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PubMed2003

A lymphatic mechanism of rotavirus extraintestinal spread in the neonatal mouse.

We used the neonatal mouse model of rotavirus infection and virus strains SA11-clone 4 (SA11-Cl4) and Rhesus rotavirus (RRV) to examine the mechanism of the extraintestinal spread of viruses following oral inoculation. The spread-competent viruses, RRV and reassortant R7, demonstrated a temporal progression from the intestine, to the terminal ileum, to the mesenteric lymph nodes (MLN), and to the peripheral tissues. SA11-Cl4 was not found outside the intestine. Reassortant virus S7, which was unable to reach the liver in previous studies (E. C. Mossel and R. F. Ramig, J. Virol. 76:6502-6509, 2002), was recovered from 60% of the MLN, suggesting that there are multiple determinants for the spread of virus from the intestine to the MLN. Phenotypic segregation analysis identified RRV genome segment 6 (VP6) as a secondary determinant of the spread of virus to the MLN (P = 0.02) in reassortant viruses containing segment 7 from the spread-incompetent parent. These data suggest that in the orally infected neonatal mouse, the extraintestinal spread of rotavirus occurs via a lymphatic pathway, and the spread phenotype is primarily determined by NSP3 and can be modified by VP6.

Animals↗
PubMed2005

Sum1p, the origin recognition complex, and the spreading of a promoter-specific repressor in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, Sum1p is a promoter-specific repressor. A single amino acid change generates the mutant Sum1-1p, which causes regional silencing at new loci where wild-type Sum1p does not act. Thus, Sum1-1p is a model for understanding how the spreading of repressive chromatin is regulated. When wild-type Sum1p was targeted to a locus where mutant Sum1-1p spreads, wild-type Sum1p did not spread as efficiently as mutant Sum1-1p did, despite being in the same genomic context. Thus, the SUM1-1 mutation altered the ability of the protein to spread. The spreading of Sum1-1p required both an enzymatically active deacetylase, Hst1p, and the N-terminal tail of histone H4, consistent with the spreading of Sum1-1p involving sequential modification of and binding to histone tails, as observed for other silencing proteins. Furthermore, deletion of the N-terminal tail of H4 caused Sum1-1p to return to loci where wild-type Sum1p acts, consistent with the SUM1-1 mutation increasing the affinity of the protein for H4 tails. These results imply that the spreading of repressive chromatin proteins is regulated by their affinities for histone tails. Finally, this study uncovered a functional connection between wild-type Sum1p and the origin recognition complex, and this relationship also contributes to mutant Sum1-1p localization.

Binding Sites↗
PubMed2004

Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection.

BACKGROUND: Lateral spreading tumours are superficial spreading neoplasms now increasingly diagnosed using chromoscopic colonoscopy. The clinicopathological features and safety of endoscopic mucosal resection for lateral spreading tumours (G-type "aggregate" and F-type "flat") has yet to be clarified in Western cohorts. METHODS: Eighty two patients underwent magnification chromoscopic colonoscopy using the Olympus CF240Z by a single endoscopist. All patients had received a previous colonoscopy where an endoscopic diagnosis of lateral spreading tumour was made. All lesions were examined initially using indigo carmine chromoscopy to delineate contour followed by crystal violet for magnification crypt pattern analysis. A 20 MHz "mini probe" ultrasound was used if T2 disease was suspected. Following endoscopic mucosal resection, patients were followed up at 3, 6, 12, and 24 months using total colonoscopy. RESULTS: Eighty two lateral spreading tumours were diagnosed in 80 patients (32% (26/82) F-type and 68% (56/82) G-type). G-type lesions were larger than F-type (G-type mean 42 (SD 14) mm v F-type 24 (6.4) mm; p<0.01). F-type lesions were more common in the right colon (F-type 77% (20/26) compared with G-type 39% (22/56); p<0.01) and more often associated with invasive disease (stage T2) (66% (10/15) v 33% (5/15); p<0.001). Fifty eight lesions underwent endoscopic mucosal resection (G-type 64% (37/58)/F-type 36% (21/58)). Local recurrent disease was detected in 17% of patients (10/58), all within six months of the index resection. Piecemeal resection and G-type morphology were significantly associated with recurrent disease (p<0.1). Overall "cure" rates for lateral spreading tumours using endoscopic mucosal resection at two years of follow-up was 96% (56/58). CONCLUSIONS: Endoscopic mucosal resection for lateral spreading tumours, staged as T1, is a safe and effective treatment despite their large size. Endoscopic mucosal resection may be an alternative to surgery in selected patients.

Adult↗
PubMed2005

Inhibition of calpain blocks pancreatic beta-cell spreading and insulin secretion.

In addition to promoting insulin secretion, an increase in cytosolic Ca(2+) triggered by glucose has been shown to be crucial for spreading of beta-cells attached on extracellular matrix (804G matrix). Calpains are Ca(2+)-dependent cysteine proteases involved in an extended spectrum of cellular responses, including cytoskeletal rearrangements and vesicular trafficking. The present work aimed to assess whether calpain is also implicated in the process of Ca(2+)-induced insulin secretion and spreading of rat pancreatic beta-cells. The results indicate calpain dependency of beta-cell spreading on 804G matrix. Indeed, treatment with three distinct calpain inhibitors (N-Ac-Leu-Leu-norleucinal, calpeptin, and ethyl(+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butyl-carbamoyl]-2-ox-iranecarboxylate) inhibited cell spreading induced by glucose and KCl, whereas cell attachment was not significantly modified. Calpain inhibitors also suppressed glucose- and KCl-stimulated insulin secretion without affecting insulin synthesis. Washing the inhibitor out of the cell culture restored spreading on 804G matrix and insulin secretory response after 24 h. In addition, incubation with calpeptin did not affect insulin secretory response to mastoparan that acts on exocytosis downstream of intracellular calcium [Ca(2+)]i. Finally, calpeptin was shown to affect the [Ca(2+)]i response to glucose but not to KCl. In summary, the results show that inhibition of calpain blocks spreading and insulin secretion of primary pancreatic beta-cells. It is therefore suggested that calpain could be a mediator of Ca(2+)-induced-insulin secretion and beta-cell spreading.

Animals↗
PubMed1993

Spreading of exogenous surfactant in an airway.

Using a theoretical model, we studied spreading of a bolus of insoluble surfactant deposited on a thin liquid layer of a model airway. Applications include instillation of exogenous surfactant as a treatment for neonatal respiratory distress syndrome, the use of surfactant carriers to deliver drugs via the lung, and the movement of liquid along the airway tree due to naturally occurring gradients of surface tension. The time-dependent governing equations were solved numerically for longitudinal axisymmetric surfactant spreading. We examined the influences of the resident liquid layer (thickness, viscosity, endogenous surfactant, airway radius), of the bolus (volume and surfactant content), and of gravity. The gradient in surface tension drives the flow toward the region of higher surface tension, ultimately creating a shocklike wave of nearly twice the initial lining thickness. Pressure gradients due to interfacial curvature (capillarity) have little effect on the rate of surfactant spread. The presence of an endogenous resident surfactant greatly augments the rate of spreading while inhibiting development of the shock. In all cases studied, the effect of circumferential curvature was negligible, indicating that the liquid layer can be treated as if it were spreading over a flat surface. Our results reveal that the surfactant spreads as time to the one-third power. Accordingly, a surfactant deposited in the trachea of a neonate would spread to the periphery in approximately 12 s.

Aerosols↗
PubMed1988

Spread of synchronous firing in longitudinal slices from the CA3 region of the hippocampus.

1. Mechanisms underlying the propagation of synchronous epileptiform activity in disinhibited hippocampal slices were examined in experimental and computer simulation studies. 2. Experiments were performed with longitudinal slices of the CA3 region. Synchronous firing was initiated by stimulating stratum radiatum fibers in the presence of picrotoxin. It propagated smoothly and without decrement at velocities close to 0.15 m/s over distances up to 10 mm. 3. In elevated extracellular calcium, neuronal firing threshold was increased and synchronous burst firing did not spread. Monophasic excitatory postsynaptic potentials (EPSPs) were recorded in cells at limited distances from a stimulus in the presence of 10 mM Ca and picrotoxin. Axonal conduction velocity, estimated from EPSP latencies, was several times faster than the spread of synchronous firing. 4. EPSPs recorded in 5-7 mM Ca and picrotoxin could consist of two components. The properties of the first component were similar to those of synaptic events recorded in 10 mM Ca. The second component was of longer latency and unlike the first component was suppressed in responses to paired stimuli at interval 50-300 ms. Recordings from cells at different distances from a stimulus suggested that the second component spread further and more slowly than the first component. 5. In computer simulations the CA3 region was represented by a spatially distributed network of 9,000 excitatory neurons and 900 inhibitory cells. Individual cells and synapses had properties based on experimental data. The effects of varying synaptic strength and connectivity on the spread of activity in the model was examined. 6. When synaptic inhibition was functional in simulations, firing was restricted to a single action potential in model cells close to the stimulus, as in experiments. Synchronous burst firing spread throughout the neuronal array when fast synaptic inhibition was absent. The velocity of propagation was slower than conduction in simulated axons when synaptic contacts made by excitatory cells were spatially limited. Propagation velocity increased with increases in the spatial extent of excitatory connectivity. 7. Increasing the threshold of neurons in a region of the model network reduced the speed at which synchronous firing spread. In experiments focal application of gamma-aminobutyric acid (GABA) elevated neuronal firing threshold and slowed the propagation of synchrony in a local region. 8. As the strength of synaptic inhibition was gradually reduced, neuronal activity spread further and faster through the simulated neuronal network.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Local production and provision of ready-to-use therapeutic food (RUTF) spread for the treatment of severe childhood malnutrition.

BACKGROUND: Ready-to-use therapeutic food (RUTF) spread has been shown to be very effective in the rehabilitation of severely malnourished children and facilitates home-based therapy of these children. OBJECTIVE: To describe how RUTF spread can be manufactured on a variety of production scales. PRINCIPLES OF PRODUCTION: RUTF spread is an edible lipid-based paste that is energy dense, resists bacterial contamination, and requires no cooking. The primary production principles include grinding all ingredients to a particle size < 200 microns, producing the food without the introduction of water, and embedding the protein and carbohydrate components of the food into the lipid matrix. The most widely used RUTF spread is a mixture of milk powder, sugar, vegetable oil, peanut butter, vitamins, and minerals. SCALE OF PRODUCTION: RUTF spread can be produced in quantities sufficient to treat several hundred children using a planetary mixer in a clinic. Production of larger quantities of RUTF spread can be achieved in partnership with local food companies. Production sufficient to meet the needs of several thousand children can be achieved with a dedicated production facility using technology appropriate for use in the developing world. Care must be taken to avoid aflatoxin contamination, and quality control testing of the product is essential. CONCLUSIONS: RUTF spread can be safely and easily produced in small or large quantities in most settings worldwide. The local availability of the necessary ingredients limits its use in some settings, and further investigation of alternative ingredients is needed to overcome this limitation.

Child Nutrition Disorders↗
PubMed2003

Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen.

Platelet spreading on immobilized fibrinogen (Fg) involves progression through a number of morphologic stages that, although distinctive, are not well understood mechanistically. Here we demonstrate that an association between GPIIb/IIIa and calcium- and integrin-binding protein (CIB) is required for the process of platelet spreading. Upon platelet adhesion to immobilized Fg, CIB localizes to the transiently formed filopodia and then redistributes diffusely along the membrane periphery of spread platelets. Immunoprecipitation analyses indicate that CIB and glycoprotein IIb/IIIa (GPIIb/IIIa) interact with each other as platelets adhere to immobilized Fg, and together they associate with the platelet cytoskeleton. Introduction of anti-CIB antibody or GPIIb cytoplasmic peptide into platelets blocks lamellipodia but not filopodia formation. GPIIb peptide-induced inhibition of platelet spreading is recovered by the incorporation of recombinant CIB protein, suggesting that interaction between CIB and GPIIb/IIIa is required for progression from filopodial to spread morphologies. Further, anti-CIB- or GPIIb peptide-induced inhibition of platelet spreading can be overcome by the addition of exogenous adenosine diphosphate (ADP). These data suggest that formation of the CIB-GPIIb/IIIa complex may be necessary for initiation of downstream signaling events, such as ADP secretion, that lead to platelet spreading.

Adenosine Diphosphate↗
PubMed2001

Rac, a small guanosine triphosphate-binding protein, and p21-activated kinase are activated during platelet spreading on collagen-coated surfaces: roles of integrin alpha(2)beta(1).

In this study, the receptors and signals involved in collagen-induced platelet spreading were examined. It was found that platelet spreading on collagen (presenting a polygon shape with a number of filopodialike projections) was inhibited by the anti-integrin alpha(2) antibody, suggesting the involvement of integrin alpha(2)beta(1) in this process. Studies with a glutathione-S-transferase fusion protein that binds specifically to activated Rac and in vitro p21-activated kinase (PAK) kinase assays revealed that Rac and PAK were activated during this collagen-activated process. Platelet spreading on collagen-coated surfaces was inhibited strongly by PP1 (a Src family kinase inhibitor) or weakly by wortmannin (a phosphatidylinositol 3-kinase [PI3-kinase] inhibitor) but not at all by Y-27632 (a Rho kinase inhibitor). The surfaces coated with anti-integrin alpha(2)beta(1) antibodies also induced platelet spreading (presenting an almost complete round shape) and activation of Rac and PAK, although more slowly than collagen-coated surfaces. The antibody-induced responses were strongly inhibited by PP1 or wortmannin but not by Y-27632. The same concentration of Y-27632 inhibited collagen-induced shape change of platelets in suspension. These findings suggest that Rac and/or PAK activation, but not Rho, may play certain roles in platelet spreading via integrin alpha(2)beta(1) and that Src family kinases and PI3-kinase participate in these processes. Furthermore, the difference between spreading on collagen and the anti-integrin antibody suggests the involvement of other receptor(s) (in addition to the integrin alpha(2)beta(1)) for collagen-induced spreading, the most likely candidate being glycoprotein VI.

Amides↗
PubMed2003

Epidemiological models for the spread of anti-malarial resistance.

BACKGROUND: The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. METHODS: We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. RESULTS: In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. CONCLUSIONS: The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.

Alleles↗
PubMed1992

Microinjection of antibodies against talin inhibits the spreading and migration of fibroblasts.

Talin is believed to be one of the key proteins involved in linking actin filaments to extracellular matrix receptors in focal adhesions. Our strategy for studying the function of talin has been to inactivate talin in living fibroblasts in tissue culture through the microinjection of affinity-purified, polyclonal anti-talin antibodies. The effect of the injected anti-talin antibodies on cell spreading was found to depend on how recently the cells had been plated. Cells that were in the process of spreading on a fibronectin substratum, and which had newly developed focal adhesions, were induced to round up and to disassemble many of the adhesions. However, if fibroblasts were allowed to spread completely before they were microinjected with the anti-talin antibody, focal adhesions remained intact and the flat morphology of the cells was unaffected. The percentage of cells that were able to maintain a spread morphology despite the injection of anti-talin antibodies increased during the first few hours after plating on fibronectin substrata. Fibroblasts that were allowed to spread completely before microinjection with the anti-talin antibody retained both intact focal adhesions and a flat, well-spread morphology, but failed to migrate effectively. Our experiments do not directly address the role of talin in mature focal adhesions, but they indicate that talin is essential for the spreading and migration of fibroblasts on fibronectin as well as for the development and initial maintenance of focal adhesions on this substratum.

Animals↗
PubMed1997

Increased degranulation and phospholipase A2, C, and D activity in RBL cells stimulated through FcepsilonR1 is due to spreading and not simply adhesion.

Rat basophilic leukemia cells will adhere to and spread out on fibronectin coated surfaces in an integrin dependent manner. Adhesion and spreading on fibronectin leads to increased degranulation, inositol phosphate production, phospholipase D activation, and increased production of prostaglandin D2 and leukotriene C4 when the cells are activated through the high affinity IgE receptor. Rat basophilic leukemia cells will also adhere to surfaces coated with anti-rat class I antibodies, poly-L-lysine, and a lectin purified from Tetragonolobus purpureas. In all cases, antigen activated cells, which were adherent, displayed increased signaling, degranulation and eicosanoid production as compared to cells which were non-adherent. Cells which adhere to either anti-rat class I antibodies or poly-L-lysine also spread even though this is not mediated through integrins. In contrast, adhesion to the lectin from Tetragonolobus did not cause any appreciable spreading unless the cells were also triggered through the IgE receptor. Cells were also able to bind to fibronectin immobilized on polystyrene beads which mimics adhesion but does not allow spreading. However, these cells exhibited no increased signaling, degranulation, or eicosanoid production. Furthermore, rat basophilic leukemia cells can be modified by incubating them in the presence of biotinylated-phosphatidylserine which becomes incorporated into the membrane. These modified cells will adhere to streptavidin coated plates while unmodified cells will not. However, these modified cells do not spread, even after activation with antigen, and they show no increased degranulation or production of eicosanoids. These results indicate that adhesion itself is not sufficient for upregulation of the cells in response to antigen and that spreading of the cells may be the critical component.

Animals↗
PubMed1980

The effect of fibronectin and substratum-attached material on the spreading of chick embryo mesoderm cells in vitro.

Endoblast and hypoblast tissue, dissected from early chick embryos, was explanted and cultured on glass or plastic substrata. These tissues grew rapidly to form epithelial sheets. Under the same conditions, mesoderm, dissected without the aid of dissociating agents, grew poorly. After 24 h in culture, the mesoderm explants consisted of a sparse outgrowth of fibroblast-like cells. When pieces of mesoderm were seeded onto the dorsal surface of the epithelia, however, the cells penetrated the sheet and rapidly spread on the substratum within 4 h. If the epithelial sheet was detached from the substratum and the mesoderm then seeded onto areas of substratum previously occupied by epithelium, similar rapid spreading occurred. This effect could be produced in the absence of serum. The method used to remove the epithelium (EDTA, detergent or manual dissection) did not influence the result. When the substratum-attached material (SAM) was examined by scanning electron microscopy, 2 types of material were seen. One type appeared to be the remains of detached filopodia and cytoplasmic lamellae, while the other appeared to be of extracellular origin. Both these types reacted positively by immunofluorescence using anti-fibronectin serum. SAM derived from mesoderm reacted negatively. When mesoderm was cultured in the presence of plasma fibronectin on unmodified plastic or glass, spreading was complete in 4-5 h and thus was similar to mesoderm seeded onto SAM. The morphology of mesoderm explants on SAM or in the presence of plasma fibronectin was more epithelial than on untreated substratum in normal medium. Hypoblast and endoblast cultured in the presence of anti-fibronectin serum failed to spread normally, apparently being unable to attach to the substratum. Mesoderm did not spread rapidly on SAM in the presence of this antiserum. Cycloheximide reversibly inhibited the spreading of hypoblast and endoblast, and this effect could be eliminated, at least for hypoblast, by the addition of plasma fibronectin. Covering attachment sites on the substratum with bovine serum albumin, thereby preventing the attachment of SAM or fibronectin, also inhibited spreading. It is proposed that mesoderm cells have low levels of surface fibronectin in comparison with endoblast and hypoblast, and that this results in a comparatively low adhesiveness, which is important for its morphogenetic activity within the embryo.

Animals↗
PubMed1983

Kinetic analysis of cell spreading. II. Substratum adhesion requirements of amniotic epithelial (FL) cells.

The kinetics of spreading of trypsinized FL cells on plastic or glass substrata covalently or passively coated with various proteins to make simplified model extracellular matrices have been measured. Kinetics have also been obtained in the presence and absence of serum and amniotic fluid. Data from such experiments are shown to be sigmoid and have been computer-fitted with great accuracy to 12 mathematical models discussed in the accompanying paper. A log normal distribution function is shown to give the best fit over 18 different types of experiment. For the first time, therefore, such data can be characterized quantitatively and compared. We obtain the simple parameters mu (mean time to spread) and sigma (standard error of the mean) and show that the cells spread most rapidly in amniotic fluid or on fibronectin 'carpets'. They also spread rapidly on a fibronectin-fibrinogen complex extracted from placenta. Spreading is slower in serum, in amniotic fluid lacking fibronectin and on type I collagen or cellular microexudate from FL cells or fibroblasts. On concanavalin A, spreading is rapid but the distribution of times to spread (as expressed by sigma) is relatively wide.

Amnion↗
PubMed2006

Empirical evidence for the effect of airline travel on inter-regional influenza spread in the United States.

BACKGROUND: The influence of air travel on influenza spread has been the subject of numerous investigations using simulation, but very little empirical evidence has been provided. Understanding the role of airline travel in large-scale influenza spread is especially important given the mounting threat of an influenza pandemic. Several recent simulation studies have concluded that air travel restrictions may not have a significant impact on the course of a pandemic. Here, we assess, with empirical data, the role of airline volume on the yearly inter-regional spread of influenza in the United States. METHODS AND FINDINGS: We measured rate of inter-regional spread and timing of influenza in the United States for nine seasons, from 1996 to 2005 using weekly influenza and pneumonia mortality from the Centers for Disease Control and Prevention. Seasonality was characterized by band-pass filtering. We found that domestic airline travel volume in November (mostly surrounding the Thanksgiving holiday) predicts the rate of influenza spread (r(2) = 0.60; p = 0.014). We also found that international airline travel influences the timing of influenza mortality (r(2) = 0.59; p = 0.016). The flight ban in the US after the terrorist attack on September 11, 2001, and the subsequent depression of the air travel market, provided a natural experiment for the evaluation of flight restrictions; the decrease in air travel was associated with a delayed and prolonged influenza season. CONCLUSIONS: We provide the first empirical evidence for the role of airline travel in long-range dissemination of influenza. Our results suggest an important influence of international air travel on the timing of influenza introduction, as well as an influence of domestic air travel on the rate of inter-regional influenza spread in the US. Pandemic preparedness strategies should account for a possible benefit of airline travel restrictions on influenza spread.

Aircraft↗
PubMed2004

Pseudopod projection and cell spreading of passive leukocytes in response to fluid shear stress.

Recent evidence suggests that circulating leukocytes respond to physiological levels of fluid shear stress. This study was designed to examine the shear stress response of individual leukocytes adhering passively to a glass surface. Human leukocytes were exposed to a step fluid shear stress with amplitude between 0.2 and 4 dyn/cm(2) and duration between 1 and 20 min. The response of the cells was determined in the form of projected cell area measurements by high-resolution observation before, during, and after fluid shear application. All cells selected initially had a round morphology. After application of fluid shear many cells projected pseudopodia and spread on the glass surface. The number of leukocytes responding with pseudopod projection and the extent of cell spreading increased with increasing amplitude and duration of fluid shear stress. Pseudopod projection after exposure to a step fluid shear occurs following a delay that is insensitive to the shear stress amplitude and duration. Leukocytes that did not project pseudopodia and spread in response to low shear stress could be shown to respond to a second shear step of higher amplitude. The spreading response requires an intact actin network and activated myosin molecules. Depleting the cell glycocalyx with protease treatment enhances the spreading response in sheared leukocytes. These results indicate that passive leukocytes respond to fluid shear stress with active pseudopod projection and cell spreading. This behavior may contribute to cell spreading on endothelium and other cells as well as to transendothelial migration of leukocytes in the microcirculation.

Cell Adhesion↗
PubMed2005

Spreading vasodilatation in resistance arteries.

Focal application of vasodilators such as acetylcholine (ACh), which evoke arterial hyperpolarization, cause coordinated dilatation along the length of an artery with minimal decay with distance from the site of application. This phenomenon is called spreading vasodilatation. In an artery wall, the endothelium is separated from the surrounding smooth muscle cell layers by an internal elastic lamina (IEL). Adjacent endothelial cells are strongly connected via gap junctions, which can allow direct communication between the cells, including the passage of small molecules and electrical current. Direct communication between an endothelial cell and a smooth muscle cell, through a hole in the IEL, has recently been observed in arteries. Spreading vasodilatation is associated with a spread of hyperpolarization which may be a key mechanism responsible for this spreading arterial vasodilatation. Endothelial cells appear to play an important role in such spread, even though the facilitating mechanisms underlying this spread are as yet unclear. These spreading responses are likely to have an important physiological role in the coordination of blood flow within a vascular network.

Animals↗
PubMed1998

Ser752 mutation to Pro or Ala in the beta3 integrin subunit differentially affects the kinetics of cell spreading to von Willebrand factor and fibrinogen.

The beta3 cytoplasmic domain of the alpha v beta3 integrin is essential for intracellular signals required for cytoskeletal rearrangements. Expression of beta3Ser752Pro mutation in heterologous cells profoundly affects cell spreading and beta3 localization into focal contacts. However, the beta3Ser752Ala substitution mostly restores normal integrin functions, suggesting that the presence of Pro is responsible for the receptor's loss of function. To further assess the role of the Ser752 of the beta3 cytoplasmic domain in the cytoskeletal organization of adherent cells, we developed a computer-assisted method of image analysis allowing the automatic classification of spread cells according to the quantitative analysis of their cell morphology. We compared adhesion and spreading to von Willebrand factor (vWF) or fibrinogen (Fg) of cells expressing beta3 wild type, beta3Ser752Pro or beta3Ser752Ala mutated integrin subunit as a chimeric alpha v beta3 receptor. The beta3Ser752Ala substitution did not impair the general ability of cells to spread, but resulted in a delayed and reduced spreading on both vWF and Fg. Moreover, the beta3Ser752Ala mutation produced modifications of the morphology of spread cells, suggesting a disorganization of their cytoskeleton. Attachment studies showed that the beta3Ser752Ala mutation did not modify the capacity of cells to attach to the substrate, indicating no change in the ligand binding affinity of the alpha v beta3 integrin. Furthermore, we identified a slight defect of beta3Ser752Pro cell attachment to vWF and Fg, beside their impairment of spreading. Taken together, these results suggest a role of Ser752 of the beta3 cytoplasmic domain in the optimal cytoskeletal organization of adherent cells.

Alanine↗