY SELECTION: Those studies detailing the interaction of lipopolysaccharide, TNF, and other cytokines, and their roles in combating infection were emphasized. Investigations that described animal and human results served as the primary database. DATA EXTRACTION: Animal studies were selected based on the relevance of the model to the pathogenesis of the human clinical syndrome. Where they provided supportive evidence, patient studies were selected on the basis of study design. DATA SYNTHESIS: TNF plays a key role in the normal immune response to infection, limiting the spread of pathogens. Exaggerated physiologic responses occur under the influence of high concentrations of TNF that are released in response to overwhelming infection, resulting in aberrations in coagulation, cell adhesion, chemotaxis/transmigration, and vascular integrity. These pathologic effects may be inhibited by anti-TNF monoclonal antibodies and recombinant soluble receptor inhibitory proteins. CONCLUSIONS: TNF exerts both physiologic and pathologic effects in response to infection; these events may lead to organ dysfunction and death. Anti-TNF therapies appear to attenuate the injurious effects of TNF.

Animals↗
PubMed2005

The evolution of information in the major transitions.

Maynard Smith and Szathmáry's analysis of the major transitions in evolution was based on changes in the way information is stored, transmitted and interpreted. With the exception of the transition to human linguistic societies, their discussion centred on changes in DNA and the genetic system. We argue that information transmitted by non-genetic means has played a key role in the major transitions, and that new and modified ways of transmitting non-DNA information resulted from them. We compare and attempt to categorise the major transitions, and suggest that the transition from RNA as both gene and enzyme to DNA as genetic material and proteins as enzymes may have been a double one. Unlike Maynard Smith and Szathmáry, we regard the emergence of the nervous system as a major transition. The evolution of a nervous system not only changed the way that information was transmitted between cells and profoundly altered the nature of the individuals in which it was present, it also led to a new type of heredity-social and cultural heredity-based on the transmission of behaviourally acquired information.

Animals↗
PubMed1991

Are syntax errors due to the amino acid sequence of neuroleukin involved in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and insulin dependent diabetes mellitus (IDDM)?

The main principles of this hypothesis are very general: (i) signal-detection from background noise is one central issue in electronics; (ii) an important source of misunderstanding at different levels of communication is the fact that a given signal may have different meanings in different contexts; (iii) the unique role of chance in developmental biology is generally appreciated (37). In AIDS the basic defect would be the human specific inability to distinguish between the amino acid sequence of neuroleukin and peptides derived from the gp120 envelope protein of HIV, resulting in a slowly progressing failure of the CD4+ T cell-mediated immunity. In IDDM the postulated HLA class II-dependent hypersensitivity to immunological noise could predispose to random contacts between cells with a different signalling language. In the ensuing dialogue neuroleukin secreted by T cells would imply a continuous demand for insulin secretion to pancreatic beta cells resulting in diabetes. This hypothesis does not contradict with the provocative ideas proposed by Duesberg concerning the relationships between HIV and AIDS (24) and the known data on the genesis of IDDM.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Computational physiology and the Physiome Project.

Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.

Biophysical Phenomena↗
PubMed1993

Tumor necrosis factor: an updated review of its biology.

OBJECTIVE: To review the role of tumor necrosis factor (TNF) in the pathogenesis of the septic shock syndrome. DATA SOURCES: The international English language literature from 1985 to present formed the basis for this review. MEDLINE was used to identify pertinent animal and human studies pertaining to the clinically relevant aspects of TNF and related cytokines. STUDY SELECTION: Those studies that focused on developments that may lead to advances in the therapy for septic shock syndrome were emphasized. Investigations that described in vivo and human results served as the primary database. DATA EXTRACTION: Animal studies were selected based on the similarity of the model pathogenesis and outcomes to the human clinical sepsis syndrome. Patient studies were selected on the basis of study design and sample size. DATA SYNTHESIS: The normal role of TNF and pathologic effects consequent to the excessive production of TNF in response to an overwhelming infection or injury are reviewed. Evidence establishes the role of TNF in septic shock syndrome. Novel therapies, such as anti-TNF monoclonal antibodies, soluble TNF receptors, or soluble TNF receptor-immunoglobulin G heavy chain fusion proteins, may confer protection against septic shock syndrome. CONCLUSIONS: TNF plays a major role in the pathogenesis of the septic shock syndrome. TNF exerts a range of beneficial and injurious effects that may ultimately lead to organ dysfunction and death. The burst of TNF release after endotoxemia promotes the progression of the shock syndrome even in the absence of further TNF release. New therapies targeted to the attenuation of TNF may hold promise for the management of patients with septic shock syndrome.

Animals↗
PubMed1997

Integrating database homology in a probabilistic gene structure model.

We present an improved stochastic model of genes in DNA, and describe a method for integrating database homology into the probabilistic framework. A generalized hidden Markov model (GHMM) describes the grammar of a legal parse of a DNA sequence. Probabilities are estimated for gene features by using dynamic programming to combine information from multiple sensors. We show how matches to homologous sequences from a database can be integrated into the probability estimation by interpreting the likelihood of a sequence in terms of the bit-cost to encode a sequence given a homology match. We also demonstrate how homology matches in protein databases can be exploited to help identify splice sites. Our experiments show significant improvements in the sensitivity and specificity of gene structure identification when these new features are added to our gene-finding system, Genie. Experimental results in tests using a standard set of annotated genes showed that Genie identified 95% of coding nucleotides correctly with a specificity of 91%, and 77% of exons were identified exactly.

Algorithms↗
PubMed2006

PathSys: integrating molecular interaction graphs for systems biology.

BACKGROUND: The goal of information integration in systems biology is to combine information from a number of databases and data sets, which are obtained from both high and low throughput experiments, under one data management scheme such that the cumulative information provides greater biological insight than is possible with individual information sources considered separately. RESULTS: Here we present PathSys, a graph-based system for creating a combined database of networks of interaction for generating integrated view of biological mechanisms. We used PathSys to integrate over 14 curated and publicly contributed data sources for the budding yeast (S. cerevisiae) and Gene Ontology. A number of exploratory questions were formulated as a combination of relational and graph-based queries to the integrated database. Thus, PathSys is a general-purpose, scalable, graph-data warehouse of biological information, complete with a graph manipulation and a query language, a storage mechanism and a generic data-importing mechanism through schema-mapping. CONCLUSION: Results from several test studies demonstrate the effectiveness of the approach in retrieving biologically interesting relations between genes and proteins, the networks connecting them, and of the utility of PathSys as a scalable graph-based warehouse for interaction-network integration and a hypothesis generator system. The PathSys's client software, named BiologicalNetworks, developed for navigation and analyses of molecular networks, is available as a Java Web Start application at http://brak.sdsc.edu/pub/BiologicalNetworks.

Computer Graphics↗