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PubMed1986

[Neurochemical aspects of interneuronal communication].

It is suggested that the term neurotransmission, which is used to designate neuronal communication at synaptic level, be associated to the less restrictive term neuromodulation. These two types of intercellular communication seem in fact to be two basically different mechanisms, both of which contribute to neuronal integration. The integration of neuronal information at cellular level appears to be more complex than the simple addition of excitatory plus inhibitory influences eliciting postsynaptic responses. Evidence has been obtained that non synaptic transmission can alter the capacity of a given synapse to transfer neuronal information from the presynaptic element to the postsynaptic neuron. For instance, presynaptic mechanisms provide evidence for the functional independence of the nerve terminals, since the release of neuromediators by the latter is sometimes independent of the axonal firing rate. Similarly, the somato-dendritic part of some neurons exhibits intrinsic functions, such as a dendritic release of neuromediator, suggesting that the control of the axonal firing rate takes place partly at this somato-dendritic level and does not depend for the totality on afferent axonic information. The intercellular operations which organize individual neurons into neuronal networks will also occur either at somato-dendritic level or at the level of specific nerve terminals selected as the result of presynaptic interactions. This integration of neuronal information also seems to take place at postsynaptic level, where cooperative interactions have been shown to occur between various receptors. These mechanisms will function at the level of a single nerve terminal containing more than one neuromediator. Neuromodulation can therefore be said to involve very efficient adaptive processes, which help to account for the fact that such large behavioral responses are expressed by such a small number of neuronal elements.

Animals↗

PubMed2003

An oriented peptide array library (OPAL) strategy to study protein-protein interactions.

One of the major questions in signal transduction is how the specificities of protein-protein interactions determine the assembly of distinct signaling complexes in response to stimuli. Several peptide library methods have been developed and widely used to study protein-protein interactions. These approaches primarily rely on peptide or DNA sequencing to identify the peptide or consensus motif for binding and may prove too costly or difficult to accommodate high throughput applications. We report here an oriented peptide array library (OPAL) approach that should facilitate high throughput proteomic analysis of protein-protein interactions. OPAL integrates the principles of both the oriented peptide libraries and array technologies. Hundreds of pools of oriented peptide libraries are synthesized as amino acid scan arrays. We demonstrate that these arrays can be used to map the specificities of a variety of interactions, including antibodies, protein domains such Src homology 2 domains, and protein kinases.

Animals↗

PubMed1991

Role of lymphocyte adhesion receptors in transient interactions and cell locomotion.

Lymphocytes adhere to other cells and extracellular matrix in the process of immunological recognition and lymphocyte recirculation. This review focuses on regulation of lymphocyte adhesion and the use of adhesion mechanisms by lymphocytes to obtain information about their immediate environment. The CD2 and LFA-1 adhesion receptors appear to have distinct roles in the regulation of adhesion and modulation of T lymphocyte activation. Adhesion mediated by interaction of CD2 with LFA-3 is dramatically altered by surface charge and adhesion receptor density in such a way that this pathway is latent in resting T lymphocytes but becomes active over a period of hours following T-cell activation. CD2 ligation can mediate or enhance T-cell activation, suggesting that signals from CD2/LFA-3 adhesive interactions are integrated with signals from the T-cell antigen receptor during immunological recognition. A model for the role of LFA-3 lateral diffusion in adhesion is presented, based on the lateral diffusion of different LFA-3 forms in glass supported planar membranes. Interaction of LFA-1 with ICAMs is also regulated by cell activation but in a different way than in interaction of CD2 with LFA-3. LFA-1 avidity for ICAMs is transiently increased by T-cell activation over a period of minutes. Cycles of avidity change are also observed for other T lymphocyte integrins which bind to extracellular matrix components. We propose that integrin avidity cycles may have an important role in the interconnected phenomena of locomotion, initial cell-cell adhesion, and cell-cell deadhesion. Recent observations on recirculation of T lymphocyte subpopulations are discussed in the context of general lessons learned from study of the CD2/LFA-3 and LFA-1/ICAM adhesion mechanisms.

Animals↗

PubMed1993

Evaluation of a social interaction coaching program in an integrated day-care setting.

We used a multiple baseline design across teachers (with a reversal phase for 1 teacher) to evaluate the direct and indirect effects of a structured coaching procedure on the teaching behaviors of 3 day-care teachers. Structured coaching preceding daily caregiver routines resulted in (a) substantial increases in adult delivery of behavioral support of social interaction during group activities with 2- and 4-year-old children and (b) marked collateral increases in positive interactions of socially withdrawn children. Long-term maintenance effects were demonstrated by both the teachers and target children, and social validity measures indicated that the teachers rated coaching very positively on several dimensions. The results are discussed in relation to in-service training of day-care staff, the concept of coaching as a setting event, and the dissemination of teaching technology related to social interaction of young children.

Adult↗

PubMedDate not supplied

Therapist-child interaction in the middle minutes of sensory integration treatment.

The purpose of this study was to describe the management of challenge during therapist-child interaction in sensory integration treatment. This descriptive and relational study of the middle minutes of treatment sessions partially replicated an earlier study of the beginning minutes. One-minute videotape clips taken from the middle minutes of 38 treatment sessions were shown to therapist judges who rated qualities of therapist and child behavior. Two patterns emerged from the correlations of ratings: work and playfulness. Work for the child involved trying hard, cooperating and seeking assistance, whereas work for the therapist involved assisting and guiding the child. Play for the child included enjoying the activity, being successful and confident, and trying hard. For the therapist, play involved being creative and behaving playfully. Patterns of work and play were different across different levels of challenge to the child.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

The role of electrostatics in the interaction of the inhibitory region of troponin I with troponin C.

We have addressed the electrostatic interactions occurring between the inhibitory region of cardiac troponin I with the C-lobe of troponin C using scanning glycine mutagenesis of the inhibitory region. We report variations in the electric potentials due to mutation of charged residues within this complex based upon the solved NMR structure (1OZS). These results demonstrate the importance of electrostatics within this complex, and it is proposed that electrostatic interactions are integral to the formation and function of larger ternary troponin complexes. To address this hypothesis, we report (15)N NMR relaxation measurements, which suggest that, within a ternary complex involving the C-lobe and the N-terminal region of troponin I (residues 34-71), the inhibitory region maintains the electrostatic interactions with the E-helix of the C-lobe as observed within the binary complex. These results imply that, in solution, the cardiac troponin complex behaves in a manner consistent with that of the crystal structure of the skeletal isoform (1YTZ). A cardiac troponin complex possessing domain orientations similar to that of the skeletal isoform provides structural insights into altered troponin I activities as observed for the familial hypertrophic cardiomyopathy mutation R144G and phosphorylation of Thr142.

Amino Acid Sequence↗

PubMed1986

Interface between membrane biology and clinical medicine.

Many enzymes that are embedded within membranes of cells are sensitive to the chemical and physical properties of the lipid components of the membrane. Because of this, the functions of these integral membrane-bound enzymes can be regulated to some extent by changes within the lipid portions of biologic membranes. That the functions of membrane-bound proteins can be manipulated by modifications of their intimate environment is not surprising. It is well known, for example, that the properties of the surrounding aqueous phase can modulate the function of proteins that are soluble in the cytosol of cells. In contrast, whereas significant changes in the chemical composition and physical properties of the aqueous portion of the cell (e.g., ionic strength and pH) are not allowed, normally tolerable fluctuations of diet appear to influence significantly the composition and properties of the lipid portions of intracellular membranes to the extent of altering the function of some membrane-bound enzymes. In addition, it appears that changes of this type can be induced by diseases that alter dietary intake and/or intermediary metabolism. In other words, it is likely that the functions of at least some integral membrane proteins can be manipulated in patients. Such manipulations may prove to be efficacious. Alternatively, the importance of diet and processes of intermediary metabolism for altering the course of certain diseases may not be fully appreciated. It is worthwhile to review, therefore, current ideas of how the lipid portion of a membrane interacts with integral proteins. The property of the lipids that appears to be most important in this regard is their viscosity. The types of manipulations of function of membrane-bound enzymes that can be achieved are illustrated by in vitro effects secondary to varying the lipids used to reconstitute pure, delipidated forms of these enzymes. The functions of pure delipidated enzymes are discussed for the hepatic drug-metabolizing enzyme uridine diphosphoglucuronyltransferase. In addition, data are presented to indicate that the function of this enzyme can be modified extensively in intact animals by changing the diet.

Cell Membrane↗

PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗

PubMed1995

A SNARE-like protein required for traffic through the Golgi complex.

The secretory pathway of eukaryotic cells comprises several distinct membrane-bound compartments which are interconnected by transport vesicles that pinch off from one membrane and fuse with the next. Targeting of these vesicles is mediated in part by interactions between integral membrane proteins on the vesicles and target organelles (soluble NSF attachment protein receptors (SNAREs)), termed v-SNAREs and t-SNAREs, respectively. SNAREs required for endoplasmic reticulum (ER)-Golgi transport and for fusion of vesicles with the plasma membrane are already known. Here we identify two yeast membrane proteins that show genetic interactions with Sed5p, which is the t-SNARE for ER-Golgi traffic. One of these membrane proteins, Sft1p, is structurally similar to the known v-SNAREs and is required for transport from an early to a later Golgi compartment. Our results indicate that a single t-SNARE can control more than one transport step, and provide the first candidate for a SNARE involved in intra-Golgi traffic.

Amino Acid Sequence↗

PubMed1997

Adenovirus type 12 DNA firmly associates with mammalian chromosomes early after virus infection or after DNA transfer by the addition of DNA to the cell culture medium.

Human adenovirus type 12 (Ad12) infects human cells productively and leads to viral replication, whereas infection of hamster cells remains abortive, with total blocks in viral DNA replication and late viral gene transcription. The intranuclear fate of Ad12 DNA in productively infected human cells and in abortively infected hamster cells was monitored by using the fluorescent in situ hybridization (FISH) technique. Human HeLa cells, primary human umbilical cord fibroblasts, hamster BHK21 cells, primary embryonal hamster cells, and the Ad12-transformed T637 hamster cell line were studied. As early as 2 h after infection, extensive association of Ad12 DNA with metaphase chromosomes was demonstrated by FISH in all of these cells. Chromosomal association continued until late (24 to 28 h) after infection, when about 100% of the human cell nuclei and 70 to 80% of the hamster cell nuclei showed distinct FISH signals. This chromosomal association of Ad12 DNA in infected cells seemed to be rather firm, since it proved to be resistant to mechanically stretching the chromosomes and to different types of chemical treatment. Moreover, laser scan microscopy of mechanically stretched chromosomes from Ad12-infected HeLa cells and from the Ad12-transformed T637 cell line, with about 20 copies of Ad12 DNA provably integrated, revealed identical FISH patterns. Therefore, it was likely that even in infected cells the chromosomal association of Ad12 DNA was very similar to the integrated state. Late in productively infected cells, large nuclear areas were taken over by viral DNA replication, as visualized by FISH in interphase nuclei. Chromosomal association at many sites was frequently limited to one chromatid, but signals in adjacent positions on both chromatids were also seen. Upon the long-term cultivation and passage of abortively infected BHK21 cells for 96 h after infection, a gradual decrease of viral DNA association with chromosomes was observed. Integration of Ad12 DNA in hamster cells early after infection was previously documented, and recombination between viral and cellular DNAs in human cells was also shown. The FISH data on extensive chromosomal association of Ad12 DNA suggest a means to study the pathway of Ad12 DNA from early steps in viral infection via chromosomal interactions to integration events. In a different approach, Ad12 DNA, Ad12 DNA with the terminal protein covalently linked to its ends (Ad12 DNA-TP), or Ad2 DNA was simply added to the culture medium of HeLa or BHK21 cells. Precipitation or selection procedures were avoided. Depending on the experimental conditions, up to 25 to 30% of the interphase nuclei of HeLa cells and 9 to 19% of the interphase nuclei of BHK21 cells showed positive FISH signals at 24 h after the addition of DNA. Viral DNA also became associated in some cases with both chromatids. The uptake of Ad12 DNA-TP appeared to be 10 to 20 times more efficient than that of Ad12 DNA completely freed of proteins. Control bacteriophage lambda, M13, or plasmid DNA could not be detected in the nuclei under these conditions.

Adenoviruses, Human↗

PubMed2026

InsightRP2-An Interdisciplinary Approach Toward Therapy Development in RP2-Associated Retinopathy.

Advancing the development of specific gene therapies for rare genetic eye disorders is a major challenge in modern translational vision research. It requires integrated clinical, molecular, mechanistic, and regulatory expertise, yet these aspects are often addressed in isolation. Combining complementary skills, knowledge, and expertise within an integrated, highly interactive research framework has the capacity to drive and advance therapeutic development. Moreover, early-stage involvement of patients and targeted clinical observation, alongside molecular and therapeutic research, potentially enable clinical trial readiness and support the translation of preclinical therapeutic innovations into clinical care. In this Perspective article, we present the InsightRP2 framework, an integrated translational strategy that incorporates clinical data, artificial intelligence-supported imaging analysis, experimental disease modeling, and adeno-associated virus design with the aim to facilitate the development of a targeted gene therapy for RP2-associated retinitis pigmentosa.

AAV↗

PubMed2006

Retrotransposon suicide: formation of Ty1 circles and autointegration via a central DNA flap.

Despite their evolutionary distance, the Saccharomyces cerevisiae retrotransposon Ty1 and retroviruses use similar strategies for replication, integration, and interactions with their hosts. Here we examine the formation of circular Ty1 DNA, which is comparable to the dead-end circular products that arise during retroviral infection. Appreciable levels of circular Ty1 DNA are present with one-long terminal repeat (LTR) circles and deleted circles comprising major classes, while two-LTR circles are enriched when integration is defective. One-LTR circles persist when homologous recombination pathways are blocked by mutation, suggesting that they result from reverse transcription. Ty1 autointegration events readily occur, and many are coincident with and dependent upon DNA flap structures that result from DNA synthesis initiated at the central polypurine tract. These results suggest that Ty1-specific mechanisms minimize copy number and raise the possibility that special DNA structures are a targeting determinant.

Base Sequence↗

PubMed2006

Direct membrane protein-DNA interactions required early in nuclear envelope assembly.

Among the earliest events in postmitotic nuclear envelope (NE) assembly are the interactions between chromatin and the membranes that will fuse to form the NE. It has been proposed that interactions between integral NE proteins and chromatin proteins mediate initial membrane recruitment to chromatin. We show that several transmembrane NE proteins bind to DNA directly and that NE membrane proteins as a class are enriched in long, basic domains that potentially bind DNA. Membrane fractions that are essential for NE formation are shown to bind directly to protein-free DNA, and our data suggest that these interactions are critical for early steps in NE assembly.

Animals↗

PubMed1999

Collaborative care models for the treatment of depression. Based on a presentation by Wayne Katon, MD.

The quality of treatment of depression in the primary care setting is limited by inadequate patient education, lack of adherence to treatment regimens, poor patient follow-up, and the absence of close collaboration between medical and mental health systems. Integrated models of care may help overcome some of these barriers and improve adherence, satisfaction with care, and outcomes. The health and economic outcomes of randomized controlled trials in which 2 models of collaborative care--psychiatrist and psychiatrist/psychologist plus primary care--were compared with usual primary care. Interventions were delivered at multiple levels and included enhanced patient education and monitoring, physician training, patient-physician interaction, and integration of a psychiatrist or psychologist into the primary care setting. After the interventions, patients with major depression showed significant improvements in adherence, satisfaction with care, and depressive outcomes, whereas, in patients with minor depression, outcomes were not significantly affected by the intervention. An analysis revealed that the cost of the interventions was higher than usual care, and that there was little evidence of any cost offset. However, in terms of cost effectiveness, the cost of successfully treating one patient with major depression was lower with the interventions, and the incremental costs of collaborative intervention were substantially lower than the usual primary care costs.

Continuity of Patient Care↗

PubMed2005

The Pseudomonas fluorescens SBW25 wrinkly spreader biofilm requires attachment factor, cellulose fibre and LPS interactions to maintain strength and integrity.

The wrinkly spreader (WS) isolate of Pseudomonas fluorescens SBW25 forms a substantial biofilm at the air-liquid interface. The biofilm is composed of an extracellular partially acetylated cellulose-fibre matrix, and previous mutagenesis of WS with mini-Tn5 had identified both the regulatory and cellulose-biosynthetic operons. One uncharacterized WS mutant, WS-5, still expressed cellulose but produced very weak biofilms. In this work, the mini-Tn5 insertion site in WS-5 has been identified as being immediately upstream of the tol-pal operon. Like Tol-Pal mutants of other Gram-negative bacteria, WS-5 showed a "leaky-membrane" phenotype, including the serendipitous ability to utilize sucrose, increased uptake of the hydrophilic dye propidium iodide, and the loss of lipopolysaccharide (LPS) expression. WS-5 cells were altered in relative hydrophobicity, and showed poorer recruitment and maintenance in the biofilm than WS. The WS-5 biofilm was also less sensitive to chemical interference during development. However, growth rate, cellulose expression and attachment were not significantly different between WS and WS-5. Finally, WS-5 biofilms could be partially complemented with WS-4, a biofilm- and attachment-deficient mutant that expressed LPS, resulting in a mixed biofilm with significantly increased strength. These findings show that a major component of the WS air-liquid biofilm strength results from the interactions between LPS and the cellulose matrix of the biofilm--and that in the WS biofilm, cellulose fibres, attachment factor and LPS are required for biofilm development, strength and integrity.

Bacterial Adhesion↗

PubMed2004

Autonomy and integrity: upholding older adult patients' dignity.

AIM: The aim of this study was to deepen understanding of the relationship between autonomy and integrity in interactions between patients and individual health care workers in real-life care situations. METHOD: The data reported here are from a 6- and 12-month follow-up of the teaching of ethics to health care professionals working with older people. The data collection method used was participant observation. Health professionals' caring behaviour in everyday situations was observed from the point of view of patients' autonomy and integrity. Theoretical frameworks relating to autonomy and integrity were used to analyse the data. FINDINGS: The structural framework was useful for identifying the two concepts and their relationship in everyday situations. The data suggest that the two concepts are ethically complex. Autonomy is grounded in respect for patients' ability to choose, decide and take responsibility for their own lives. Autonomy varies within and between individuals and is dependent on context and on those involved. It stresses the intrinsic value of patients, which marks their worth independently of others. Integrity, however, is bound to patients' very existence, no matter what their physical and mental conditions, and must be respected regardless of their ability to act autonomously. CONCLUSION: The concepts of autonomy and integrity appear to presuppose one another and to be indivisible if older adult patients' dignity is to be maintained. This implies that when patients' autonomy is supported their integrity is protected and, consequently, their dignity upheld.

Adult↗

PubMed2006

Developing a medical image content repository for e-learning.

The integration of medical informatics and e-learning systems could provide many advanced applications including training, knowledge management, telemedicine, etc. Currently, both the domains of e-learning and medical image have sophisticated specifications and standards. It is a great challenge to bring about integration. In this paper, we describe the development of a Web interface for searching and viewing medical images that are stored in standard medical image servers. With the creation of a Web solution, we have reduced the overheads of integration. We have packaged Digital Imaging and Communications in Medicine (DICOM) network services as a component that can be used via a Web server. The Web server constitutes a content repository for searching, editing, and storing Web-based medical image content. This is a simple method by which the use of Picture Archiving and Communication System (PACS) can be extended. We show that the content repository can easily interact and integrate with a learning system. With the integration, the user can easily generate and assign medical image content for e-learning. A Web solution might be the simplest way for system integration. The demonstration in this paper should be useful as a method of expanding the usage of medical information. The construction of a Web-based repository and integrated with a learning system may be also applicable to other domains.

Computer Security↗

PubMed1998

The neuropsychology of 3-D space.

The neuropsychological literature on 3-D spatial interactions is integrated using a model of 4 major behavioral realms: (a) peripersonal (visuomotor operations in near-body space), (b) focal extrapersonal (visual search and object recognition), (c) action extrapersonal (orienting in topographically defined space), and (d) ambient extrapersonal (orienting in earth-fixed space). Each is associated with a distinct cortical network: dorsolateral peripersonal, predominantly ventrolateral focal-extrapersonal, predominantly ventromedial action-extrapersonal, and predominantly dorsomedial ambient-extrapersonal systems. Interactions in 3-D space are also regulated neurochemically with dopaminergic and cholinergic excitation associated with extrapersonal activation and noradrenergic and serotonergic excitation associated with peripersonal activation. This model can help explain the 3-D imbalances in prominant neuropsychological disorders.

Humans↗