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At least 415 records · Page 23Linked to original sources
PubMed2005

Integrin-mediated dendrite branch maintenance requires Abelson (Abl) family kinases.

Dendrite arbor structure is a critical determinant of nervous system function that must be actively maintained throughout life, but the signaling pathways that regulate dendrite maintenance are essentially unknown. We report that the Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases are required for maintenance of cortical dendrites in the mouse brain. arg-/- cortical dendrites initially develop normally and are indistinguishable from wild-type dendrites at postnatal day 21. Dendrite branches are not efficiently maintained in arg-/- neurons, leading to a reduction in dendrite arbor size by early adulthood. More severe dendrite loss is observed in abl-/-arg-/- neurons. Elevation of Arg kinase activity in primary cortical neurons promotes axon and dendrite branching. Activation of integrin receptors by adhesion to laminin-1 or Semaphorin 7A also promotes neurite branching in cortical neurons, but this response is absent in arg-/- neurons because of the reduced dynamic behavior of mutant neurite branches. These data suggest that integrin signaling through Abl and Arg support cortical dendrite branch maintenance by promoting dendrite branch dynamics in response to adhesive cues.

Actins↗
PubMed1997

New method for monitoring the functional state of a dynamic cardiomyoplasty.

OBJECTIVE: To assess the impact of a dynamic cardiomyoplasty on failing hearts, it is essential to estimate the contraction force of the skeletal muscle and how its contraction is synchronized with the heart cycle. METHODS: In a 6-month study a small fluid-filled, balloon-mounted catheter was placed between the myocardium and the muscular wrap in five adult female Boor goats and two female domestic pigs. The catheter was connected to a subcutaneous measuring chamber whereby pressure monitoring could be accomplished. Distinct pressure signals as a result of function of the dynamic cardiomyoplasty and the heart were detected initially in all animals. RESULTS: Maximal relative pressure from the dynamic cardiomyoplasty was calculated as 336.2% +/- 69.4% on day 24 +/- 6.1 (n = 7) and end-stage pressure as 59.8% +/- 9.7% on day 174.6 +/- 13.1 (n = 4). A functional loss of pressure signals from the dynamic cardiomyoplasty was correlated to severe histologic muscle damage (n = 3). Pressure signals transferred from the contracting myocardium to the catheter showed defined segments of contraction, ejection, and filling periods, allowing a mechanical synchronization of the dynamic cardiomyoplasty to the heart cycle. CONCLUSIONS: This monitoring catheter enabled the assessment of the functional state of the dynamic cardiomyoplasty and allowed a synchronization to the heart cycle. It will promote understanding and might help to avoid muscle damage in dynamic cardiomyoplasty for an improved outcome of the surgical treatment of end-stage heart failure.

Animals↗
PubMed2003

Dynamics of the metal-dependent transcription factor complex in vivo at the mouse metallothionein-I promoter.

The in vivo association of transcription factors with the metallothionein-I promoter was examined using chromatin immunoprecipitation (ChIP) assays. The results demonstrated that c-fos is rapidly recruited along with the metal response element-binding transcription factor-1 (MTF-1) to this promoter in response to zinc or cadmium, and that this recruitment is reversed in the visceral yolk sac by a zinc-deficient diet in vivo, and in cultured cells after lowering the zinc concentration in the medium or during prolonged zinc exposure. In contrast, the interactions of c-jun, USF-1, USF-2 and Sp1 with this promoter are metal-independent. Studies of knockout cells revealed that the recruitment of c-fos to the MT-I promoter requires MTF-1, but that c-fos is not essential for recruitment of MTF-1 and metal-induction of MT-I gene expression. Studies of Hepa cells stably-transfected with reporter genes driven by the MT-I promoter suggested two in vivo binding sites for USF-1 and -2. In contrast, Sp1 was apparently associated with a single binding site (upstream of -153 bp). In addition, maximal recruitment of c-fos by metals required sequences and/or other proteins that interact upstream of -153 bp. In summary, these studies extend our understanding of the complexity and dynamics of the transcription factor complex that forms at the MT-I promoter in vivo in response to metals.

Animals↗
PubMed2002

Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle.

EB1 is an evolutionarily conserved protein that localizes to the plus ends of growing microtubules. In yeast, the EB1 homologue (BIM1) has been shown to modulate microtubule dynamics and link microtubules to the cortex, but the functions of metazoan EB1 proteins remain unknown. Using a novel preparation of the Drosophila S2 cell line that promotes cell attachment and spreading, we visualized dynamics of single microtubules in real time and found that depletion of EB1 by RNA-mediated inhibition (RNAi) in interphase cells causes a dramatic increase in nondynamic microtubules (neither growing nor shrinking), but does not alter overall microtubule organization. In contrast, several defects in microtubule organization are observed in RNAi-treated mitotic cells, including a drastic reduction in astral microtubules, malformed mitotic spindles, defocused spindle poles, and mispositioning of spindles away from the cell center. Similar phenotypes were observed in mitotic spindles of Drosophila embryos that were microinjected with anti-EB1 antibodies. In addition, live cell imaging of mitosis in Drosophila embryos reveals defective spindle elongation and chromosomal segregation during anaphase after antibody injection. Our results reveal crucial roles for EB1 in mitosis, which we postulate involves its ability to promote the growth and interactions of microtubules within the central spindle and at the cell cortex.

Anaphase↗
PubMed1998

Neutrophil elastase promotes rapid exocytosis in human airway gland cells by producing cytosolic Ca2+ oscillations.

The molecular and ionic mechanisms responsible for the regulation of mucus exocytosis in human airway gland cells remain poorly defined. To determine whether dynamic changes of intracellular free Ca2+ concentration [Ca2+]i can promote different exocytotic responses, we monitored dynamic changes in [Ca2+]i and secretory granule (SG) exocytosis in individual human tracheal submucosal serous gland (HTG) cells. These changes were in response to exposure of the cells to three different secretagogues associated with airway inflammation and disease: human neutrophil elastase (HNE), histamine, and ATP. Dynamic changes in [Ca2+]i from single cells were determined with Indo-1/AM using quantitative UV laser microspectrofluorometry. The rate of SG exocytosis was measured in single cells by fluorescence videomicroscopy of SG degranulation and by the ELISA method. Exposure of HTG cells to a low concentration of HNE (1.0 microM) caused a high rate of SG exocytosis (52% decrease in the initial quinacrine fluorescence) during the first 8-min stimulation period compared with that observed following exposure of the cells to 100 microM histamine (10% decrease) or 100 microM ATP (6% decrease). In contrast to a rapid and transient rise in [Ca2+]i induced by histamine (1.0-100 microM) and ATP (10-100 microM), HNE (0.01-1 microM) generated asynchronous oscillations in [Ca2+]i over the first 8-min period. Depletion of internal Ca2+ stores with thapsigargin (500 nM) induced a significant reduction (P < 0.01) in the observed increases in [Ca2+]i upon addition of each of the secretagogues, but did not greatly affect the SG exocytotic responses. Interestingly, the removal of extracellular Ca2+ (+5 mM EGTA) significantly reduced (P < 0.01) both the [Ca2+]i increases and the rate of SG exocytosis following exposure to the secretagogues. We also demonstrate that the influx of extracellular Ca2+ and [Ca2+]i oscillations rather than the absolute level of [Ca2+]i regulate the rapid onset and extent of exocytotic responses to HNE in airway gland cells. Taken together, these results provide strong evidence that [Ca2+]i is a critical intracellular messenger in the regulation of exocytosis process in human airway gland cells.

Adenosine Triphosphatases↗
PubMed2006

The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression.

FarUpStream Element (FUSE) Binding Protein (FBP) binds the human c-myc FUSE in vitro only in single-stranded or supercoiled DNA. Because transcriptionally generated torsion melts FUSE in vitro even in linear DNA, and FBP/FBP Interacting Repressor (FIR) regulates transcription through TFIIH, these components have been speculated to be the mechanosensor (FUSE) and effectors (FBP/FIR) of a real-time mechanism controlling c-myc transcription. To ascertain whether the FUSE/FBP/FIR system operates according to this hypothesis in vivo, the flux of activators, repressors and chromatin remodeling complexes on the c-myc promoter was monitored throughout the serum-induced pulse of transcription. After transcription was switched on by conventional factors and chromatin regulators, FBP and FIR were recruited and established a dynamically remodeled loop with TFIIH at the P2 promoter. In XPB cells carrying mutant TFIIH, loop formation failed and the serum response was abnormal; RNAi depletion of FIR similarly disabled c-myc regulation. Engineering FUSE into episomal vectors predictably re-programmed metallothionein-promoter-driven reporter expression. The in vitro recruitment of FBP and FIR to dynamically stressed c-myc DNA paralleled the in vivo process.

Cell Line↗
PubMed2026

Structural Features of DNA in TATA-Containing and TATA-Less Core Promoters of RNA Polymerase II Differ.

Nucleotide motifs in the core promoters of eukaryotic protein-coding genes transcribed by RNA polymerase II (Pol II) play an important role in the transcription process. We analyzed the role of an octanucleotide located in the TATA box position. Depending on whether this octanucleotide can form a complex with the TATA-binding protein (TBP), the promoter is classified as either TATA-containing or TATA-less. We analyzed the differences in the primary and spatial structures, as well as their dynamics, in TATA-containing and TATA-less promoters of mammals and plants. We divided the complete promoter sets of six organisms (H. sapiens, M. musculus, C. familiaris, A. thaliana, Z. mays, and H. vulgare) from the EPDnew database into TATA-containing and TATA-less fractions. The sizes of the TATA-containing promoter fractions are significantly smaller than those of the TATA-less fractions in all studied organisms, except in A. thaliana, where the sizes of both fractions are approximately equal. We characterized promoter architecture using variation profiles of various base-pair step parameters, minor-groove width, and the conformational dynamics of native DNA. The architectures of TATA-containing and TATA-less promoters differ significantly. The possible mechanistic influence of DNA structural features on the formation of the pre-initiation complex (PIC) in both types of promoters is discussed.

Promoter Regions, Genetic↗
PubMed2026

Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.

Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.

CCCTC-Binding Factor↗
PubMed2005

Altered microtubule dynamics by expression of modified alpha-tubulin protein causes right-handed helical growth in transgenic Arabidopsis plants.

The proper organization of cortical microtubule arrays is essential for anisotropic growth in plants but how distinct array patterns are formed is not understood. Here, we report a relationship between microtubule dynamics and array organization using transgenic plants expressing modified tubulins. When green fluorescent protein (GFP) or a hemaglutinin epitope tag was fused to the N-terminus of tubulins and expressed in Arabidopsis plants, these tubulins were incorporated into microtubules along with endogenous tubulins. Plants expressing the modified beta-tubulins were phenotypically normal and possessed transversely oriented cortical arrays in the epidermal cells of the root elongation zone; however, the expression of modified alpha-tubulins caused right-handed helical growth, increased trichome branching, and a shallow left-handed (S-form) helical array organization. In cells expressing the modified alpha-tubulins, microtubule dynamicity was suppressed and polymerization was promoted, and GFP-EB1 (End Binding 1) labeled larger regions of the microtubule end more frequently, when compared with control cells. We propose that the N-terminal appendage introduced into alpha-tubulin inhibits GTP hydrolysis, thus producing polymerization-prone microtubules with an extended GTP cap. Consistent with this interpretation, plants expressing an alpha-tubulin mutated in the GTPase-activating domain exhibited similar microtubule properties, with regard to dynamics and the localization of GFP-EB1, and showed right-handed helical growth.

Arabidopsis↗
PubMed1996

Orgasm without organisms: science or propaganda?

The worldwide epidemic of sexually transmitted diseases (STDs) presents a major public health challenge to medical practitioners and educators as they seek to implement preventive educational strategies in the adolescent population. The serious consequences of many STDs and the insufficient impact of condom promotion in this high-risk group have led to increasing recognition that sexual intercourse is medically unwise for young adolescents. As a result of this recognition, some educators have proposed that adolescent sexuality education focus on the explicit teaching of noncoital sexual activities, sometimes called outercourse. This paper explores the emergence of this educational strategy, the assertion that noncoital sexual activities will positively impact the rising incidence of STDs and unplanned pregnancy in teenagers, and the hypothetical benefits of adolescent noncoital sex.

Adolescent↗
PubMed2006

Dynamic recruitment of transcription factors and epigenetic changes on the ER stress response gene promoters.

Response to stresses that alter the function of the endoplasmic reticulum is an important cellular function, which relies on the activation of specific genes. Several transcription factors (TFs) are known to affect this pathway. Using RT-PCR and ChIP assays, we studied the recruitment of promoter-specific TFs, general TFs and epigenetic marks in activated promoters. H3-K4 di- and tri-methylation and H3-K79 di-methylation are present before induction. H3 acetylation is generally high before induction, and H4 acetylation shows a promoter-specific increase. Interestingly, there is a depletion of histone H3 under maximal induction, explaining an apparent decrease of H3-K4 tri-methylation and H3-K79 di-methylation. Pol II is found enriched on some promoters under basal conditions, unlike TBP and p300, which are recruited selectively. Most genes are bound by XBP-1 after induction, some before induction, presumably by the inactive isoform. ATF6 and CHOP associate to largely different set of genes. C/EBPbeta is selective and binding to the CHOP promoter precedes that of XBP-1, ATF6 and CHOP. Finally, one of the ER-stress inducible genes analyzed, HRD1, is not bound by any of these factors. Among the constitutive TFs, NF-Y, but not Sp1, is found on all genes before induction. Intriguingly, siRNA interference of the NF-YB subunit indicates transcriptional impairment of some, but not all genes. These data highlight a previously unappreciated complexity of TFs binding and epigenetic changes, pointing to different TFs-specific pathways within this broad response.

Acetylation↗
PubMed1997

Retinoid-induced chromatin structure alterations in the retinoic acid receptor beta2 promoter.

Transcription of the retinoic acid receptor beta2 (RARbeta2) gene is induced by retinoic acid (RA) in mouse P19 embryonal carcinoma (EC) cells. Here we studied RA-induced chromatin structure alterations in the endogenous RARbeta2 promoter and in an integrated, multicopy RARbeta2 promoter in EC cells. RA markedly increased restriction site accessibility within the promoter, including a site near the RA responsive element (RARE) to which the nuclear receptor retinoid X receptor (RXR)-RAR heterodimer binds. These changes coincided with RA-induced alterations in the DNase I hypersensitivity pattern in and around the promoter. These changes became undetectable upon removal of RA, which coincided with the extinction of transcription. Analyses with receptor-selective ligands and an antagonist showed that increase in restriction site accessibility correlates with transcriptional activation, which parallels the RA-induced in vivo footprint of the promoter. Despite these changes, the micrococcal nuclease digestion profile of this promoter was not altered by RA. These results indicate that concurrent with the binding of the RXR-RAR heterodimer to the RARE, the local chromatin structure undergoes dynamic, reversible changes in and around the promoter without globally affecting the nucleosomal organization.

Animals↗
PubMedDate not supplied

Health promotion technology transfer: organizational perspectives.

This paper explores the relationship between organizational dynamics and program dissemination. Specifically, it is an analysis of factors affecting the directed diffusion of health promotion innovations which target schools and worksites as delivery channels. Technology transfer is the construct which is used to capture this notion of directed diffusion. The term is defined for the purposes of the paper as all strategically planned efforts to promote, influence, or accelerate the natural diffusion or dissemination processes. The paper has three main objectives: first to identify the theoretical perspectives which have influenced my thinking in the area of health promotion technology transfer; second, to describe an organizing framework for the study of health promotion technology transfer; and third, to recommend directions for health promotion planning efforts in the future and the role that research might play in that process.

Child↗
PubMedDate not supplied

Determinants of breastfeeding in developing countries: overview and policy implications.

Breastfeeding can play a major role in fertility regulation in developing countries. The effect of breastfeeding is enhanced when the incidence of breastfeeding is high and the duration extended. These factors are more likely to occur when suckling at the breast is frequent. Sociological and behavioral factors can also influence a woman's decision to initiate and terminate breastfeeding. The effects of urbanization, maternal education, and socioeconomic status act through the intervening variables of sociocultural factors, health services, employment status of women, and availability of breastmilk substitutes. Strategies to alter these intervening variables include educational campaigns and support groups for lactating women, changes in health services, availability of child care facilities near employment centers, and enforcement of the international code of marketing of breastmilk substitutes.

Breast Feeding↗
PubMed2006

Proteolytic turnover of the Gal4 transcription factor is not required for function in vivo.

Transactivator-promoter complexes are essential intermediates in the activation of eukaryotic gene expression. Recent studies of these complexes have shown that some are quite dynamic in living cells owing to rapid and reversible disruption of activator-promoter complexes by molecular chaperones, or a slower, ubiquitin-proteasome-pathway-mediated turnover of DNA-bound activator. These mechanisms may act to ensure continued responsiveness of activators to signalling cascades by limiting the lifetime of the active protein-DNA complex. Furthermore, the potency of some activators is compromised by proteasome inhibition, leading to the suggestion that periodic clearance of activators from a promoter is essential for high-level expression. Here we describe a variant of the chromatin immunoprecipitation assay that has allowed direct observation of the kinetic stability of native Gal4-promoter complexes in yeast. Under non-inducing conditions, the complex is dynamic, but on induction the Gal4-promoter complexes 'lock in' and exhibit long half-lives. Inhibition of proteasome-mediated proteolysis had little or no effect on Gal4-mediated gene expression. These studies, combined with earlier data, show that the lifetimes of different transactivator-promoter complexes in vivo can vary widely and that proteasome-mediated turnover is not a general requirement for transactivator function.

Chromatin Immunoprecipitation↗
PubMed2007

Cdc42 and ARP2/3-independent regulation of filopodia by an integral membrane lipid-phosphatase-related protein.

Filopodia are dynamic cell surface protrusions that are required for proper cellular development and function. We report that the integral membrane protein lipid-phosphatase-related protein 1 (LPR1) localizes to and promotes the formation of actin-rich, dynamic filopodia, both along the cell periphery and the dorsal cell surface. Regulation of filopodia by LPR1 was not mediated by cdc42 or Rif, and is independent of the Arp2/3 complex. We found that LPR1 can induce filopodia formation in the absence of the Ena/Vasp family of proteins, suggesting that these molecules are not essential for the development of the protrusions. Mutagenesis experiments identified residues and regions of LPR1 that are important for the induction of filopodia. RNA interference experiments in an ovarian epithelial cancer cell line demonstrated a role for LPR1 in the maintenance of filopodia-like membrane protrusions. These observations, and our finding that LPR1 is a not an active lipid phosphatase, suggest that LPR1 may be a novel integral membrane protein link between the actin core and the surrounding lipid layer of a nascent filopodium.

Actin-Related Protein 2↗