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At least 253 records · Page 14Linked to original sources
PubMed2005

Biophysical and pharmacological aspects of K+ channels in T lymphocytes.

Voltage-gated Kv1.3 and Ca2+-activated IKCa1 K+ channels play a pivotal role in antigen-dependent activation and proliferation of lymphocytes. These channels primarily determine the membrane potential of T cells, and thus regulate the magnitude of the Ca2+ signal required for efficient gene transcription and subsequent proliferation. Although these facts are generally well described and acknowledged, some recent discoveries have motivated research in this field, which is reviewed herein along with the basic biophysical characterization of Kv1.3 and IKCa1. The discovery of T cell subset-specific expression of Kv1.3 points towards the potential therapeutic use of high affinity and high specificity Kv1.3 inhibitors as specific immunosuppressors in the management of autoimmune diseases, such as Multiple Sclerosis. In meeting the demands for an ideal immunosuppressor, several laboratories have discovered potent natural Kv1.3- specific inhibitors and engineered peptides which have a better pharmacological profile based on the biophysical characterization of the interaction surface between the channel pore and the toxins. In contrast to the generally accepted permissive role of Kv1.3 during lymphocyte activation, the discovery of the localization of Kv1.3 in the immunological synapse might open new opportunities in the regulation of T cell activation by this channel species.

Amino Acid Sequence↗
PubMed2003

Structure-function relationship in P-type ATPases--a biophysical approach.

P-type ATPases are a large family of membrane proteins that perform active ion transport across biological membranes. In these proteins the energy-providing ATP hydrolysis is coupled to ion-transport that builds up or maintains the electrochemical potential gradients of one or two ion species across the membrane. P-type ATPases are found in virtually all eukaryotic cells and also in bacteria, and they are transporters of a broad variety of ions. So far, a crystal structure with atomic resolution is available only for one species, the SR Ca-ATPase. However, biochemical and biophysical studies provide an abundance of details on the function of this class of ion pumps. The aim of this review is to summarize the results of preferentially biophysical investigations of the three best-studied ion pumps, the Na,K-ATPase, the gastric H,K-ATPase, and the SR Ca-ATPase, and to compare functional properties to recent structural insights with the aim of contributing to the understanding of their structure-function relationship.

Adenosine Triphosphatases↗
PubMed2005

Light-driven enzymatic catalysis of DNA repair: a review of recent biophysical studies on photolyase.

More than 50 years ago, initial experiments on enzymatic photorepair of ultraviolet (UV)-damaged DNA were reported [Proc. Natl. Acad. Sci. U. S. A. 35 (1949) 73]. Soon after this discovery, it was recognized that one enzyme, photolyase, is able to repair UV-induced DNA lesions by effectively reversing their formation using blue light. The enzymatic process named DNA photoreactivation depends on a non-covalently bound cofactor, flavin adenine dinucleotide (FAD). Flavins are ubiquitous redox-active catalysts in one- and two-electron transfer reactions of numerous biological processes. However, in the case of photolyase, not only the ground-state redox properties of the FAD cofactor are exploited but also, and perhaps more importantly, its excited-state properties. In the catalytically active, fully reduced redox form, the FAD absorbs in the blue and near-UV ranges of visible light. Although there is no direct experimental evidence, it appears generally accepted that starting from the excited singlet state, the chromophore initiates a reductive cleavage of the two major DNA photodamages, cyclobutane pyrimidine dimers and (6-4) photoproducts, by short-distance electron transfer to the DNA lesion. Back electron transfer from the repaired DNA segment is believed to eventually restore the initial redox states of the cofactor and the DNA nucleobases, resulting in an overall reaction with net-zero exchanged electrons. Thus, the entire process represents a true catalytic cycle. Many biochemical and biophysical studies have been carried out to unravel the fundamentals of this unique mode of action. The work has culminated in the elucidation of the three-dimensional structure of the enzyme in 1995 that revealed remarkable details, such as the FAD-cofactor arrangement in an unusual U-shaped configuration. With the crystal structure of the enzyme at hand, research on photolyases did not come to an end but, for good reason, intensified: the geometrical structure of the enzyme alone is not sufficient to fully understand the enzyme's action on UV-damaged DNA. Much effort has therefore been invested to learn more about, for example, the geometry of the enzyme-substrate complex, and the mechanism and pathways of intra-enzyme and enzyme <-->DNA electron transfer. Many of the key results from biochemical and molecular biology characterizations of the enzyme or the enzyme-substrate complex have been summarized in a number of reviews. Complementary to these articles, this review focuses on recent biophysical studies of photoreactivation comprising work performed from the early 1990s until the present.

Biophysics↗
PubMed2004

Electrical neuroimaging based on biophysical constraints.

This paper proposes and implements biophysical constraints to select a unique solution to the bioelectromagnetic inverse problem. It first shows that the brain's electric fields and potentials are predominantly due to ohmic currents. This serves to reformulate the inverse problem in terms of a restricted source model permitting noninvasive estimations of Local Field Potentials (LFPs) in depth from scalp-recorded data. Uniqueness in the solution is achieved by a physically derived regularization strategy that imposes a spatial structure on the solution based upon the physical laws that describe electromagnetic fields in biological media. The regularization strategy and the source model emulate the properties of brain activity's actual generators. This added information is independent of both the recorded data and head model and suffices for obtaining a unique solution compatible with and aimed at analyzing experimental data. The inverse solution's features are evaluated with event-related potentials (ERPs) from a healthy subject performing a visuo-motor task. Two aspects are addressed: the concordance between available neurophysiological evidence and inverse solution results, and the functional localization provided by fMRI data from the same subject under identical experimental conditions. The localization results are spatially and temporally concordant with experimental evidence, and the areas detected as functionally activated in both imaging modalities are similar, providing indices of localization accuracy. We conclude that biophysically driven inverse solutions offer a novel and reliable possibility for studying brain function with the temporal resolution required to advance our understanding of the brain's functional networks.

Biophysics↗
PubMed2005

Beyond bistability: biophysics and temporal dynamics of working memory.

Working memory has often been modeled and conceptualized as a kind of binary (bistable) memory switch, where stimuli turn on plateau-like persistent activity in subsets of cells, in line with many in vivo electrophysiological reports. A potentially related form of bistability, termed up- and down-states, has been studied with regard to its synaptic and ionic basis in vivo and in reduced cortical preparations. Also single cell mechanisms for producing bistability have been proposed and investigated in brain slices and computationally. Recently, however, it has been emphasized that clear plateau-like bistable activity is rather rare during working memory tasks, and that neurons exhibit a multitude of different temporally unfolding activity profiles and temporal structure within their spiking dynamics. Hence, working memory seems to be a highly dynamical neural process with yet unknown mappings from dynamical to computational properties. Empirical findings on ramping activity profiles and temporal structure will be reviewed, as well as neural models that attempt to account for it and its computational significance. Furthermore, recent in vivo, neural culture, and in vitro preparations will be discussed that offer new possibilities for studying the biophysical mechanisms underlying computational processes during working memory. These preparations have revealed additional evidence for temporal structure and spatio-temporally organized attractor states in cortical networks, as well as for specific computational properties that may characterize synaptic processing during high-activity states as during working memory. Together such findings may lay the foundations for highly dynamical theories of working memory based on biophysical principles.

Action Potentials↗
PubMed1993

Teaching high-resolution nuclear magnetic resonance to graduate students in biophysics.

Teaching modern methods of high resolution, multi-dimensional nuclear magnetic resonance (NMR) spectroscopy in the limited time usually available is a challenge because of the breadth and complexity of the subject. Here we present two outlines for lectures on basic principles and biophysical applications of NMR, either in one lecture or in six to twelve lectures. We advocate emphasizing the versatility of NMR, and its numerous applications to biophysical questions. An annotated list of references is provided.

Biophysics↗
PubMed1997

On the bifurcation of blood vessels--Wilhelm Roux's doctoral thesis (Jena 1878)--a seminal work for biophysical modelling in developmental biology.

Wilhelm Roux's doctoral thesis described the relationship between the angle and diameter of bifurcating blood vessels. We have re-read this work in the light of biophysics and developmental biology and found two remarkable aspects hidden among a multitude of observations, rules and exceptions to these rules. First, the author identified the major determinants involved in vascular development; genetics, cybernetics, and mechanics; moreover, he knew that he could not deal with the genetic and regulatory aspects, and could hardly treat the mechanical part adequately. Second, he was deeply convinced that the laws of physics determine the design of organisms, and that a necessity for optimality was inherent in development. We combined the analysis of diameter relationships with the requirement for optimality in a stochastic biophysical model, and concluded that a constant wall-stress condition could define a minimum wall-tissue optimum during arterial development. Hence, almost 120 years after Wilhelm Roux's pioneering work, our model indicates one possible way in which physical laws have determined the evolution of regulatory and structural properties in vessel wall development.

Animals↗
PubMedDate not supplied

Biophysical constraints for protein structure prediction.

Though highly desirable, neither a single experimental technique nor a computational approach can be sufficient enough to rationalize a protein structure. The incorporation of biophysical constraints, which can be rationalized based on conventional biophysical measurements, might lead to considerable improvement of the simulation procedures. In this regard, our analysis of 180 proteins in different conformational states allows prediction of the overall protein dimension based on the chain length, i.e., the protein molecular weight, with an accuracy of 10%.

Algorithms↗
PubMedDate not supplied

Ceramide-platform formation and -induced biophysical changes in a fluid phospholipid membrane.

To understand the formation and properties of ceramide-enriched domains in cell membranes, the biophysical properties of the binary system palmitoyloleoylphosphatidylcholine (POPC)/palmitoylceramide were thoroughly characterized. Diverse fluorescent probes and parameters were necessary to unravel the complexity of this apparently simple system. For the first time, a complete phase diagram is reported, characterizing the lamellar phases of these mixtures, and providing a quantitative framework integrating biophysical and biological studies. The diagram suggests that in resting cells no ceramide domains exist, but upon apoptotic stimuli, platforms may form. Moreover, our data show that 2 mol% of Cer strongly affects the POPC fluid matrix, suggesting that a small increase in Cer levels can significantly affect cell membrane properties. In this work, we also show that Cer domains, formed in conditions similar to physiological, are extremely ordered and rigid. The domains composition is estimated from the phase diagram and their large size was concluded from fluorescence resonance energy transfer. Dynamic light scattering and electron microscopy were used to characterize the system morphology, which is highly dependent on ceramide content and includes vesiculation and tubular structure formation.

Anisotropy↗
PubMed2004

A cell-based screen for function of the four-helix bundle protein Rop: a new tool for combinatorial experiments in biophysics.

Combinatorial methodologies have revolutionized studies in biomolecular function, but they have so far proven less useful for understanding macromolecular structure and stability. This is largely because of the difficulty of screening libraries of molecules for biophysical properties, and the difficulty of interpreting structural effects in complicated molecules. Here, we report a novel, robust, cell-based screen for function of the four-helix bundle protein, Rop. By expression of green fluorescent protein from a ColE1 plasmid, the screen reports the copy number of the plasmid, which is modulated in Escherichia coli by Rop. We have engineered the screen so that the fluorescent phenotype can correspond to either Rop activity or lack thereof. We have used the screen to demonstrate with systematically constructed Rop core variants that not all molecules that bind small stem-loop RNAs in vitro are active in vivo. Rop is well understood from structural work and systematic mutations, which makes it possible to construct rational, targeted libraries. This screen makes it possible to rapidly interrogate such libraries effectively for proper protein folding and stability. In addition to its intended utility for combinatorial experiments in biophysics, the screen will allow further dissection of the mechanism of Rop-mediated plasmid copy number regulation in vivo.

Bacterial Proteins↗
PubMed2004

Establishment of an atopic dermatitis-like skin model in a hairless mouse by repeated elicitation of contact hypersensitivity that enables to conduct functional analyses of the stratum corneum with various non-invasive biophysical instruments.

BACKGROUND/AIMS: Pathogenesis of atopic dermatitis (AD) has been studied in animal models such as the NC/Nga mouse strain or Balb/C mice that are repeatedly treated with 2,4,6-trinitro-1-chrolobenzene (TNCB). These mice exhibit features of chronic contact dermatitis, including an intensified early type skin reaction, increased number of mast cells and elevated serum IgE levels with a shift of cutaneous cytokine expression from a type 1 to type 2 profile. However, it is difficult to investigate the unique skin changes of AD such as dry skin, barrier dysfunction, and increased turnover of the stratum corneum (SC) in these animals with biophysical instruments because of the presence of their fur coats. In this study, we succeeded in establishing a mouse model of AD in hairless mice that are suitable for various functional analyses of the SC as well as for examining the immunological characteristics of human AD by treating TNCB-contact sensitized hairless mice with 1% TNCB every other day for 36 days. METHODS: In hairless animals treated with TNCB every 2 days for 36 days, we measured time courses of skin swelling induced by contact hypersensitivity reaction on days 0, 6, 20 and 36. During the time course, non-invasive measurements for skin surface condition with biophysical instruments were conducted, and the area size and the rear surface villi of corneocytes obtained were measured. Also skin samples and blood samples were taken at each time point for histology and measurement of serum IgE level. RESULTS: A gradual intensification of an early type contact hypersensitivity reaction was observed over the treatment period. These mice exhibited reduced SC hydration, heightened trans-epidermal water loss, and increased skin thickness. These mice also showed a decrease in the surface area size of each corneocytes and marked villus formation on their rear surface. Histologically, there was an increase in the number of CD4 and CD8 positive T cells in the epidermis. Also observed was a marked increase in the number of dermal mast cells and eosinophils, which correlated with elevated serum IgE levels induced by TNCB treatments. CONCLUSIONS: From the results obtained we conclude that repeated treatments of TNCB-sensitized hairless mice with TNCB provides a useful means by which to study the pathological characteristics of AD skin lesions as well as their immunological characteristics.

Administration, Topical↗
PubMed2006

Biophysical and phenomenological models of multiple spike interactions in spike-timing dependent plasticity.

Spike-timing dependent plasticity (STDP) is a form of associative synaptic modification which depends on the respective timing of pre- and post-synaptic spikes. The biophysical mechanisms underlying this form of plasticity are currently not known. We present here a biophysical model which captures the characteristics of STDP, such as its frequency dependency, and the effects of spike pair or spike triplet interactions. We also make links with other well-known plasticity rules. A simplified phenomenological model is also derived, which should be useful for fast numerical simulation and analytical investigation of the impact of STDP at the network level.

Action Potentials↗
PubMed2004

Biophysical evidence that connexin-36 forms functional gap junction channels between pancreatic mouse beta-cells.

Connexin-36 (Cx36) is the only gap junction protein that has been unambiguously identified in rodent pancreatic beta-cells. However, properties of gap junction channel unitary currents between beta-cells remain unrevealed. To address whether Cx36 forms functional channels in beta-cells, we characterized biophysical properties of macro- and microscopic junctional currents recorded from dual whole cell voltage clamp isolated pairs of dispersed mouse beta-cells. Electrical coupling was recorded in 80% of cell pairs with a junctional conductance (g(j)) of 355 +/- 45 pS (n = 20). Transjunctional voltage dependence was identified in three of seven cell pairs with high-input membrane resistances. Normalized steady-state g(j) (Gj) and transjunctional-voltage relation were well described by a two-state Boltzmann equation [maximal conductance (Gmax) = 1.0, voltage-insensitive conductance (Gmin) = 0.3 and 0.28, voltage gating sensitivity (A) = 0.21 and 0.23, and voltage at which one-half of the initial voltage-dependent conductance was reached (Vo) = -85 and 87 mV for negative and positive potentials, respectively]. Halothane reversibly uncoupled beta-cell pairs, and, during recovery, unitary conductances of 5-10 pS were recorded while using patch pipettes containing mainly CsCl. Although these properties are similar to those previously described for Cx36 channels in mammalian cell systems, we found that beta-cell junctional currents were insensitive to quinine. Cx36 transcript and protein expression in islets and freshly dispersed cell preparations was confirmed by RT-PCR and immunofluorescence. In conclusion, biophysical properties of junctional channels between beta-cells are similar but not identical to those previously described for homomeric Cx36 channels. Cell type-specific mechanisms that may account for these differences are discussed.

Animals↗
PubMed1999

On the role of biophysical properties of cortical neurons in binding and segmentation of visual scenes.

Neuroscience is progressing vigorously, and knowledge at different levels of description is rapidly accumulating. To establish relationships between results found at these different levels is one of the central challenges. In this simulation study, we demonstrate how microscopic cellular properties, taking the example of the action of modulatory substances onto the membrane leakage current, can provide the basis for the perceptual functions reflected in the macroscopic behavior of a cortical network. In the first part, the action of the modulatory system on cortical dynamics is investigated. First, it is demonstrated that the inclusion of these biophysical properties in a model of the primary visual cortex leads to the dynamic formation of synchronously active neuronal assemblies reflecting a context-dependent binding and segmentation of image components. Second, it is shown that the differential regulation of the leakage current can be used to bias the interactions of multiple cortical modules. This allows the flexible use of different feature domains for scene segmentation. Third, we demonstrate how, within the proposed architecture, the mapping of a moving stimulus onto the spatial dimension of the network results in an increased speed of synchronization. In the second part, we demonstrate how the differential regulation of neuromodulatory activity can be achieved in a self-consistent system. Three different mechanisms are described and investigated. This study thus demonstrates how a modulatory system, affecting the biophysical properties of single cells, can be used to achieve context-dependent processing at the system level.

Animals↗
PubMed2006

Biophysical aspects of photodynamic therapy.

Over the last three decades photodynamic therapy (PDT) has been developed to a useful clinical tool, a viable alternative in the treatment of cancer and other diseases. Several disciplines have contributed to this development: chemistry in the development of new photosensitizing agents, biology in the elucidation of cellular processes involved in PDT, pharmacology and physiology in identifying the mechanisms of distribution of photosensitizers in an organism, and, last but not least, physics in the development of better light sources, dosimetric concepts and construction of imaging devices, optical sensors and spectroscopic methods for determining sensitizer concentrations in different tissues. Physics and biophysics have also helped to focus on the role of pH for sensitizer accumulation, dose rate effects, oxygen depletion, temperature, and optical penetration of light of different wavelengths into various types of tissue. These are all important parameters for optimally effective PDT. The present review will give a brief, physically based, overview of PDT and then discuss some of the main biophysical aspects of this therapeutic modality.

Animals↗
PubMed2001

[The history of medical physics and biophysics at the Humboldt University in Berlin].

The present Institute of Medical Physics and Biophysics (former Institute of Radiation Research) was established on September 1st in 1923 by Walter Friedrich (1883-1968). It was after the Institute in Frankfurt A.M. (founded by Friedrich Dessauer in 1921) - the second Institute of its kind in Germany. As a physicist who wrote his dissertation under Wilhelm Conrad Röntgen, he did research together with a Gynecologist in Friedburg on problems of radiation therapy and the prevention of radiation injuries. Thus Friedrich became one of the first German Biomedical Physicists and was appointed to a professorship at the university of Berlin and its faculty of medicine. The paper gives a survey of the history of the Institute of Radiation Research in the twenties, in the time of Nazi-rule, the period after the World War II and in the era of GDR until 1990 and up to the present time. The succession of directorship of the Institute and the main research subjects in medical physics and biophysics have been sketched.

Academies and Institutes↗
PubMed2002

[Biophysical measurement of cutaneous hydration in vivo].

The skin, because of its involvement in health, comfort and aesthetics, is a particular "organ". Cutaneous hydration is essential for the dermatologist and the cosmetician. For the dermatologist, "dry skin" is a clinical sign of an often unclear pathogenetic disorder and for the cosmetician it is a discomfort related to aging, climatic effects or sun exposure and should be compensated or prevented. The essential measurement and objective quantification of cutaneous hydration has led to the development of various techniques, based on differing biophysical principles and studies aimed at providing better understanding of the mechanisms involved. Faced with an abundance of information and means, the aim of this review is to briefly present the various techniques and instrumental measurements of hydration in vivo, their biophysical principles and their pertinence for the clinician.

Biophysics↗
PubMedDate not supplied

[L.A. Bliumenfeld and quantum conceptions in biophysics].

The development of quantum conceptions in biophysics and the role of experimental and theoretical works of L.A. Blumenfeld in this process were considered. The influence of his investigations on the researches of other scientists in the field of quantum biophysics was shown.

Biophysics↗