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At least 595 records · Page 33Linked to original sources
PubMed2006

Sequence-specific association in aqueous media by integrating hydrogen bonding and dynamic covalent interactions.

Oligoamide strands that associate in a sequence-specific fashion into hydrogen-bonded duplexes in nonpolar solvents were converted into disulfide cross-linked duplexes in aqueous media. Thus, by incorporating trityl-protected thiol groups, which allows the reversible formation of disulfide bonds, into the oligoamide strands, only duplexes consisting of complementary hydrogen-bonding sequences were formed in aqueous solution as well as in methanol. The sequence-specific cross-linking of oligoamide strands was confirmed by MALDI-TOF, reverse-phase HPLC, and by isolating a cross-linked duplex. This study demonstrates that the sequence-specificity characteristic of multiply hydrogen-bonded systems can be extended into competitive media through the interplay of H-bonding and reversible covalent interactions, based on which a new class of molecular associating and ligating units that are compatible with both polar and nonpolar environments can be conveniently obtained.

Amides↗
PubMed2003

GDE1/MIR16 is a glycerophosphoinositol phosphodiesterase regulated by stimulation of G protein-coupled receptors.

Previously we identified MIR16 (membrane interacting protein of RGS16) as an integral membrane glycoprotein that interacts with regulator of G protein signaling proteins and shares significant sequence homology with bacterial glycerophosphodiester phosphodiesterases (GDEs), suggesting that it is a putative mammalian GDE. Here we show that MIR16 belongs to a large, evolutionarily conserved family of GDEs with a characteristic putative catalytic domain that shares a common motif (amino acids 92-116) with the catalytic domains of mammalian phosphoinositide phospholipases C. Expression of wild-type MIR16 (renamed GDE1), but not two catalytic domain mutants (E97A/D99A and H112A), leads to a dramatic increase in glycerophosphoinositol phosphodiesterase (GPI-PDE) activity in HEK 293T cells. Analysis of substrate specificity shows that GDE1/MIR16 selectively hydrolyzes GPI over glycerophosphocholine. The GPI-PDE activity of GDE1/MIR16 expressed in HEK 293T cells can be regulated by stimulation of G protein-coupled, alpha/beta-adrenergic, and lysophospholipid receptors. Membrane topology studies suggest a model in which the catalytic GDE domain faces the lumenextracellular space and the C terminus faces the cytoplasm. Our results suggest that by serving as a PDE for GPI with its activity regulated by G protein signaling, GDE1/MIR16 provides a link between phosphoinositide metabolism and G protein signal transduction.

Amino Acid Sequence↗
PubMed2005

Analysis of flowering pathway integrators in Arabidopsis.

Flowering is regulated by an integrated network of several genetic pathways in Arabidopsis. The key genes integrating multiple flowering pathways are FT, SOC1 and LFY. To elucidate the interactions among these integrators, genetic analyses were performed. FT and SOC1 share the common upstream regulators CO, a key component in the long day pathway, and FLC, a flowering repressor integrating autonomous and vernalization pathways. However, the soc1 mutation further delayed the flowering time of long day pathway mutants including ft, demonstrating that SOC1 acts partially independently of FT. Although soc1 did not show an obvious defect in flower meristem determination on its own, it dramatically increased the number of coflorescences in a lfy mutant, which is indicative of a defect in floral initiation. Therefore, double mutant analysis shows that the three integrators have both overlapping and independent functions in the determination of flowering time and floral initiation. The expression analysis showed that FT regulates SOC1 expression, and SOC1 regulates LFY expression, but not vice versa, which is consistent with the fact that FT and LFY have the least overlapping functions among the three integrators. The triple mutation ft soc1 lfy did not block flowering completely under long days, indicating the presence of other integrators. Finally, vernalization accelerated flowering of flc ft soc1 and ft soc1 lfy triple mutants, which shows that the vernalization pathway also has targets other than FLC, FT, SOC1 and LFY. Our genetic analysis reveals the intricate nature of genetic networks for flowering.

Arabidopsis↗
PubMed2005

Pathway analysis of coronary atherosclerosis.

Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.

Adult↗
PubMed2003

Evo-Devo: evolutionary developmental mechanisms.

Evolutionary developmental biology (Evo-Devo) as a discipline is concerned, among other things, with discovering and understanding the role of changes in developmental mechanisms in the evolutionary origin of aspects of the phenotype. In a very real sense, Evo-Devo opens the black box between genotype and phenotype, or more properly, phenotypes as multiple life history stages arise in many organisms from a single genotype. Changes in the timing or positioning of an aspect of development in a descendant relative to an ancestor (heterochrony and heterotopy) were two evolutionary developmental mechanisms identified by Ernst Haeckel in the 1870s. Many more have since been identified, in large part because of our enhanced understanding of development and because new mechanisms emerge as development proceeds: the transfer from maternal to zygotic genomic control; cell-to-cell interactions; cell differentiation and cell migration; embryonic inductions; functional interactions at the tissue and organ levels; growth. Within these emergent processes, gene networks and gene cascades (genetic modules) link the genotype with morphogenetic units (cellular modules, namely germ layers, embryonic fields or cellular condensations), while epigenetic processes such as embryonic inductions, tissue interactions and functional integration, link morphogenetic units to the phenotype. Evolutionary developmental mechanisms also include interactions between individuals of the same species, individuals of different species, and species and their biotic and/or abiotic environment. Such interactions link ecological communities. Importantly, there is little to distinguish the causality that underlies these interactions from that which underlies inductive interactions within embryos.

Animals↗
PubMed2002

Direct interactions between corepressors and coactivators permit the integration of nuclear receptor-mediated repression and activation.

The unliganded thyroid hormone receptor beta (TRbeta) represses the basal transcriptional activity of target genes, in part through interactions with the nuclear receptor corepressor (N-CoR). In this study we have identified a rather unexpected interaction between N-CoR and the nuclear receptor coactivator ACTR. We have demonstrated in vitro and in intact cells that N-CoR directly associates with ACTR and that the interaction surfaces on N-CoR and ACTR are distinct from those required for TR binding. The significance of this finding was demonstrated by showing that N-CoR facilitates an interaction between unliganded-TRbeta and ACTR. One possible consequence of the formation of the trimeric complex of N-CoR/ACTR/unliganded-TR is that N-CoR may raise the local concentration of ACTR at target gene promoters. In support of this hypothesis it was demonstrated that the presence of N-CoR can enhance TRbeta-mediated transcriptional activation. It is proposed, therefore, that TRbeta- mediated activation and repression are integrally linked in a manner that is not predicted by the current models of nuclear receptor action.

Acetyltransferases↗
PubMed1999

Comparison of the potentials of mean force for alanine tetrapeptide between integral equation theory and simulation.

The dielectrically consistent reference interaction site model (DRISM) integral equation theory is applied to determine the potential of mean force (PMF) for an alanine tetramer. A stochastic dynamics simulation of the alanine tetramer using this PMF is then compared with an explicit water molecular dynamics simulation. In addition, comparison is also done with simulations using other solvent models like the extended reference interaction site model (XRISM) theory, constant dielectric and linear distance-dependent dielectric models. The results show that the DRISM method offers a fairly accurate and computationally inexpensive alternative to explicit water simulations for studies on small peptides.

Algorithms↗
PubMedDate not supplied

[Specifics of cognitive behavioral therapy in schizophrenia. Integrated program of psychological therapy].

According to the authors, information processing disorders contribute essentially to the vulnerability of the schizophrenic patient. Attentional/perceptual and cognitive disorders exert a pervasive influence on more complex levels of overt behavior in schizophrenia. Conversely, behavioral deficits influence cognitive functioning as well. Psychosocial rehabilitation of patients with schizophrenia must therefore address the impact of disordered attentional/perceptual and conceptual processes and their integrating organization on behavior as well as the effects of behavioral dysfunctions on cognition. The Integrated Psychological Treatment Program (IPT) for schizophrenic patients provides means of addressing these interactions. The designation "integrated" implies that the treatment is directed at cognitive disorders as well as behavioral/social deficits by using highly structured interventions, and is carried out with "reality-oriented" material. This treatment approach has been developed by Brenner and al., since 1976. The original IPT includes five subprograms: Cognitive Differentiation, Social Perception, Verbal Communication, Social Skills and Interpersonal Problem Solving. Patients first work on improving disordered basic cognitive functions in the Cognitive Differentiation subprogram. Exercises are directed at impairments in attentional/perceptual and conceptual processes. Mastery of this subprogram leads to the Social Perception subprogram, which aims at disturbances in processes of stimulus discrimination and interpretation on perceiving and assessing social interactions. The Verbal Communication subprogram follows successful completion of the previous subprograms and trains associative-semantic processes as well as basic skills necessary for conversation. In the Social Skills subprogram, interpersonal behaviors and self-instructions required for gaining instrumental and emotional aims are taught.(ABSTRACT TRUNCATED AT 250 WORDS)

Affective Symptoms↗
PubMed2000

A model of troponin-I in complex with troponin-C using hybrid experimental data: the inhibitory region is a beta-hairpin.

We present a model for the skeletal muscle troponin-C (TnC)/troponin-I (TnI) interaction, a critical molecular switch that is responsible for calcium-dependent regulation of the contractile mechanism. Despite concerted efforts by multiple groups for more than a decade, attempts to crystallize troponin-C in complex with troponin-I, or in the ternary troponin-complex, have not yet delivered a high-resolution structure. Many groups have pursued different experimental strategies, such as X-ray crystallography, NMR, small-angle scattering, chemical cross-linking, and fluorescent resonance energy transfer (FRET) to gain insights into the nature of the TnC/TnI interaction. We have integrated the results of these experiments to develop a model of the TnC/TnI interaction, using an atomic model of TnC as a scaffold. The TnI sequence was fit to each of two alternate neutron scattering envelopes: one that winds about TnC in a left-handed sense (Model L), and another that winds about TnC in a right-handed sense (Model R). Information from crystallography and NMR experiments was used to define segments of the models. Tests show that both models are consistent with available cross-linking and FRET data. The inhibitory region TnI(95-114) is modeled as a flexible beta-hairpin, and in both models it is localized to the same region on the central helix of TnC. The sequence of the inhibitory region is similar to that of a beta-hairpin region of the actin-binding protein profilin. This similarity supports our model and suggests the possibility of using an available profilin/actin crystal structure to model the TnI/actin interaction. We propose that the beta-hairpin is an important structural motif that communicates the Ca2+-activated troponin regulatory signal to actin.

Amino Acid Sequence↗
PubMed2004

Functionally and structurally integrated computational modeling of ventricular physiology.

Computational biology is integrative in several ways. Functionally, computational models are valuable for integrating the many interacting processes within biochemical networks and the many interacting physiological subsystems within the cell. Structurally detailed models provide a way of integrating across scales of biological organization from molecule to organism. Data integration across diverse laboratory and clinical measurements is another unique strength of computational biology. We describe examples of all three categories of integration by using recent advances in modeling cardiac excitation-contraction coupling and whole-heart electromechanics in health and disease.

Animals↗
PubMed2006

Expanding the scope of health information systems. Challenges and developments.

OBJECTIVES: To identify current challenges and developments in health information systems. METHODS: Reports on HIS, eHealth and process support were analyzed, core problems and challenges were identified. RESULTS AND CONCLUSION: Health information systems are extending their scope towards regional networks and health IT infrastructures. Integration, interoperability and interaction design are still today's core problems. Additional problems arise through the integration of genetic information into the health care process. There are noticeable trends towards solutions for these problems.

Computational Biology↗
PubMed1991

[Interactions of the infant with its partners: evaluation of preventive and therapeutic approaches].

Interactions between the infant and its partners are defined and described on three levels: behavior, affect, fantasy, with a special focus on the functioning of the infant. The dynamics of the parent/infant relationships are analyzed along transactional theories: the infant and its partners influence each other in a constant process of developing and changing. Together with acknowledging the baby's active role in the relation, we seek better understanding of how the infant shapes up throughout transactions. Different assessment methods of the interactions are analyzed both within a clinical framework and a research framework, and examples of assessment format are given. The transactional perspective in clinical practice with the infant introduces a new model for understanding the pathogenesis of relational disturbances. It appears necessary to conceptualize a specific nosology of interactive pathology, beyond the reference to parental or infant pathology; we thus propose a classification of interactive disturbances by integrating the three levels (behavior, affect, fantasy). The aim of this investigation of interactions, based on an attempt to synthetize anglo-saxon and european research in the field, is to outline a new perspective in clinical concepts and practice which is not solely focused on the description of behaviors in infant interactions with its partners. This viewpoint, resolutely psychopathological in its orientation, implies an empathic approach which leads to important therapeutic changes and legitimizes early preventive interventions.

Affect↗
PubMed1999

Immunological self/nonself discrimination: integration of self vs nonself during cognate T cell interactions with antigen-presenting cells.

The hypothesis is presented that immunological integration of nonefficacious vs efficacious T cell antigen receptor (TCR) signals are foundational for self/nonself discrimination and that multiple integrative mechanisms are intrinsic to the molecular to molar organization of an adaptive immune response. These integrative mechanisms are proposed to adaptively regulate expression of costimulatory signals, such that foreign proteins are associated with the expression of costimulatory signals, whereas self-proteins are associated with the lack of costimulatory signaling. Overall, this model offers several unique contributions to the study of immunology. First, this model postulates that cognate TCR/major histocompatibility complex (MHC) interactions are sufficient to adaptively mediate immunological self/nonself discrimination. This model thereby offers a unique alternative to models that largely rely on innate immunity to prime immune discrimination. Second, the integrative model argues that the immune system can simultaneously reinforce self-tolerance and promote immunity to foreign organisms at the same time and in the same location. Many alternative models presume that pathogenic self-reactive T cells do not exist at the outset of an immune response against foreign agents. Third, the integrative model uniquely predicts relationships between immunodeficiency and autoimmune pathogenesis. Fourth, this model illustrates the regulatory advantages of cognate antigen presenting cell (APC) systems (i.e., T cell or B cell APC) compared to nonspecific APC. Cognate APC systems together with the respective clonotypic responders may comprise a fundamental "network" of lymphoid cells. Such networks would have clone-specific regulatory capabilities and may be central for immunological self/nonself discrimination. Fifth, this model provides an explanation for "infectious" tolerance without creating specialized subsets of "suppressor" or "regulatory" T cells. Each mature T cell retains the potential to reinforce tolerance or mediate immunity, depending on the specific antigenic cues present in the immediate environment.

Animals↗