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PubMed2001

A freely diffusible form of Sonic hedgehog mediates long-range signalling.

The secreted protein Sonic hedgehog (Shh) exerts many of its patterning effects through a combination of short- and long-range signalling. Three distinct mechanisms, which are not necessarily mutually exclusive, have been proposed to account for the long-range effects of Shh: simple diffusion of Shh, a relay mechanism in which Shh activates secondary signals, and direct delivery of Shh through cytoplasmic extensions, termed cytonemes. Although there is much data (using soluble recombinant Shh (ShhN)) to support the simple diffusion model of long-range Shh signalling, there has been little evidence to date for a native form of Shh that is freely diffusible and not membrane-associated. Here we provide evidence for a freely diffusible form of Shh (s-ShhNp) that is cholesterol modified, multimeric and biologically potent. We further demonstrate that the availability of s-ShhNp is regulated by two functional antagonists of the Shh pathway, Patched (Ptc) and Hedgehog-interacting protein (Hip). Finally, we show a gradient of s-ShhNp across the anterior-posterior axis of the chick limb, demonstrating the physiological relevance of s-ShhNp.

Animals↗
PubMed2001

Design, simulation and application of a new micromixing device for time resolved infrared spectroscopy of chemical reactions in solution.

We present a novel micromachined fast diffusion based mixing unit for the study of rapid chemical reactions in solution with stopped-flow time resolved Fourier transform infrared spectroscopy (TR-FTIR). The presented approach is based on a chip for achieving lamination of two liquid sheets of 10 microm thickness and approximately 1 mm width on top of each other and operation in the stopped-flow mode. The microstructure is made on infrared transmitting calcium fluoride discs and built up with two epoxy negative photoresist layers and one silver layer in between. Due to the highly laminar flow conditions and the short residence time in the mixer there is hardly any mixing when the two liquid streamlines pass through the mixing unit, which allows one to record a mid-IR transmission spectrum of the analytes prior to reaction. When the flow is stopped, the reactant streams are arrested in the flow-cell and rapidly mixed by diffusion due to the reduced interstream distances and the reaction can be directly followed with hardly any dead time. On the basis of two model reactions-neutralisation of acetic acid with sodium hydroxide as well as saponification of methyl monochloroacetate-the performance of the mixing device was tested revealing proper functioning of the device with a time for complete mixing of less than 100 ms. The experimental results were supported by numerical simulations using computational fluid dynamics (CFD), which allowed a reliable, quantitative analysis of concentration, pressure and flow profiles in the course of the mixing process.

Journal Article↗
PubMedDate not supplied

Time-resolved near-field optics: exciton transport in semiconductor nanostructures.

We present a systematic, temperature-dependent study of excitonic real-space transfer into single GaAs quantum wires using time-resolved low-temperature near-field luminescence spectroscopy. Excitons generated by local short pulse optical excitation in a 250 nm spot undergo diffusive transport over a length of several micrometres and are subsequently trapped into the quantum wire by optical phonon emission. The effect of local energy barriers in the vicinity of the quantum wire on the real-space transfer dynamics is monitored directly by mapping the time-resolved quantum wire luminescence. Experiments at variable temperatures are compared to numerical simulations based on drift-diffusive model calculations, and the spatio-temporal evolution of the two-dimensional exciton distribution within the nanostructure is visualized.

Journal Article↗
PubMed2003

Fast gating in the Shaker K+ channel and the energy landscape of activation.

An early component of the gating current in Shaker K+ channels with a time constant of approximately 12 microsec has been recorded with a high-speed patch-clamp setup. This fast component was found to be part of the gating current associated with the opening and closing of the channel. With regard to an energy-landscape interpretation of protein kinetics, the voltage and temperature dependence of the fast component may be explained by a combination of drift diffusion and barrier jumping in the initial stages of channel activation. The data were modeled by a gating particle undergoing Brownian motion in a one-dimensional diffusion landscape that featured diminishing electrical resistance and entropy in the direction of channel activation. The final open state of the channel was reasoned to be narrow and deep to account for successful subtraction of linear-charge displacements at positive potentials. The overall picture of gating that emerges from these studies is that the channel experiences incremental organization from a relaxed state in the early steps of activation to a rigidly structured open state.

Animals↗
PubMed2001

Cell behavior in traveling wave patterns of myxobacteria.

Cells in the early stages of starvation-induced fruiting body development migrate in a highly organized periodic pattern of equispaced accumulations that move as traveling waves. Two sets of waves are observed moving in opposite directions with the same wavelength and speed. To learn how the behavior of individual cells contributes to the wave pattern, fluorescent cells were tracked within a rippling population. These cells exhibit at least three types of organized behavior. First, most cell movement occurs along the same axis as the rippling movement. Second, there is a high degree of cell alignment parallel to the direction of rippling, as indicated by the biased movement. Third, by controlling the reversal frequency, cell movement becomes periodic in a rippling field. The periodicity of individual cells matches the period of macroscopic rippling. This last behavior is unique to a rippling population and, on the basis of Myxococcus xanthus genetic data, we conclude that this periodicity is linked to the C signal, a nondiffusible cell contact-mediated signaling molecule. When two cells moving in opposite directions meet end to end, they transmit the C signal to each other and in response reverse their gliding direction. This model of traveling waves represents a new mode of biological pattern formation that depends on cell-contact interactions rather than reaction diffusion.

Chemotaxis↗
PubMed2002

Markedness and the grammar in lexical diffusion of fricatives.

This paper examines the contributions of markedness and a child's grammar to the process of lexical diffusion in phonological acquisition. Archival data from 19 preschoolers with functional phonological delays were submitted to descriptive analyses of productive sound change in fricatives. Children's presenting fricative inventory, the fricatives newly learned, and their position of occurrence were varied, with word frequency and neighbourhood density measured. Results indicated that lexical diffusion of fricatives occurred differentially by word position. Positional, featural and structural markedness further converged such that change in unmarked structure of any type was implemented in low frequency words. A child's presenting fricative inventory was not directly affiliated with systematic patterns of diffusion. These results have clinical applications for the evaluation of productive sound change and theoretical implications for deterministic models of lexical diffusion and processing models of word recognition.

Child↗
PubMed2004

Spin diffusion of correlated two-spin states in a dielectric crystal.

Reciprocal space measurements of spin diffusion in a single crystal of calcium fluoride (CaF2) have been extended to dipolar ordered states. The experimental results for the component of the spin diffusion rate parallel to the external field are D(parallel)(D)=29+/-3x10(-12) cm(2)/s for the [001] direction and D(parallel)(D)=33+/-4x10(-12) cm(2)/s for the [111] direction. The measured diffusion rates for dipolar order are faster than those for Zeeman order and are considerably faster than predicted by simple theoretical models. It is suggested that constructive interference in the transport of the two-spin states is responsible for this enhancement. As expected, the anisotropy in the diffusion rates is observed to be significantly less for dipolar order compared to the Zeeman case.

Journal Article↗
PubMed1985

Ammonia and bicarbonate transport by rat cortical collecting ducts perfused in vitro.

We measured bicarbonate and ammonia transport by isolated perfused cortical collecting ducts from deoxycorticosterone-treated rats. With no ammonia in the perfusate and bath solutions, the collecting ducts secreted bicarbonate. The bicarbonate secretion was prevented when the rats were given 40 mM NH4Cl to drink. When 4 mM total ammonia was added to the perfusate and bath, the collecting ducts secreted ammonia and the direction of bicarbonate transport reversed toward absorption. Under those conditions the collected total ammonia concentration exceeded the value predicted by the diffusion-trapping model, assuming pH equilibrium. However, when carbonic anhydrase was added to the perfusate (to assure pH equilibrium), the collected total ammonia concentration decreased to the level predicted by the diffusion-trapping model. We conclude that rat cortical collecting ducts can secrete bicarbonate at substantial rates; the rate of bicarbonate secretion is modified by changes in the acid-base intake of the rats; ammonia secretion occurs by simple nonionic diffusion in this segment; the ammonia secretion is enhanced by the presence of acidic pH disequilibrium in the lumen; and ammonia in the perfusion and bath solutions inhibits bicarbonate secretion by rat cortical collecting ducts, a response that may be important for the regulation of renal bicarbonate excretion.

Ammonia↗
PubMed1998

A bovine mammary endothelial/epithelial cell culture model of the blood/milk barrier.

The complex nature of the mammary gland has hampered in-depth studies of the relationship of the circulatory system to cells lining the teat ducts and alveoli of the gland. This study reports an in vitro model of endothelial and epithelial cells separated by a subcellular matrix that simulates the blood milk barrier of the bovine mammary gland. Dual chamber culture dishes with a porous membrane separating the upper and lower chamber were used. Endothelial and epithelial cells were cultured on opposite sides of the porous membrane. A collagen and fibroblast subcellular matrix, separating the 2 cell layers, simulated the in vivo interstitial tissue. Changes in surface binding of anti-bodies to polymorphonuclear neutrophils (PMN) following their migration from the upper to the lower chamber simulated the passage of PMN from blood to milk. Changes in the binding of antibodies to PMN agreed with results observed following the migration of PMN from blood to milk in vivo. This gives credence to the model's potential value for studies where more direct observation of the blood/milk barrier is required. The model will be further tested for its usefulness as an assay for determining: 1) antibiotic diffusion from milk to blood and from blood to milk, 2) cytotoxicity of prophylactic and therapeutic mammary infusion products, 3) factors affecting bacterial adhesion and penetration of mammary epithelial tissue, 4) effectiveness of antibodies present in lacteal secretions in preventing bacterial adhesion, and 5) the feasibility of gene constructs to induce synthesis and secretion of mastitis-preventing compounds and prophylactic and therapeutic compounds for treatment of human disorders.

Animals↗
PubMed1999

Peripheral nerve injection injury with antiemetic agents.

Antiemetics are widely used drugs, frequently administered to alleviate postoperative and postchemotherapeutic nausea and vomiting. While antiemetics do not induce peripheral neurotoxicity when administered systemically, it is not known whether peripheral nerve injury can occur as a result of inadvertent intraneural injection during intramuscular administration. The purpose of this study was to characterize the neurotoxic effect of three commonly used antiemetic agents (promethazine, dimenhydrinate, and prochlorperazine) as compared to saline in the rat sciatic nerve model. Intrafascicular and extrafascicular injection as well as direct application of the antiemetic drugs were performed. Nerves were harvested at 2 weeks postoperatively for histology and morphometry, with an additional sacrifice point at 8 weeks for the intrafascicular injection group. Injection injuries caused by antiemetic drugs differed depending on the agent injected and the location of injection. Extrafascicular injection and direct application caused no damage. Intrafascicular injection caused diffuse axonal injury in the promethazine and dimenhydrinate groups, while prochlorperazine caused only focal injury. Regeneration was prominent at 8 weeks in all intrafascicular injection groups in this rat model. Prochlorperazine thus appears to be less neurotoxic when injected intraneurally and should preferentially be used for intramuscular injections.

Animals↗
PubMedDate not supplied

Fractionation of macromolecules in an alternating transverse electric field: simulation of the method.

An electric field of alternating polarity applied in a direction transverse to the direction of solute transport is used as the basis of a method for the separation of biological macromolecules. The method derives directly from the ability of an electric field to induce movement of a charged macromolecule and from the physics of laminar fluid flow; no adsorptive immobile phase component is involved. The method is simulated by computer for the case of solute molecules in a solvent flowing through a narrow chamber of rectangular cross section. A voltage differential of periodically reversed polarity generates an electric field orthogonal to the direction of solvent flow. Solute molecules repetitively traverse the solvent channel at rates determined by their electrophoretic mobility. During the transit across the channel, solute molecules are transported in the direction of solvent flow; at the channel wall, solvent velocity is negligible and solute transport is limited to that provided by transient diffusion into a mobile solvent zone. Molecules of different intrinsic electrophoretic mobility are separated. The computer model was used to illustrate the process and to demonstrate the 'tunability' of the method as a function of the oscillation frequency and voltage wave form. Because of this tunability, a single instrument can function as the equivalent of several different chromatographic systems. Because fractionation is effected by direct physicochemical phenomena rather than via interaction with chromatographic sites, variations in fractionation results arising from formation of polymers for gel electrophoresis, packing of chromatography columns, or deterioration of columns with use are avoided. This method may be of particular use for the purification of nucleic acid fragments and for the analysis of protein: nucleic acid interactions.

Chemical Fractionation↗
PubMed1995

Ogston gel electrophoretic sieving: how is the fractional volume available to a particle related to its mobility and diffusion coefficient(s)?

The Ogston-Morris-Rodbard-Chrambach model (OMRCM) of gel electrophoresis assumes that the mobility mu of charged particles is proportional to the fractional volume (f) of the gel that is available to them. If the gel is random, as described by Ogston, the (semi-log) Ferguson plot is the method of choice for analyzing experimental data since it permits an estimate of the gel's mean pore size to be made. However, the Ferguson plot is rarely linear; this is usually "explained" by the deformation of the anisotropy of the particle, the nonrandom or variable architecture or the gel, or the onset of some other migration mechanism. Many authors have refined this model, but the original assumption that mu varied; is directly proportional to f has not been seriously examined. Also, the model says nothing of the effect of the field intensity, the connectivity of the gel pores, nor anything about the diffusion coefficient. We have developed a Monte-Carlo computer simulation algorithm to study the electrophoretic sieving of simple particles in gels. In this brief communication, we report important preliminary results which indicate that the basic assumptions of the OMRCM are wrong. We use a two-dimensional periodic gel since the OMRCM becomes trivial in this case. Our results show that the relationship between f and mu is not the one assumed by the OMRCM. Moreover, we find that the Einstein relation between the diffusion coefficient and the mobility is not valid. This is due to the fact that the particles do not have a uniform probability of visiting the various sites that are available to them. We thus conclude that the Ferguson plot is intrinsically nonlinear; the curvature of the plot is, in fact, related to the intensity of the electric field as well as to the degree of randomness of the gel fibers.

Algorithms↗
PubMed1994

Modelling of radiation-induced DNA damage: the early physical and chemical event.

A Monte Carlo track structure calculation of single- and double-strand breaks induced by direct energy deposition in DNA and by interacting diffusible .OH radicals with DNA has been made for low energy electrons. The .OH radicals generated within 4 nm of linear segments of DNA were diffused in order to mimic the mean diffusion distance in the cellular environment. The reactions of the radical species .OH, .H and e-aq were included in this study. The calculated values for the yield of single- and double-strand breaks have been compared with experimentally determined values from the literature. The calculations indicate, too, that the majority of dsb have additional associated damage, constituting clustered lesions of varying complexity.

DNA↗
PubMed2004

Purine nucleoside phosphorylase and fludarabine phosphate gene-directed enzyme prodrug therapy suppresses primary tumour growth and pseudo-metastases in a mouse model of prostate cancer.

Gene-directed enzyme prodrug therapy based on the E. coli purine nucleoside phosphorylase (PNP) gene produces efficient tumour cell killing. PNP converts adenosine analogs into toxic metabolites that diffuse across cell membranes to kill neighbouring untransduced cells (PNP-GDEPT). Interference with DNA, RNA and protein synthesis kills dividing and non-dividing cells, an important consideration for slow-growing prostate tumours. This study examined the impact of administering PNP-GDEPT into orthotopically grown RM1 prostate cancers (PCas) on the growth of lung pseudo-metastases of immunocompetent mice. C57BL/6 mice bearing orthotopic RM1 PCas received a single intraprostatic injection of OAdV220 (10(10) particles), a recombinant ovine atadenovirus containing the PNP gene controlled by the Rous Sarcoma virus promoter, followed by fludarabine phosphate (approximately 600 mg/m(2)/day) administered intraperitoneally (ip) once daily for 5 days. Pseudo-metastases were induced 2 days after intraprostatic vector administration by tail-vein injection of untransduced RM1 cells. Mice given PNP-GDEPT showed a significant reduction both in prostate volume (approximately 50%) and in lung colony counts (approximately 60%). Apoptosis was increased two-fold in GDEPT-treated prostates compared with controls (P < 0.01), but was absent in the lungs. Staining for proliferating cell nuclear antigen (PCNA) indicated that proliferation of both RM1 prostate tumours (P < 0.01) and lung colonies (P < 0.01) was significantly suppressed after GDEPT. Although prostate tumour immune cell infiltration did not differ significantly between treatments, immunostaining for Thy-1.2 (CD90) showed that GDEPT promoted Thy-1.2(+) cell infiltration into the prostate tumour site. This study showed that a single course of PNP-GDEPT significantly suppressed local PCa growth and reduced lung colony formation in the aggressive RM1 tumour model.

Adenoviridae↗
PubMedDate not supplied

Radon (222Rn) in ground water of fractured rocks: a diffusion/ion exchange model.

Ground waters from fractured igneous and high-grade sialic metamorphic rocks frequently have elevated activity of dissolved radon (222Rn). A chemically based model is proposed whereby radium (226Ra) from the decay of uranium (238U) diffuses through the primary porosity of the rock to the water-transmitting fracture where it is sorbed on weathering products. Sorption of 226Ra on the fracture surface maintains an activity gradient in the rock matrix, ensuring a continuous supply of 226Ra to fracture surfaces. As a result of the relatively long half-life of 226Ra (1601 years), significant activity can accumulate on fracture surfaces. The proximity of this sorbed 226Ra to the active ground water flow system allows its decay progeny 222Rn to enter directly into the water. Laboratory analyses of primary porosity and diffusion coefficients of the rock matrix, radon emanation, and ion exchange at fracture surfaces are consistent with the requirements of a diffusion/ion-exchange model. A dipole-brine injection/withdrawal experiment conducted between bedrock boreholes in the high-grade metamorphic and granite rocks at the Hubbard Brook Experimental Forest, Grafton County, New Hampshire, United States (42 degrees 56'N, 71 degrees 43'W) shows a large activity of 226Ra exchanged from fracture surfaces by a magnesium brine. The 226Ra activity removed by the exchange process is 34 times greater than that of 238U activity. These observations are consistent with the diffusion/ion-exchange model. Elutriate isotopic ratios of 223Ra/226Ra and 238U/226Ra are also consistent with the proposed chemically based diffusion/ion-exchange model.

Diffusion↗
PubMed2002

Water content and its intracellular distribution in intact and saline perfused rat hearts revisited.

Precise estimation of cellular water content is a necessary basis for quantitative studies of metabolic control in the heart; however, marked discrepancies in water spaces of heart tissue are found in the literature. Reasons for this wide diversity are analyzed, and the conclusion is that the most probable value of total intracellular water content is 615 ml H(2)O/kg of wet mass (wm) and intracellular content of dry substance is 189 g/kg wm in intact in vivo rat heart. An extracellular water of 174 ml per kg wm and 22 g of dry mass per kg wm in vascular and interstitium spaces account for the rest of the tissue mass. These values can be directly related to normoosmotic saline perfused hydrated hearts, characterized by water accumulation in the extracellular spaces. Due to essentially intact heart cells, the experimentally determined dry mass, water and metabolite contents of these hydrated hearts can be extrapolated to the original morphological configuration of an intact heart muscle before the onset of edema. Such an 'extrapolated' heart is defined as a standardized perfused heart (SPH). SPH is the heart in its original morphological configuration, characterized by cell density and cellular water contents of the intact heart, but with perfusate in the extracellular spaces. The total cellular water is distributed in the cell compartments of SPH and intact hearts according to volumes of particular compartments and density of their dry mass. The volumes of bulk water phases in different organelles, accessible to diffusion of low molecular metabolites, were obtained after corrections for the fraction of 'bound' water of 0.3 g per g of compartmental dry mass content. The diffusible water spaces are proposed to be 321, 55, 153, 21 and 8 ml/kg wm for myofibrils, sarcoplasm, mitochondria, sarcoplasmic reticulum and nuclei, respectively. The SPH model allows direct comparison of metabolic data for intact and perfused hearts. We used this model to analyze the penetration of extracellular marker into cells of intact and hydrated perfused rat hearts.

Adenosine Triphosphate↗
PubMed2003

Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model.

Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 microl/min), the distribution of cytotoxicity in NK1 receptor-expressing neurons was predicted to reach an asymptotic limit at 6-8 h in the transverse direction at the level of the infusion cannula tip ( approximately 60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life approximately 60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.

Chronic Disease↗
PubMed2006

The emergence and diffusion of DNA microarray technology.

UNLABELLED: The network model of innovation widely adopted among researchers in the economics of science and technology posits relatively porous boundaries between firms and academic research programs and a bi-directional flow of inventions, personnel, and tacit knowledge between sites of university and industry innovation. Moreover, the model suggests that these bi-directional flows should be considered as mutual stimulation of research and invention in both industry and academe, operating as a positive feedback loop. One side of this bi-directional flow--namely; the flow of inventions into industry through the licensing of university-based technologies--has been well studied; but the reverse phenomenon of the stimulation of university research through the absorption of new directions emanating from industry has yet to be investigated in much detail. We discuss the role of federal funding of academic research in the microarray field, and the multiple pathways through which federally supported development of commercial microarray technologies have transformed core academic research fields. RESULTS AND CONCLUSION: Our study confirms the picture put forward by several scholars that the open character of networked economies is what makes them truly innovative. In an open system innovations emerge from the network. The emergence and diffusion of microarray technologies we have traced here provides an excellent example of an open system of innovation in action. Whether they originated in a startup company environment that operated like a think-tank, such as Affymax, the research labs of a large firm, such as Agilent, or within a research university, the inventors we have followed drew heavily on knowledge resources from all parts of the network in bringing microarray platforms to light. Federal funding for high-tech startups and new industrial development was important at several phases in the early history of microarrays, and federal funding of academic researchers using microarrays was fundamental to transforming the research agendas of several fields within academe. The typical story told about the role of federal funding emphasizes the spillovers from federally funded academic research to industry. Our study shows that the knowledge spillovers worked both ways, with federal funding of non-university research providing the impetus for reshaping the research agendas of several academic fields.

Journal Article↗