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At least 109 records · Page 6Linked to original sources
PubMed1994

The roles of starvation and selective substrates in the emergence of araB-lacZ fusion clones.

The araB-lacZ fusion system has been a key case in the 'directed mutation' controversy. Fusions did not occur detectably during normal growth but formed readily after prolonged incubation on selective Ara-Lac medium. To distinguish the roles of starvation stress and selective substrates in coding sequence fusions, we applied sib selection and PCR technologies. Sib selection of the prefusion strain, MCS2, starved under aerobic conditions permitted us to isolate active fusion clones which had never been in contact with arabinose or lactose. Hence, a directive role for selective substrates is not essential. Aerobiosis was necessary for fusions to appear in glucose-starved cultures. The difference in fusion formation between normal and starved conditions is best explained by the response of a signal transduction network to physiological stimuli to activate Mu prophage joining of araB and lacZ sequences. PCR analysis revealed that direct plating on selective Ara-Lac agar yielded mostly a single class of 'standard' fusions, while sib selection yielded a broader spectrum of fusion structures. Standard fusions were found to occur within a narrow 9 bp window in lacZ. The high frequency of standard fusions in glucose-starved cultures suggested efficient and/or specific Mu action.

Base Sequence↗
PubMed1990

Effects of proteoglycan extraction on the tensile behavior of articular cartilage.

We undertook an interdisciplinary biomechanical and biochemical study to explore the extent and manner in which the total pool of proteoglycans influences the kinetic and static behavior of bovine articular cartilage in tension. Two biomechanical tests were used: (a) the viscoelastic creep test and (b) a slow constant-rate uniaxial tension test; and two enzymatic proteoglycan extraction procedures were used: (a) chondroitinase ABC treatment and (b) a sequential enzymatic treatment with chondroitinase ABC, trypsin, and Streptomyces hyaluronidase. We found that the viscoelastic creep response of all cartilage specimens may be divided into two distinct phases: an initial phase (less than 15 s), characterized by a rapid increase in strain following load application, and a late phase (15 s less than or equal to t less than 25,000 s), characterized by a more gradual increase in strain. A major finding of this study is that the kinetics of the creep response is greatly influenced by the glycosaminoglycan content of the tissue. For untreated and control specimens, the initial response comprises about 50% of the total strain, while for chondroitinase ABC and sequentially extracted specimens, the initial response comprises up to 83% of the total strain. Furthermore, most untreated and control specimens did not reach equilibrium within the 25,000 s test period, while enzymatically digested specimens often reached equilibrium in less than 100 s. Thus, we conclude that through their physical restraints on collagen, the bulk of proteoglycan present in the tissue acts to retard fibrillar reorganization and alignment under tensile loading, thereby effectively preventing sudden extension of the collagen network. In contrast, the results of our slow constant-rate uniaxial tension experiment show that essentially complete extraction of proteoglycan glycosaminoglycans does not affect the intrinsic tensile stiffness and strength of cartilage specimens or the collagen network in a significant manner. Hence, an important function of the bulk proteoglycans (i.e., the large aggregating type) in cartilage is to retard the rate of stretch and alignment when a tensile load is suddenly applied. This mechanism may be useful in protecting the cartilage collagen network during physiological situations, where sudden impact forces are imposed on a joint.

Animals↗
PubMed2005

Plasticity of dendritic excitability.

Dendrites are equipped with a plethora of voltage-gated ion channels that greatly enrich the computational and storage capacity of neurons. The excitability of dendrites and dendritic function display plasticity under diverse circumstances such as neuromodulation, adaptation, learning and memory, trauma, or disorders. This adaptability arises from alterations in the biophysical properties or the expression levels of voltage-gated ion channels-induced by the activity of neurotransmitters, neuromodulators, and second-messenger cascades. In this review we discuss how this plasticity of dendritic excitability could alter information transfer and processing within dendrites, neurons, and neural networks under physiological and pathological conditions.

Adaptation, Physiological↗
PubMed2006

Kainate receptors.

Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.

Animals↗
PubMed1993

A geometrical description of horizontal cell networks in the turtle retina.

Networks of physiologically identified H2 horizontal cells in the turtle retina were labeled by intracellular injection of Neurobiotin. We obtained a quantitative description of the neighbourhood relations in the dye-coupled cell mosaics by using the somata as centers for the Voronoi-Delaunay construction. Computational models simulating the experimental data are presented.

Animals↗
PubMed1991

Human thyrotropin receptor gene: expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation.

Human thyrotropin (TSH) receptor steady-state transcript levels were analyzed by Northern blot analysis in thyroids of patients with thyroid carcinoma, with hyperfunctioning adenoma and in normal controls. In control tissue and benign tumors expression levels of TSH receptor mRNA were high whereas in anaplastic carcinomas no normal TSH receptor mRNA was detected. In papillary and follicular tumors it varied from normal to markedly reduced levels. Thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA were strongly expressed in normal tissue and in hyperfunctioning adenomas but were completely lost in all anaplastic tumors. In papillary tumors expression of TPO and Tg mRNA varied from normal to a complete loss of expression of either TPO, Tg or both. Tg and TPO steady-state expression did not correlate to TSH receptor transcript levels. C-myc mRNA was highly expressed in anaplastic carcinomas, very variable in normal controls and in differentiated thyroid tumors and low in hyperfunctioning adenomas. In summary, TSH receptor mRNA is persistently expressed in all differentiated thyroid tissues and tumors but lost in undifferentiated carcinomas. Its persistence far along the transformation pathway further supports the concept that this gene which inserts the thyrocytes in the physiological regulatory network is almost constitutively expressed in this cell.

Adolescent↗
PubMed1992

Innate chaos: I. The origin and genesis of complex morphologies and homeotic regulation.

The genesis of complex morphologies is an inherent property of all dynamically expanding natural systems. In the inorganic and prebiotic world, chaotic movement of quantitable particles results in formation of ordered streamlined structures or micelles close to phase boundaries. In the course of chemical and colloid crystallization or development of living organisms, complex morphologies emerge, due to unusual chaotic attraction, diffusion limited aggregation (DLA) and multifractal organization suggesting that common mechanisms direct the morphogenesis in a wide range of natural systems. The development of a multicellular organism from a single fertilized oocyte requires intensive clonal proliferation sequential determinations and the organization of terminally differentiated cells in morphologically stable homeostatic functional units. Comparative data on insect and vertebrate embryogenesis revealed that the spatial organization of the developing body is orchestrated by several mechanisms: maternal effect genes or cell position specify the initial polarities and the main axes, while metameric segmentation, intrasegment identity and cell fate are determined by the programmed expression of morphogenetic determinants. They include evolutionarily conserved DNA binding proteins containing homeobox or pair-box sequences, endogenous ligands, activating specific nuclear hormone receptors, and humoral growth factors acting via specific membrane receptors and more ubiquitous transducing pathways. Morphogenetic regulators form intratissual gradients and demark fields required for the correct realization of the developmental programme. It has been recognized that the cell's freedom is limited to stringent developmental choices that in the end results in the formation of coherent cell colonies, many of them displaying chaotic behaviour. The linkage between embryonic regulation and adult tissue differentiation is not completely elucidated, however, data are emerging to show that several morphogenetic regulators may function throughout life in different human tissues. Genetically transmissible deletions or acquired impairments likely contribute to malignant tissue growth. Diffusible morphogenetic regulators may reverse the malignant phenotype in some cases and induce clinical remission. Further work is needed, however, to identify the dominant components of physiological regulatory networks and to understand what hierarchical organization and chaotic behaviour represent in order to elaborate new combined therapeutic protocols.

Cell Transformation, Neoplastic↗
PubMed2005

Self-assembling peptide amphiphile nanofiber matrices for cell entrapment.

We have developed a class of peptide amphiphile (PA) molecules that self-assemble into three-dimensional nanofiber networks under physiological conditions in the presence of polyvalent metal ions. The assembly can be triggered by adding PA solutions to cell culture media or other synthetic physiological fluids containing polyvalent metal ions. When the fluids contain suspended cells, PA self-assembly entraps cells in the nanofibrillar matrix, and the cells survive in culture for at least three weeks. We also show that entrapment does not arrest cell proliferation and motility. Biochemical and ultrastructural analysis by electron microscopy indicate that entrapped cells internalize the nanofibers and possibly utilize PA molecules in their metabolic pathways. These results demonstrate that PA nanofibrillar matrices have the potential to be used for cell transplantation or other tissue engineering applications.

Animals↗
PubMed2006

Role of neurotrophic factors in depression.

Major depression is associated with reduced volumes in the hippocampus and prefrontal cortex, whereas antidepressant treatments promote several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation, in the hippocampus. Several neurotrophic factors are associated with depression or antidepressant action. Stress suppresses brain-derived neurotrophic factor (BDNF) synthesis in the hippocampus, at least partially through a sustained modification of chromatin structure. Essentially all antidepressant treatments increase BDNF synthesis and signaling in the hippocampus and prefrontal cortex. This signaling is required for the behavioral effects of antidepressant drugs in rodents, and increased BDNF levels in the hippocampus mimic the behavioral effects of antidepressants. However, injection of BDNF into the mesolimbic dopamine pathway produces an opposing depression-like response. One hypothesis emerging from these data proposes that mood disorders reflect failed function of critical neuronal networks, whereas a gradual network recovery through activity-dependent neuronal plasticity induces the antidepressant effect. Neurotrophic factors themselves do not control mood, but they act as necessary tools in the activity-dependent modulation of networks, the physiological function of which determines how a plastic change influences mood.

Animals↗
PubMed2005

Oscillatory coupling in writing and writer's cramp.

Writing is a highly skilled and overlearned movement. In patients suffering from writer's cramp, a focal task-induced dystonia, writing is impaired or even impossible due to involuntary muscle contractions and abnormal posture, which occur as soon as the person picks up a pen or within writing a few words. The underlying pathophysiological mechanisms of this movement disorder are not fully understood up to now. The aim of the present study was to unravel the oscillatory network underlying physiological writing in healthy subjects and dystonic writing in writer's cramp patients. Using whole-head magnetoencephalography (MEG) and the analysis tool dynamic imaging of coherent sources (DICS) we studied oscillatory neural coupling during writing in eleven healthy subjects and eight patients suffering from writer's cramp. Simultaneous recording of brain activity with MEG and activity of forearm and hand muscles with surface electromyography (EMG) was performed while subjects were writing for five minutes with their dominant right hand. Applying DICS sources of strongest cerebro-muscular coherence and cerebro-cerebral coherence during writing were identified, which consistently included six brain areas in both, the control subjects and the patients: contralateral and ipsilateral sensorimotor cortex, ipsilateral cerebellum, contralateral thalamus, contralateral premotor and posterior parietal cortex. Coherence between cortical sources and muscles appeared primarily in the frequency of writing movements (3-7 Hz) while coherence between cerebral sources occurred primarily around 10 Hz (8-13 Hz). Interestingly, consistent coupling between both sensorimotor cortices was observed in patients only, whereas coupling between ipsilateral cerebellum and the contralateral posterior parietal cortex was found in control subjects only. These results are consistent with the often described bilateral pathophysiology and impaired sensorimotor integration in writer's cramp patients.

Adult↗
PubMed2026

The genomic alchemist's arsenal: A comprehensive review of gene recruitment, regulatory rewiring, and the evolutionary arms race in snake envenomation.

Snake venom represents a striking example of evolutionary innovation, in which ancestral physiological gene networks have been co-opted into potent biochemical weapons. Advances in multi-omics, single-cell genomics, and structural bioinformatics have catalyzed a conceptual shift from descriptive toxin cataloging to a systems-level understanding of venom evolution, regulation, and function. This Review integrates genomic, cellular, and structural perspectives to delineate the molecular architecture underpinning venom diversification and target-site co-evolution. Emphasis is placed on regulatory mechanisms driving rapid expression plasticity, including super-enhancer activity, transposable element insertion, spatial heterogeneity within the venom gland, and non-coding RNA-mediated modulation. At the protein level, the review examines how hypervariable toxins engage in structural arms races with prey targets, and how multi-toxin complex formation, functional synergy, and molecular dynamics simulations inform models of lethality and resistance. A comparative framework is provided by contrasting high-potency predatory snake venoms with low-potency defensive venoms of hymenopterans such as bees and wasps, revealing how ecological selective pressures shape toxin potency, composition, and target specificity across taxa. Finally, current translational strategies are evaluated, with a focus on the relative merits of recombinant human monoclonal antibodies versus catalytic-site small-molecule inhibitors as deployable interventions for snakebite. By synthesizing evolutionary genomics, structural biology, comparative toxinology, and synthetic antivenomics, this Review outlines a predictive framework for anticipating venom evolutionary trajectories and for designing broad-spectrum, next-generation therapeutics.

Animals↗
PubMed1999

Making sense of the COP9 signalosome. A regulatory protein complex conserved from Arabidopsis to human.

The COP9 signalosome, once defined as a repressor complex of light-activated development in Arabidopsis, has recently been found in humans and is probably present in most multicellular organisms. The COP9 signalosome is closely related to the lid sub-complex of the 26S proteasome in structural composition and probably shares a common evolutionary ancestor. A multifaceted role of the COP9 signalosome in cell-signaling processes is hinted at by its associated novel kinase activity, as well as the involvement of its subunits in regulating multiple cell-signaling pathways and cell-cycle progression. The molecular genetic studies in Arabidopsis suggest that the complex functions as part of a highly conserved regulatory network, whose physiological role in animals remains to be determined.

Animals↗
PubMed2003

Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives.

The recognition that angiogenesis is a key early event in tumor progression and metastasis has led to the development of new strategies for cancer therapy. The generation of a new blood vessel network under physiological conditions is regulated by the concerted action of activators and inhibitors. Perturbation of this balance, as it occurs in solid tumor growth and metastasis, appears to be a critical point in tumorigenesis. This has led to the "angiogenic switch" hypothesis: the point at which a tumor acquires the potential to induce angiogenesis is a critical step towards malignancy. Based on experimental evidence, prevention of blood vessel development appears to be the mechanism of action of many successful chemopreventive drugs of natural or synthetic origin: a novel concept that we termed "angioprevention". The hypothesis that anti-angiogenesis is at the basis of tumor prevention also suggests that many anti-angiogenic drugs could be used for chemoprevention in higher risk populations or in early intervention. There is a growing body of experimental evidence that anti-angiogenic strategies will contribute to the future therapy of cancer, several compounds with anti-angiogenic properties are now under clinical investigation including anti-inflammatory compounds, as inflammation may play a key role in angiogenesis. We must persevere in the development of novel, powerful and safer angiogenesis inhibitors and in the use of anti-angiogenic drugs in combination with other natural or synthetic anti-cancer agents in a biological therapy strategy.

Angiogenesis Inhibitors↗
PubMed2001

Analysis of temporal patterns of communication signals.

Temporal pattern is a crucial feature of communication signals, and neurons in the brains of many animals respond selectively to behaviorally relevant temporal features of sensory stimuli. Many aspects of neural function contribute to this selectivity, including membrane biophysics, channel properties, synaptic physiology and network structure.

Animal Communication↗
PubMed1990

Neural gradient models for the measurement of image velocity.

Although gradient schemes for detecting the motion of images and measuring their velocities are commonly used in computer vision, and although there is increasing evidence to support the existence of such schemes in biological vision, little attention has been directed to suggesting how such computations might be realized by neural hardware. This paper proposes two simple models, consisting of physiologically realistic networks of neurons, that approximate the gradient scheme. Computer simulations demonstrate that the models measure the speed of an object or pattern independently of its structural properties.

Computer Simulation↗
PubMed2003

Self-assembly combining two bioactive peptide-amphiphile molecules into nanofibers by electrostatic attraction.

We describe a new approach to peptide-amphiphile (PA) nanofiber preparation that allows PAs with different bioactive amino acid sequences to be combined into a single fiber. Oppositely charged PAs are synthesized separately and then mixed to produce gels of nanofiber networks at physiological pH. Transmission electron microscopy reveals the formation of fibers approximately 7 nm in diameter and several micrometers long in these dimeric systems. On the basis of NMR and microscopy, we suggest that these nanofibers are cylindrical micelles of mixed composition, formed due to electrostatic attraction between the oppositely charged PAs. This strategy for self-assembly may be useful in cell therapies that can be implemented without invasive surgery or in in vitro tissue engineering.

Amino Acid Sequence↗
PubMed1985

Communication and control in reproduction: the ubiquity of periodic phenomena.

Two statements will be presented and defended in this paper. First, it is claimed that oscillations are common in all biological systems. From the subcellular to the organismic levels of organization, oscillations are the normal operational mode for many biochemical and physiological control networks. Second, it will be demonstrated that periodic control offers several functional advantages over steady-state control.

Animals↗
PubMed1995

Mast cells in the cytokine network: the what, where from and what for.

The basic understanding of mast cell ontogeny and function has been fundamentally changed in recent years with observations that the cells produce and respond to a broad range of cytokines. These rapidly accruing data and their potential significance were discussed at the recent symposium "Mast Cells in the Cytokine Network", and the overview lectures of most speakers are summarized in this special journal issue. In the present introductory manuscript, the organizers of the meeting discuss data fundamental to an understanding of the topic and highlight aspects of special interest. They consider mast cells to be defined most reliably by their unique ultrastructure since the cells are highly heterogeneous in dependence of the species studied, their tissue location, their stage of development and probably also in relation to cytokines. Most other characteristics of mast cells are shared with diverse other cell types. Murine mast cell development is induced by several cytokines. These factors are mostly ineffective in human cells except for stem cell factor which causes mast cell development from CD34+/c-kit+ progenitors. There is however recent evidence that fibroblasts and keratinocytes produce additional growth factors for human mast cells. Regarding cytokine secretion, most molecules known so far are produced by both murine and human mast cells. The cells furthermore bear receptors for several cytokines, enabling them to respond in an autocrine and paracrine fashion. Mast cells may thus function within a complex cytokine network, affecting physiological as well as immunological and inflammatory processes.

Animals↗