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PubMed2004

Alphav-integrin utilization in human beta-cell adhesion, spreading, and motility.

The role of individual integrins in human beta-cell development and function is largely unknown. This study describes the contribution of alpha(v)-integrins to human beta-cell adhesion, spreading, and motility. Developmental differences in alpha(v)-integrin utilization are addressed by comparing the responses of adult and fetal beta-cells, and vitronectin is used as a substrate based on its unique pattern of expression in the developing pancreas. Fetal and adult beta-cells attached equally to vitronectin and integrin alpha(v)beta(5) was found to support the adhesion of both mature and immature beta-cell populations. Fetal beta-cells were also observed to spread and migrate on vitronectin, and integrin alpha(v)beta(1) was found to be essential for these responses. In contrast to their fetal counterparts, adult beta-cells failed to either spread or migrate and this deficit was associated with a marked down-regulation of alpha(v)beta(1) expression in adult islet preparations. The integrin alpha(v)beta(3) was not found to support significant beta-cell attachment or migration. Based on our findings, we conclude that integrins alpha(v)beta(5) and alpha(v)beta(1) are important mediators of human beta-cell adhesion and motility, respectively. By supporting fetal beta-cell migration, alpha(v)beta(1) could play an important role in early motile processes required for islet neogenesis.

Adult↗
PubMed2004

The cAMP-Epac-Rap1 pathway regulates cell spreading and cell adhesion to laminin-5 through the alpha3beta1 integrin but not the alpha6beta4 integrin.

Laminin-5 is an important constituent of the basal lamina. The receptors for laminin-5, the integrins alpha3beta1 and alpha6beta4, have been associated with epithelial wound migration and carcinoma invasion. The signal transduction mechanisms that regulate these integrins are not well understood. We report here that the small GTPase Rap1 regulates the adhesion of a number of cell lines to various extracellular matrix proteins including laminin-5. cAMP also mediates cell adhesion and spreading on laminin-5, a process that is independent of protein kinase A but rather dependent on Epac1, a cAMP-dependent exchange factor for Rap. Interestingly, although both alpha3beta1 and alpha6beta4 mediate adhesion to laminin-5, only alpha3beta1-dependent adhesion is dependent on Rap1. These results provide evidence for a function of the cAMP-Epac-Rap1 pathway in cell adhesion and spreading on different extracellular matrix proteins. They also define different roles for the laminin-binding integrins in regulated cell adhesion and subsequent cell spreading.

Actins↗
PubMed2005

Mislocalization or reduced expression of Arf GTPase-activating protein ASAP1 inhibits cell spreading and migration by influencing Arf1 GTPase cycling.

ADP-ribosylation factor (Arf) family of small GTP-binding proteins plays a central role in membrane trafficking and cytoskeletal remodeling. ASAP1 (Arf-GAP containing SH3, ankyrin repeats, and PH domain) is a phospholipid-dependent Arf GTPase-activating protein (Arf-GAP) that binds to protein-tyrosine kinases Src and focal adhesion kinase. Using affinity chromatography and mass spectrometry (MS), we identified the adaptor protein CD2-associated protein (CD2AP) as a candidate binding partner of ASAP1. Both co-immunoprecipitation and GST pull-down experiments confirmed that CD2AP stably interacts with ASAP1 through its N-terminal SH3 domains. Using a mislocalization strategy, we show that sequestration of endogenous ASAP1 to mitochondria with a CD2AP SH3-mito fusion protein (the three N-terminal SH3 domains of CD2AP fused to Listeria monocytogenes ActA mitochondria-targeting sequence) inhibited REF52 cell spreading and migration in response to fibronectin stimulation. Using an alternative strategy we show that suppressing ASAP1 expression with small interfering RNA duplexes also significantly retarded cell spreading and inhibited cell migration. Furthermore, abrogation of ASAP1 function using either small interfering RNAs or mislocalization approaches caused an increase of GTP loading on Arf1 and loss of paxillin from adhesions. These results taken together with our previous observations that overexpression of ASAP1 inhibits cell spreading and alters paxillin localization to adhesions (Liu, Y., Loijens, J. C., Martin, K. H., Karginov, A. V., and Parsons, J. T. (2002) Mol. Biol. Cell. 13, 2147-2156) suggest that the recruitment of certain adhesion components such as paxillin requires dynamic GTP/GDP turnover of Arf1 GTPase.

ADP-Ribosylation Factor 1↗
PubMed2005

A new functional role of the fibrinogen RGD motif as the molecular switch that selectively triggers integrin alphaIIbbeta3-dependent RhoA activation during cell spreading.

A number of RGD-type integrins rely on a synergistic site in addition to the canonical RGD site for ligand binding and signaling, although it is still unclear whether these two recognition sites function independently, synergistically, or competitively. Experimental evidence has suggested that fibrinogen binding to the RGD-type integrin alphaIIbbeta3 occurs exclusively through the synergistic gamma(400-411) sequence, thus questioning the functional role of the RGD recognition site. Here we have investigated the respective role of the fibrinogen gamma(400-411) sequence and the RGD motif in the molecular events leading to ligand-induced alphaIIbbeta3-dependent Chinese hamster ovary (CHO) cell or platelet spreading, by using intact fibrinogen and well characterized plasmin-generated fibrinogen fragments containing either the RGD motif (fragment C) or the gamma(400-411) sequence (fragment D), and CHO cells expressing resting wild type (alphaIIbbeta3wt), constitutively active (alphaIIbbeta3T562N), or non-functional (alphaIIbbeta3D119Y) receptors. Our data provide evidence that the gamma(400-411) site by itself is able to initiate alphaIIbbeta3 clustering and recruitment of intracellular proteins to early focal complexes, mediating cell attachment, FAK phosphorylation, and Rac1 activation, while the RGD motif subsequently acts as a molecular switch on the beta3 subunit to trigger cell spreading. More importantly, we show that the premier functional role of the RGD site is not to reinforce cell attachment but, rather, to imprint a conformational change on the beta3 subunit leading to maximal RhoA activation and actin cytoskeleton organization in CHO cells as well as in platelets. Finally, alphaIIbbeta3-dependent RhoA stimulation and cell spreading, but not cell attachment, are Src-dependent and phosphoinositide 3-kinase-independent and are inhibited by the Src antagonist PP2.

Amino Acid Motifs↗
PubMed1999

Doxorubicin does not spread systemically following a local injection into the eyelids of rabbits.

PURPOSE: An experimental treatment for benign essential blepharospasm and hemifacial spasm involves the direct injection of doxorubicin into the eyelids to permanently kill muscle. This study examined the extent of local and systemic spread of doxorubicin after localized injections of low doses into the eyelid and determined the length of time doxorubicin was retained in the eyelid after injection. METHODS: Two mg doxorubicin was injected subcutaneously into the lower eyelids of rabbits. After various time periods, the eyelids were removed and dissected into three separate specimens consisting of skin, subcutaneous connective tissue including orbicularis oculi muscle, or palpebral conjunctiva. Nearby tissues were also collected, including facial muscles and extraocular muscles. Urine, blood, kidney, spleen, heart and liver samples were collected. All tissues were prepared for HPLC determination of doxorubicin concentration. RESULTS: Doxorubicin was detected in all three eyelid specimens for the first 4 days after injection, although by the fourth day the level of doxorubicin was greatly reduced. On and after the seventh day, there was no detectable doxorubicin in the treated eyelid tissues. There were no detectable levels of doxorubicin in the urine or any other body tissue at any of the post-injection intervals examined. There was no long term retention in any of the eyelid tissues examined. CONCLUSIONS: The well described array of serious systemic side effects caused by the use of high systemic doses of doxorubicin as a chemotherapeutic agent made it critical to ascertain how long doxorubicin remained within the injected eyelids, and to determine to what extent and with what time course local injections of chemically intact doxorubicin might spread systemically. The short retention of the active or unmetabolized drug at the injection site is important, since more than one set of injections has been required for satisfactory amelioration of muscle spasms in blepharospasm and hemifacial spasm patients. The lack of detectable systemic spread of the drug distant from the local site of injection as well as the lack of long term retention of the locally injected doxorubicin lends support for the safety of doxorubicin administered in this manner to blepharospasm and hemifacial spasm patients.

Animals↗
PubMed2001

The effect of natural enemies on the spread of barley yellow dwarf virus (BYDV) by Rhopalosiphum padi (Hemiptera: Aphididae).

The effects of two natural aphid enemies, adult Coccinella septempunctata Linneaus, a predator, and Aphidius rhopalosiphi de Stefani Perez, a parasitoid, on spread of barley yellow dwarf virus (BYDV) transmitted by the bird cherry-oat aphid, Rhopalosiphum padi (Linnaeus) were studied under laboratory conditions. Predators or parasitoids were introduced to trays of durum wheat seedlings and the patterns of virus infection were observed after two, seven and 14 days of exposure. More plants were infected with BYDV in control trays without A. rhopalosiphi than in trays with the parasitoid present, both seven and 14 days after the introduction of parasitoids. Patterns of virus infection were found to be similar over time in trays with a parasitoid present and in control trays. More plants were infected in trays with C. septempunctata present than in control trays, both two and seven days after the introduction of the coccinellid. The spread of virus infections progressed differently over time for the two treatments (predator and parasitoid), differences between treatments being most marked after two days and seven days, when more plants exposed to predators but fewer exposed to parasitoids were infected with BYDV compared to their respective controls. However, by the 14th day 88% of all plants were infected and there was no significant difference between the two treatments. The role of natural enemies in spread of BYDV is discussed.

Animals↗
PubMed2006

Modelling the spread of HIV/AIDS in China: the role of sexual transmission.

The study presented here is an exploration of the implications of patterns of sexual behaviour for the spread of HIV in China, using a bio-behavioural macrosimulation model. To reflect the uncertainty surrounding key parameters, analyses of varied scenarios are used to show a range of possible outcomes consistent with variations in selected biological and behavioural inputs. The latter are estimated from a nationwide survey of sexual behaviour recently conducted in China, a country with an emerging HIV/AIDS epidemic, where it is feared that HIV/AIDS will spread to the general population via heterosexual transmission. The results highlight the primacy of the levels and distribution of sexual activity in the population. They offer some guidelines for understanding and interpreting the potential implications of current and prospective changes in sexual behaviour for the spread of HIV/AIDS in the world's largest population, and also highlight the need to collect better data on sexual behaviour for the estimation of key model inputs.

Adult↗
PubMed2005

Spontaneous transdural spread of glioblastoma with atypical presentation.

The dura provides an excellent protection against infiltration by malignant tumours. It is extremely rare for glial tumour cells to infiltrate the dura and subsequently invade adjacent structures. We report an interesting case of glioblastoma of the temporal lobe with spontaneous transdural spread to the skull base and infratemporal fossa. This is the first radiologically documented case of transdural spread of glioblastoma before and after the spread without previous craniotomy.

Brain Neoplasms↗
PubMed1999

Perianal streptococcal dermatitis. The possible protective role of alpha-streptococci against spread and recurrence of group A streptococcal throat infection.

OBJECTIVE: To follow the spread of beta-haemolytic streptococci group A (GAS) within a family and examine the protective activity of normally occurring alpha-streptococci against GAS tonsillitis. DESIGN: Follow up of recurrent GAS throat infection within a family. SETTING: Intra familial spread of GAS. PATIENTS: A family of four, the mother suffering from recurrent streptococcal tonsillitis and a son with perianal streptococcal dermatitis. RESULTS: The strain of the GAS found in the perianal region of the boy was identical with that found in the throat of his mother. She had recurrent streptococcal tonsillitis, while the boy remained healthy in the throat. She lacked interfering alpha-streptococci in the throat, while the boy had a massive growth of alpha-streptococci in his throat with capacity to inhibit the growth of the streptococcal isolate. MAIN OUTCOME MEASURES: Infection with GAS within a family correlated with the growth-inhibiting activity of the alpha-streptococci in vitro. CONCLUSIONS: The study demonstrated the spread of GAS from a patient with streptococcal dermatitis to the throat of another person within the family, and the hindrance of induction of infection in patients carrying interfering alpha-streptococci.

Anus Diseases↗
PubMed1987

Soil contamination by some organic micropollutants related to sewage sludge spreading.

The aim of the present publication is to give some information on soil contamination by 4 different micropollutant classes due to sewage sludge spreading. The soil under research shows an accumulation of light molecular weight PAHs and PCBs, DEHP and 4-NP just after spreading, but one month later the concentration of these micropollutant groups fall to the concentration detected just before the sludge spreading. As far as the soil concentration is concerned, only PAHs and PCBs are precipitation dependent. Some test plots, enriched during 10 years with fertilisers, pig-dung or sewage sludges show only an increase of the PAH concentrations of the plots amended with sludges. In the same way, the sewage sludge is chiefly responsible for the increase of PCBs in the soils, but pig-dung seems to contain quantities of these micropollutants which have to be taken into consideration.

Chromatography, High Pressure Liquid↗
PubMed1995

Associative spread as a mediating variable in the generation effect.

Memory retention is greater for information that is subject-produced rather than experimenter-provided; this enhancement has been labelled the generation effect. One explanation of this phenomenon, the Lexical Activation Hypothesis, assumes that lexical representation is a necessary condition for emergence of the effect. A corollary to this hypothesis, the Lexical Spread Hypothesis (Nairne, Pusen, & Widner, 1985), emphasises associative spread as a mediating variable. This single-factor explanation has relied for its support exclusively on recognition performance. In the present study, four experiments examined the viability of this hypothesis, under recognition and free-recall conditions. A two-factor explanation is proposed to account for the findings of the present study. It appears that associative spread does not mediate the generation effect, when a recognition test is administered, but may mediate free-recall performance, where retrieval networks play a more significant role in memory performance. An alternative explanation, based on the benefits to memory retention obtained from disruptions of familiar orthographic patterns, is proposed to account for the recognition findings.

Adolescent↗
PubMed2005

Glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system of mice.

Induction of apoptosis by rabies virus (RV) has been reported to be associated with the expression of the glycoprotein (G), but inversely correlated with pathogenicity. To further delineate the association between the expression of the G and the induction of apoptosis, recombinant RVs with replacement of only the G gene were used to infect mice by the intracerebral route. Recombinant viruses expressing the G from attenuated viruses expressed higher level of the G and induced more apoptosis in mice than recombinant RV expressing the G from wild-type (wt) or pathogenic RV, demonstrating that it is the G gene that determines the level of G expression and, consequently, the induction of apoptosis. Likewise, recombinant viruses expressing the G from wt or pathogenic RV are more pathogenic in mice than those expressing G from attenuated RV, confirming the inverse correlation between RV pathogenicity and the induction of apoptosis. To investigate the mechanism by which induction of apoptosis attenuates viral pathogenicity, mice were infected with wt or attenuated RV by the intramuscular route. It was found that low doses of attenuated RV induced apoptosis in the spinal cord and failed to spread to the brain or produce neurological disease. On the other hand, apoptosis was not observed in the spinal cord of mice infected with the same doses of wt RV and the virus spread to various parts of the brain and induced fatal neurologic disease. These results suggest that glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system (CNS) of mice.

Animals↗
PubMed2005

Murine cytomegalovirus (MCMV) spreads to and replicates in the retina after endotoxin-induced disruption of the blood-retinal barrier of immunosuppressed BALB/c mice.

The goal of this study was to determine whether disruption of the blood-retinal barrier (BRB) facilitates spread of MCMV to the retina in immunosuppressed (IS) BALB/c mice. IS mice were inoculated intravenously (i.v.) with murine cytomegalovirus (MCMV) or with macrophages infected with MCMV for 4 days in vitro. The BRB was disrupted by injection of sodium iodate (i.v.) or lipopolysaccharide (LPS, i.v. or anterior chamber). Frozen sections of ocular tissue were examined for MCMV antigens. The results showed that MCMV-infected cells were observed only in the choroid and ciliary body in IS mice with an intact BRB. After LPS injection, a few positive cells were observed in the retina of IS mice after i.v. injection of MCMV. In lipopolysaccharide (LPS)-treated IS mice, a few PKH-26-positive macrophages or MCMV-positive cells were observed in the retina at 1 or 2 days after injection of macrophages. No PKH-26-positive cells or virus-infected cells were noted in the retina of phosphate-buffered saline (PBS)-treated mice. Ten days after injection of virus-infected macrophages, MCMV-infected cells were observed in choroid and ciliary body of both LPS- and PBS-treated mice, but they were observed in the retina only in LPS-treated mice. The results support the idea that disruption of the BRB allows MCMV to spread to the retina of IS mice and that monocytes/macrophages disseminate MCMV to the retina in mice with a disrupted BRB. By extrapolation, damage to the BRB in immunosuppressed patients may facilitate spread of CMV-infected monocytes/macrophages to the retina.

Animals↗
PubMed1993

Integrins in point contacts mediate cell spreading: factors that regulate integrin accumulation in point contacts vs. focal contacts.

We have studied the function and distribution of the alpha 1 beta 1, alpha 5 beta 1 and alpha 6 beta 1 heterodimers on type-1 astrocytes with antibodies specific for integrin subunits (alpha 1, alpha 5, alpha 6, and beta 1). The alpha 1 beta 1 heterodimer mediates adhesion to laminin and collagen, the alpha 5 beta 1 to fibronectin in an RGD-dependent manner. The alpha 5 beta 1 integrin is found in focal contacts in long-term cultures of well-spread astrocytes colocalizing with vinculin and the termini of actin stress fibers. alpha 1 beta 1 heterodimers can occasionally be found as small aggregates within focal contacts but they do not accumulate there. Instead, alpha 1 beta 1 integrins are found in punctate deposits called point contacts which are distributed over the upper and the lower cell surfaces whether laminin, collagen, fibronectin or polylysine is used as a substratum. Unlike focal contacts, point contacts contain clathrin but rarely codistribute with actin or vinculin. Two observations indicate that these point contacts are functional. First, mAb 3A3, directed against the rat alpha 1 subunit, inhibits the attachment of astrocytes to laminin and collagen. Second, during the spreading of astrocytes, a band of point contacts forms around the cell perimeter at a time when no focal contacts are visible. While alpha 1 beta 1 integrins are found only in point contacts in astrocytes, the alpha 6 beta 1 integrin, another laminin receptor, is localized within focal contacts. Moreover, alpha 1 beta 1 heterodimers accumulate in focal contacts in fibroblasts. Thus, the alpha subunit contributes, independent of its ligand, to functional integrin heterodimer accumulation in focal contacts or in point contacts. This accumulation varies among different cell types with apparently identical heterodimers as well as with the motile state (spreading vs. flattened) of the same cells.

Actins↗
PubMed1993

Spreading of human endothelial cells on fibronectin or vitronectin triggers elevation of intracellular free calcium.

Intracellular calcium ([Ca2+]i) was measured in FURA 2-loaded endothelial cells plated on fibronectin or vitronectin. Average values for [Ca2+]i increased to approximately twofold above basal levels by approximately 1 h after plating, and then declined. The increase in [Ca2+]i required extracellular calcium. Substituting potassium for sodium in the medium reduced the elevation of [Ca2+]i, a result that rules out the involvement of Na-Ca exchangers or voltage-dependent calcium channels, but that is consistent with the involvement of voltage-independent calcium channels. Plating cells on an anti-integrin beta 1 subunit antibody gave a similar [Ca2+]i response, but clustering beta 1 integrins with the same antibody, or occupying integrins with RGD (arg-gly-asp) peptides had no effect. Time course measurements on single cells revealed that in each cell [Ca2+]i rose abruptly at some point during spreading, from the basal level to a higher steady-state level that was maintained for some time. The elevated [Ca2+]i was unrelated to previously observed changes in intracellular pH, because chelating the Ca2+ in the medium failed to inhibit the elevation of pHi that occurred during cell spreading. In conclusion, these results show that integrin-mediated cell spreading can regulate [Ca2+]i, and the pathways involved are distinct from those that regulate intracellular pH.

Calcium↗
PubMed1995

Nuclear spreads: I. Visualization of bipartite ribosomal RNA domains.

Visualization of nuclear architecture is key to the understanding of the association between RNA synthesis and processing. This architecture is obscured by the high density of components in most nuclei. We have developed a method of spreading nuclei and nucleoli that reduces overlap of weakly associated components. Strong interactions among nuclear components are not disrupted by this method. Spread nucleoli remained structurally distinct and functionally competent in ribosomal RNA synthesis. Nascent ribosomal RNA colocalized with RNA polymerase I and fibrillarin, a protein required for processing of ribosomal RNA. Colocalization of nascent transcripts and fibrillarin was seen in nucleoli spread over several microns, suggesting a strong interaction. These data suggest that nucleoli are superassemblies of bipartite domains, each composed of a ribosomal RNA synthesis center tightly associated with areas likely to be involved in ribosomal RNA processing.

Animals↗
PubMed1999

Listeria monocytogenes exploits normal host cell processes to spread from cell to cell.

The bacterial pathogen, Listeria monocytogenes, grows in the cytoplasm of host cells and spreads intercellularly using a form of actin-based motility mediated by the bacterial protein ActA. Tightly adherent monolayers of MDCK cells that constitutively express GFP-actin were infected with L. monocytogenes, and intercellular spread of bacteria was observed by video microscopy. The probability of formation of membrane-bound protrusions containing bacteria decreased with host cell monolayer age and the establishment of extensive cell-cell contacts. After their extension into a recipient cell, intercellular membrane-bound protrusions underwent a period of bacterium-dependent fitful movement, followed by their collapse into a vacuole and rapid vacuolar lysis. Actin filaments in protrusions exhibited decreased turnover rates compared with bacterially associated cytoplasmic actin comet tails. Recovery of motility in the recipient cell required 1-2 bacterial generations. This delay may be explained by acid-dependent cleavage of ActA by the bacterial metalloprotease, Mpl. Importantly, we have observed that low levels of endocytosis of neighboring MDCK cell surface fragments occurs in the absence of bacteria, implying that intercellular spread of bacteria may exploit an endogenous process of paracytophagy.

Actin Cytoskeleton↗
PubMed2003

Integrin-linked kinase is required for laminin-2-induced oligodendrocyte cell spreading and CNS myelination.

Early steps in myelination in the central nervous system (CNS) include a specialized and extreme form of cell spreading in which oligodendrocytes extend large lamellae that spiral around axons to form myelin. Recent studies have demonstrated that laminin-2 (LN-2; alpha2beta1gamma1) stimulates oligodendrocytes to extend elaborate membrane sheets in vitro (cell spreading), mediated by integrin alpha6beta1. Although a congenital LN-2 deficiency in humans is associated with CNS white matter changes, LN-2-deficient (dy/dy) mice have shown abnormalities primarily within the peripheral nervous system. Here, we demonstrate a critical role for LN-2 in CNS myelination by showing that dy/dy mice have quantitative and morphologic defects in CNS myelin. We have defined the molecular pathway through which LN-2 signals oligodendrocyte cell spreading by demonstrating requirements for phosphoinositide 3-kinase activity and integrin-linked kinase (ILK). Interaction of oligodendrocytes with LN-2 stimulates ILK activity. A dominant negative ILK inhibits LN-2-induced myelinlike membrane formation. A critical component of the myelination signaling cascade includes LN-2 and integrin signals through ILK.

Adenoviridae↗