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PubMed2001

Ontologies of developmental anatomy: their current and future roles.

A central problem in current biology is elucidating the molecular networks that drive developmental change and physiological function. Such knowledge is needed partly to understand these networks, partly to be able to manipulate them, and partly to understand and help treat those human congenital abnormalities that arise as a result of mutation. Thus far, bioinformatics technology has been of limited use in this enterprise, mainly because its core focus has been on sequence technology and data archiving. For bioinformatics to be of use in this next tier of investigations, genetic and protein data need to be both archived and searchable by tissue since this is the level at which these networks operate. The resulting databases in turn require ontologies of developmental anatomy that can provide the formal infrastructure for handling gene expression, microarray and other tissue-based data. Here, the progress in making such ontologies, particularly for the developing mouse, is reported and the uses to which they are and will be put, together with the resources and tools currently available for investigating molecular networks and the genetic basis of congenital abnormalities, are considered.

Anatomy↗
PubMed2005

Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia.

Understanding the complexity and dynamics of cancer cells in response to effective therapy requires hypothesis-driven, quantitative, and high-throughput measurement of genes and proteins at both spatial and temporal levels. This study was designed to gain insights into molecular networks underlying the clinical synergy between retinoic acid (RA) and arsenic trioxide (ATO) in acute promyelocytic leukemia (APL), which results in a high-quality disease-free survival in most patients after consolidation with conventional chemotherapy. We have applied an approach integrating cDNA microarray, 2D gel electrophoresis with MS, and methods of computational biology to study the effects on APL cell line NB4 treated with RA, ATO, and the combination of the two agents and collected in a time series. Numerous features were revealed that indicated the coordinated regulation of molecular networks from various aspects of granulocytic differentiation and apoptosis at the transcriptome and proteome levels. These features include an array of transcription factors and cofactors, activation of calcium signaling, stimulation of the IFN pathway, activation of the proteasome system, degradation of the PML-RARalpha oncoprotein, restoration of the nuclear body, cell-cycle arrest, and gain of apoptotic potential. Hence, this investigation has provided not only a detailed understanding of the combined therapeutic effects of RA/ATO in APL but also a road map to approach hematopoietic malignancies at the systems level.

Antineoplastic Agents↗
PubMed2003

Six3 and Six6 activity is modulated by members of the groucho family.

Six3 and Six6 are two genes required for the specification and proliferation of the eye field in vertebrate embryos, suggesting that they might be the functional counterparts of the Drosophila gene sine oculis (so). Phylogenetic and functional analysis have however challenged this idea, raising the possibility that the molecular network in which Six3 and Six6 act may be different from that described for SO. To address this, we have performed yeast two-hybrid screens, using either Six3 or Six6 as a bait. In this paper, we report the results of the latter screen that led to the identification of TLE1 (a transcriptional repressor of the groucho family) and AES (a potential dominant negative form of TLE proteins) as cofactors for both SIX6 and SIX3. Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES, but that SIX3 also interacts with TLE proteins via the WDR domain. Tle1 and Aes are expressed in the developing eye of medaka fish (Oryzias latipes) embryos, overlapping with the distribution of both Six3 and Six6. Gain-of-function studies in medaka show a clear synergistic activity between SIX3/SIX6 and TLE1, which, on its own, can expand the eye field. Conversely, AES alone decreases the eye size and abrogates the phenotypic consequences of SIX3/6 over-expression. These data indicate that both Tle1 and Aes participate in the molecular network that control eye development and are consistent with the view that both Six3 and Six6 act in combination with either Tle1 and/or Aes.

Animals↗
PubMed2002

Report from the third international meeting of the Attention-Deficit Hyperactivity Disorder Molecular Genetics Network.

Growing evidence of a genetic contribution to attention-deficit hyperactivity disorder (ADHD) has prompted investigators from around the world to convene annually to discuss ways of facilitating collaboration and sharing information about their work on this topic. The number of participants in the meeting has grown each year as a result of enthusiastic responses to each previous conference. This third annual meeting, held in Boston, began with presentations of ongoing and proposed collaborations. The status of Hypescheme, an operational criteria checklist developed in an effort to promote the reliable communication of information related to ADHD, was reviewed. A symposium was conducted to review current evidence for whether DSM-IV subtypes breed true. Finally, new data from individual research sites were presented. Despite recent advances, more work is needed to better characterize heritable aspects of the ADHD phenotype as well as the actual candidate genes themselves.

Attention Deficit Disorder with Hyperactivity↗
PubMed1987

Age-related changes in human vitreous structure.

Changes in vitreous structure that occur with aging are important in the pathogenesis of vitreous liquefaction (synchisis senilis), vitreous detachment, and retinal disease. Vitreous morphology was studied in 59 human eyes post-mortem using dark-field horizontal slit illumination of the entire dissected vitreous. In many individuals younger than 30 years, the vitreous was homogeneous in structure. Middle-aged individuals had macroscopic fibers in the central vitreous, which coursed anteroposteriorly and inserted into the vitreous base and the vitreous cortex, posteriorly. During senescence, the vitreous volume was reduced, the vitreous body was collapsed (syneresis), and the fibers were thickened, tortuous, and surrounded by liquid vitreous. This sequence of age-related changes probably results from a progressive reorganization of the hyaluronic acid and collagen molecular networks. Characterization of the molecular events underlying these changes will elucidate the mechanisms of the phenomena of synchisis, syneresis, and detachment, and may provide methods with which to prevent or induce vitreous detachment prophylactically.

Adolescent↗
PubMed2002

Active fluidization of polymer networks through molecular motors.

Entangled polymer solutions and melts exhibit elastic, solid-like resistance to quick deformations and a viscous, fluid-like response to slow deformations. This viscoelastic behaviour reflects the dynamics of individual polymer chains driven by brownian motion: since individual chains can only move in a snake-like fashion through the mesh of surrounding polymer molecules, their diffusive transport, described by reptation, is so slow that the relaxation of suddenly imposed stress is delayed. Entangled polymer solutions and melts therefore elastically resist deforming motions that occur faster than the stress relaxation time. Here we show that the protein myosin II permits active control over the viscoelastic behaviour of actin filament solutions. We find that when each actin filament in a polymerized actin solution interacts with at least one myosin minifilament, the stress relaxation time of the polymer solution is significantly shortened. We attribute this effect to myosin's action as a 'molecular motor', which allows it to interact with randomly oriented actin filaments and push them through the solution, thus enhancing longitudinal filament motion. By superseding reptation with sliding motion, the molecular motors thus overcome a fundamental principle of complex fluids: that only depolymerization makes an entangled, isotropic polymer solution fluid for quick deformations.

Actins↗
PubMed2001

Quasi-three-dimensional network of molecular interactions and electronic structure of a new organic semiconductor, ET(NCS)0.77.

The radical cation salt ET(NCS)0.77 [bis(ethylenedithio)tetrathiafulvalene thiocyanate (1/0.77)] has been prepared for the first time by electrocrystallization and its crystal and electronic structure at 110 K was investigated. The unit-cell dimensions are orthorhombic, a = 6.638 (1), b = 8.309 (2), c = 28.776 (6) A, V = 1587.1 (6) A3, space group Pbcm, Z = 4. The compound has a layered structure. The ET radical cations of the conducting cationic layer build stacks. In the anionic layer the thiocyanate groups form polymeric chains where they are oriented in a 'head-to-tail' mode. The structure has short intermolecular contacts of the cation-cation, anion-anion and cation-anion types, which leads to the formation of a three-dimensional structure of intermolecular interactions. This phenomenon is very rare in molecular conductors. Tight binding band structure calculations suggest, however, that the interlayer interactions through the anions are weak and that the incomplete occupation of the anion sites is the reason for the activated conductivity of the salt.

Journal Article↗
PubMed2000

How do drug-induced topoisomerase I-DNA lesions signal to the molecular interaction network that regulates cell cycle checkpoints, DNA replication, and DNA repair?

Recent results suggest that potentially lethal DNA lesions may result when replication forks encounter trapped topoisomerase-DNA complexes or some other types of DNA damage. Such events produce what are called replication-encounter lesions. These lesions have the characteristic that they may allow single stranded DNA-associated replication protein A (RPA) to become juxtaposed to dsDNA end-associated DNA-protein kinase. Our results suggest that DNA-protein kinases may then hyperphosphorylate the RPA2 subunit. We discuss a possible pathway by which hyperphosphorylation of RPA2 could lead to the release of active p53. This could constitute a pathway for signaling the presence of replication-encounter lesions to the p53-dependent cell cycle arrest and/or apoptosis initiator systems.

Apoptosis↗
PubMed2006

Analyzing molecular reaction networks: from pathways to chemical organizations.

Pathways are typically the central concept in the analysis of biochemical reaction networks. A pathway can be interpreted as a chain of enzymatical reactions performing a specific biological function. A common way to study metabolic networks are minimal pathways that can operate at steady state called elementary modes. The theory of chemical organizations has recently been used to decompose biochemical networks into algebraically closed and self-maintaining subnetworks termed organizations. The aim of this paper is to elucidate the relation between these two concepts. Whereas elementary modes represent the boundaries of the potential behavior of the network, organizations define metabolite compositions that are likely to be present in biological feasible situations. Hence, steady state organizations consist of combinations of elementary modes. On the other hand, it is possible to assign a unique (and possibly empty) set of organizations to each elementary mode, indicating the metabolites accompanying the active pathway in a feasible steady state.

Cell Physiological Phenomena↗
PubMed2000

Thirty-three novel mutations in the protein C gene. French INSERM network on molecular abnormalities responsible for protein C and protein S.

We analyzed the protein C gene (PROC) with the denaturing gradient gel electrophoresis (DGGE) scanning strategy in a series of 129 patients with suspected protein C (PC) deficiency (93 with low plasma PC levels and 36 with borderline level). At least one sequence variation was found in 104 of the 129 patients. Thirty-nine sequence variations (found in 72 patients) were already reported detrimental mutations. Thirty-three were novel sequence variations, of which 19 (found in 25 patients) were probably detrimental. Five novel mutations (A1T, R9H, S11R, S12R and K193Q) were associated with qualitative plasma PC deficiency, suggesting or confirming the functional importance of amino acids at these positions. This strategy confirmed the diagnosis of inherited PC deficiency in 79/93 (84.9%) patients with low plasma PC levels and 14/36 (38.8%) patients with borderline values. In order to explain abnormal PC levels observed in patients who did not carry detrimental mutations, screening for the -1654C/T and -1641A/G PROC promoter polymorphisms known to influence plasma PC concentrations was performed. The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations.

Adult↗
PubMed1995

Identification of mutations in 90 of 121 consecutive symptomatic French patients with a type I protein C deficiency. The French INSERM Network on Molecular Abnormalities Responsible for Protein C and Protein S deficiencies.

By studying the protein C gene of 121 consecutive patients with symptomatic type I protein C deficiency, we detected 55 different candidate mutations in 90 cases. The mutations, 76% of which were missense changes, were distributed throughout the gene. More than half the missense mutations involved Cys, Phe, Pro, or Gly, amino acids known to affect the structure of the polypeptide chain by various mechanisms. Thus, 40% of protein C deficiencies may be caused by polypeptide chain instability rather than a lack of expression of the mutated allele; this may also account for phenotypic heterogeneity. Seventeen of the 55 different mutations were found in apparently unrelated families. Half the French families we studied bore one of these 17 mutations. The wide variety of mutations suggests that both sporadic cases and a founder effect contribute to the spectrum of protein C mutations in a given population. The differences in both unique and recurrent mutations in French and Dutch populations-the only large population samples so far studied-support this hypothesis.

Base Sequence↗
PubMed1997

Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand Disease.

Type 2 vWD is defined by qualitative defects of vWF and is subdivided into four subtypes: 2N, 2B, 2A and 2M. The characterization of 150 unrelated French cases with type 2 vWD emphasizes the heterogeneity of this group. In 51 cases of type 2N vWD, new mutations were found not only in the D' domain (Cys25Tyr and Cys95Phe) but also in the D3 domain (Asp116Asn and Cys297Arg). In 42 cases of type 2B vWD, no new mutation was detected. In 45 cases with type 2A phenotype, three new candidate mutations were found in the A2 domain: Gln793Arg, Val841Phe and Leu876Pro. In addition, four new candidate mutations were detected in the A1 domain: Cys509Gly, Arg545His, Arg552Cys and Cys695Tyr. Finally, five new candidate mutations were identified in 12 patients with 2M (or unclassified) phenotype: Leu513Pro, Gly561A1a, Glu596Lys, Arg611Leu and IIe662Phe. For all candidate mutations, expression studies are in progress. This study of a large number of French variants of vWD brings further insight into the relationship between phenotype and genotype.

Amino Acid Sequence↗
PubMed2006

Characterization of supersaturated lidocaine/polyacrylate pressure sensitive adhesive systems: thermal analysis and FT-IR.

Supersaturated and crystallized lidocaine (LC)/pressure sensitive adhesive (PSA) systems have been studied by differential scanning calorimetry (DSC) and FT-IR with the objective of characterizing the thermodynamic states and compatibility of the two-component systems. Analysis of the phase behavior of LC/DT2287 systems indicates that LC and DT2287 are thermodynamically miscible within the composition range containing less than approximately 20% w/w LC, beyond which LC may crystallize from the blends forming a separated crystalline phase. The composition dependence of the glass transition temperature (T(g)) was used to characterize the physical and thermodynamic states of the supersaturated systems. The Fox, Gordon-Taylor, Kwei, Kovacs, and Brekner, Schneider and Cantow (BSC) equations were employed to conduct the analysis. It was found that the PSA in the supersaturated LC/PSA systems underwent significant entropic relaxation upon mixing. LC in the miscible systems is absorbed into and swells the polymer network of the PSA, thereby exhibiting reduced molecular mobility, while the PSA attains significant molecular conformation relaxation and entropy increase. It was also found that LC molecules extensively participate in molecular relaxation of the PSA throughout the composition range studied. The molecular mobility of LC is inhibited as the volume fraction of DT2287 increases, suggesting that the PSA molecular network reduces the molecular mobility of LC by closely involving LC molecules in its relaxation, and thereby may enhancing the physical stability of the systems. No strong intermolecular interactions between the two components were found based upon the results of T(g)-composition analysis, and was confirmed by FT-IR studies. This indicates that the analysis based on the BSC equation provides more precise characterization of polymer systems than the T(g) -composition analysis based on other equations cited.

Acrylic Resins↗
PubMed2006

Influence of metabolic network structure and function on enzyme evolution.

BACKGROUND: Most studies of molecular evolution are focused on individual genes and proteins. However, understanding the design principles and evolutionary properties of molecular networks requires a system-wide perspective. In the present work we connect molecular evolution on the gene level with system properties of a cellular metabolic network. In contrast to protein interaction networks, where several previous studies investigated the molecular evolution of proteins, metabolic networks have a relatively well-defined global function. The ability to consider fluxes in a metabolic network allows us to relate the functional role of each enzyme in a network to its rate of evolution. RESULTS: Our results, based on the yeast metabolic network, demonstrate that important evolutionary processes, such as the fixation of single nucleotide mutations, gene duplications, and gene deletions, are influenced by the structure and function of the network. Specifically, central and highly connected enzymes evolve more slowly than less connected enzymes. Also, enzymes carrying high metabolic fluxes under natural biological conditions experience higher evolutionary constraints. Genes encoding enzymes with high connectivity and high metabolic flux have higher chances to retain duplicates in evolution. In contrast to protein interaction networks, highly connected enzymes are no more likely to be essential compared to less connected enzymes. CONCLUSION: The presented analysis of evolutionary constraints, gene duplication, and essentiality demonstrates that the structure and function of a metabolic network shapes the evolution of its enzymes. Our results underscore the need for systems-based approaches in studies of molecular evolution.

Amino Acid Substitution↗