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PubMed1985

Comparison of the effects of argon fluoride (ArF) and krypton fluoride (KrF) excimer lasers on ocular structures.

We evaluated the effects of argon fluoride (ArF) and krypton fluoride (KrF) excimer lasers on ocular structures. We produced corneal incisions, optical iridotomy, capsulotomy, and retinotomy with these lasers. Incisions produced with ArF showed sharply defined borders with minimal coagulative effects to the adjacent structures. Cuts created with KrF showed coagulative necrosis of the wound edges ranging from two to five um in width. From our study it appears that ArF has photoablative action and KrF has a predominantly photoablative action with minimal photocoagulative effect on the tissue.

Animals↗
PubMed1983

Venous admixture (Qva/Q) and true shunt (Qs/Qt) in ARF patients: effects of PEEP at constant FIO2.

Venous admixture (Qva/Q) in ARF patients is due to both true right to left shunt (Qs/Qt: perfusion of truly unventilated areas) and to maldistribution [Qva-Qs)/Qt: effects of unevenness of ventilation/perfusion ratio). Using the retention rate of sulphur hexafluoride we determined the effects of PEEP on Qs/Qt and (Qva-Qs)/Qt at a constant FIO2 for each patient (0.57 +/- 0.19 SD, range 0.4-0.95). Eleven patients with ARF (treated either by CPPV or CPAP) were studied on 16 occasions. Each measurement was repeated at two levels of PEEP, 5 cm H2O below and 5 cm H2O above the patient's clinically determined PEEP level. The increase in PEEP resulted in: - a decrease in Qva/Q (from 0.37 +/- 0.13 to 0.27 +/- 0.12, p less than 0.01); - a parallel decrease in Qs/Qt (from 0.29 +/- 0.16 to 0.22 +/- 0.14, p less than 0.01); there was a positive correlation between Qva/Q and Qs/Qt changes (r = 0.53, p less than 0.05). No significant variation was demonstrated in (Qva-Qs)/Qt (from 0.074 +/- 0.045 to 0.054 +/- 0.048). On the other hand there was a negative correlation between the fraction of Qva/Q due to the maldistribution and FIO2: (Qva-Qs)/Qva = 0.75-0.86 FIO2 (r = 0.74, p less than 0.01). We conclude that: PEEP decreased Qva/Q mainly through changes in Qs/Qt but did not have a definite effect on (Qva-Qs)/Qt. Maldistribution was responsible for a significant portion of Qva/Q in those ARF patients tolerating a relatively low FIO2 (0.4-0.6).

Acute Disease↗
PubMed1996

Right ventricular myocardial function in ARF patients. PEEP as a challenge for the right heart.

OBJECTIVE: To examine the hemodynamic effects of external positive end-expiratory pressure (PEEP) on right ventricular (RV) function in acute respiratory failure (ARF) patients. DESIGN: Prospective, with retrospective analysis on the basis of RV volume response to PEEP. SETTING: General intensive care unit in a university teaching hospital. PATIENTS: 20 mechanically ventilated ARF patients (mean lung injury score = 2.6 +/- 0.45 SD). INTERVENTION: Incremental levels of PEEP (0-5-10-15 cmH2O) were applied and RV hemodynamics were studied by means of a Swan-Ganz catheter with a fast-response thermistor for right ventricular ejection fraction (RVEF) measurement. According to their response to PEEP 15, two groups of patients were defined: group A (9 patients) with unchanged or increased RV end-diastolic volume index (RVEDVI) and group B (11 patients) with decreased RVEDVI. MEASUREMENTS AND RESULTS: At zero PEEP (ZEEP) the hemodynamic parameters of the two groups did not differ. In group A, cardiac index (CI) and stroke volume index (SI) decreased at all PEEP levels (5, 10, and 15 cmH2O), while RVEF started to decrease only at a PEEP of 10 cmH2O (-10.8%), and RVES(systolic)VI increased only at PEEP 15 cmH2O (+21.5%). RVEDVI was not affected by PEEP. In group B, CI and SI decreased at all PEEP levels (5, 10, and 15 cmH2O). Similarly, RVEDVI started to decrease at PEEP 5 cmH2O, while RVESVI decreased only at PEEP 15 cmH2O (-21.4%). RVEF was not affected by PEEP in this group. In each patient the slope of the relationship between RVEDVI and right ventricular stroke work index (RVSWI), expressing RV myocardial performance, was studied. This relationship was significant (no change in RV contractility) in 8 of 11 patients in group B and in only 2 patients in group A. In 4 patients in group A, PEEP shifted the RVSWI/RVEDVI ratio rightward in the plot, indicating a decrease in RV myocardial performance in these patients. CONCLUSIONS: PEEP affects RV function in ARF patients. The decrease in cardiac output is more often associated with a preload decrease and no change in RV contractility. On the other hand, the finding of increased RV volumes with PEEP may be associated with a reduction in RV myocardial performance. Thus, these results suggest that assessment of RV function by PEEP and preload recruitable stroke work may disclose otherwise unpredictable alterations in RV function.

Adult↗
PubMed2005

[Acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSRA)--an update].

Betahemolytic strains of streptococcus A are able to induce a spectrum of immunologically induced diseases, depending on the immunogenic M structure of the bacteria as well as on the genetic determined reaction of the host. In acute rheumatic fever (ARF) the Jones criteria, revised and modified several times and updated in 1992, remain the diagnostic standard. Echocardiography, still not included in the Jones criteria, has become a very important diagnostic tool, especially as half of the ARF induced carditis cases are clinically inapparent. Diagnosis may be very difficult if arthritis is the only major sign, especially if not occurring in the typical migrating pattern, a fact frequently reported from countries with a high risk of ARF. Poststreptococcal reactive arthritis (PSRA) has been described as a different entity as well as a part of rheumatic fever. There is a lack of validated diagnostic criteria to establish a reliable diagnosis. There are no accepted recommendations for antibiotic prophylaxis in PSRA.

Anti-Bacterial Agents↗
PubMed2004

INK4a-ARF alterations in Barrett's epithelium, intraepithelial neoplasia and Barrett's adenocarcinoma.

INTRODUCTION: The INK4a-ARF [CDKN2A]- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16INK4a and p14ARF, which act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway to the carcinogenesis of Barrett's adenocarcinoma, we analysed the alterations of p14ARF and p16INK4a in preneoplastic and neoplastic lesions of this disease. MATERIALS AND METHODS: After microdissection, DNA of 15 Barrett's adenocarcinomas, 40 Barrett's intraepithelial neoplasms (n=20 low- and n=20 high-grade) and 15 Barrett's mucosa without neoplasia was analysed for INK4-ARF inactivation using DNA sequence and loss of heterozygosity (LOH) analysis, methylation-specific polymerase chain reaction, restriction-enzyme-related polymerase chain reaction and immunohistochemistry. RESULTS: We detected 9p21 LOH, p16INK4a methylation and p16INK4a mutations in Barrett's adenocarcinomas in 5 of 15 (33%), 8 of 15 (53%) and 1 of 15 (7%) patients, respectively. P14ARF was methylated in 3 of 15 (20%) adenocarcinomas. In Barrett's intraepithelial neoplasia, p16INK4a was altered in 12 of 20 (60%) high-grade and in 4 of 20 (20%) low-grade intraepithelial neoplasms. In Barrett's mucosa without intraepithelial neoplasia p16(INK4a) was methylated in one case (7%). P14ARF was intact in Barrett's mucosa without intraepithelial neoplasia. CONCLUSIONS: We conclude that most Barrett's intraepithelial neoplasms contain genetic and/or epigenetic INK4a-ARF alterations. Methylation of p16INK4a appears to be the most frequent epigenetic defect in the neoplastic progression of Barrett's tumourigenesis.

Barrett Esophagus↗
PubMed1993

A synthetic peptide of the N-terminus of ADP-ribosylation factor (ARF) inhibits regulated exocytosis in adrenal chromaffin cells.

We have investigated the role of ADP-ribosylation factor (ARF) in regulated exocytosis in digitonin-permeabilized adrenal chromaffin cells by the use of a synthetic peptide, hARF1(2-17), based on the N-terminus of the protein. hARF1(2-17) inhibited Ca(2+)-dependent but not basal exocytosis, whereas equimolar levels of other synthetic peptides were ineffective. The inhibitory effect of hARF1(2-17) was dose-dependent and half-maximal at 12 microM. GTP gamma S-induced secretion in the presence of non-stimulatory CA2+ concentrations was also inhibited by hARF1(2-17). These results point to a hitherto unsuspected role for ARF in regulated exocytosis, and the potency of the hARF1(2-17) peptide suggests that ARF is essential for exocytosis in bovine adrenal chromaffin cells.

ADP-Ribosylation Factors↗
PubMed1993

Effect of ArF-193 nm excimer laser on human dentinal tubules. A scanning electron microscopic study.

The purpose of this study was to evaluate the effects of the ArF-193 nm excimer laser on the dentinal tubules of extracted human teeth under a scanning electron microscope. Fifteen 3 mm thick slices were cut with an electric saw at the cementoenamel junction from 15 extracted human teeth. A diamond bur was used to remove the cementum layer and expose the dentinal tubules. Each slice was scored by a permanent marker into four equal quadrants. The ArF excimer laser was applied for 5 seconds on three of the quadrants with fluences that ranged from 0.2 J/cm2 to 15 J/cm2 and pulse repetition of 25 Hz. The untouched quadrant served as a control. The specimens were mounted on stubs, sputter coated by gold, and examined by a scanning electron microscope. The effects of the ArF excimer laser irradiation varied. Laser fluences of 0.2, 0.5, and 1.0 J/cm2 had no effect. Although fluence of 15 J/cm2 caused significant removal of peritubular dentin, melting and resolidification of the dentinal smear layer was also observed under the scanning electron microscope with a laser fluence of 5 J/cm2.

Argon↗
PubMed1996

Cloning of a novel member (ARL5) of the ARF-family of Ras-related GTPases.

A novel ras-related GTPase with a unique structure was cloned by PCR-amplification with degenerate primers and screening of a rat fat cell cDNA library. The deduced amino acid sequence of the cDNA comprises all 6 GTP binding motifs which are conserved in Ras-related GTPases. The sequence is similar to that of ADP-ribosylation factors (ARF), and shows several structural features typical for the ARF-family. Because its closest relative is the GTPase ARL1 (49% identical amino acids, 54% identical nucleotides within the coding region), the protein was designated ARL5 (ARF-like protein 5). Low amounts of mRNA were found in most rat tissues examined (heart, skeletal muscle, fat, liver, kidney, lung, spleen, intestine, testis, and thymus) with highest levels in brain, intestine, and thymus.

3T3 Cells↗
PubMed2005

The plasticity of p19 ARF null hepatic stellate cells and the dynamics of activation.

In the healthy adult liver, quiescent hepatic stellate cells (HSCs) present the major site for vitamin A storage in cytoplasmic lipid droplets. During liver injury due to viral infection or alcohol intoxication, HSCs get activated and produce high amounts of extracellular matrix components for tissue repair and fibrogenesis. Employing p19 ARF deficiency, we established a non-transformed murine HSC model to investigate their plasticity and the dynamics of HSC activation. Primary HSCs isolated from livers of adult p19 ARF null mice underwent spontaneous activation through long-term passaging without an obvious replicative limit. The immortalized cell line, referred to as M1-4HSC, showed stellate cell characteristics including the expression of desmin, glial fibrillary acidic protein, alpha-smooth muscle actin and pro-collagen I. Treatment of these non-tumorigenic M1-4HSC with pro-fibrogenic TGF-beta1 provoked a morphological transition to a myofibroblastoid cell type which was accompanied by enhanced cellular turnover and impaired migration. In addition, M1-4HSCs expressed constituents of cell adhesion complexes such as p120(ctn) and beta-catenin at cell borders, which dislocalized in the cytoplasm during stimulation to myofibroblasts, pointing to the epitheloid characteristics of HSCs. By virtue of its non-transformed phenotype and unlimited availability of cells, the p19(ARF) deficient model of activated HSCs and corresponding myofibroblasts render this system a highly valuable tool for studying the cellular and molecular basis of hepatic fibrogenesis.

Actins↗
PubMed2005

ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress.

Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, beta-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated in p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53.

Animals↗
PubMed2006

Bcl-xL gain of function and p19 ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms.

Overexpression of Bcl-xL, loss of p19 ARF, and loss of p53 all accelerate Myc oncogenesis. All three lesions are implicated in suppressing Myc-induced apoptosis, suggesting that this is a common mechanism by which they synergize with Myc. However, using an acutely switchable model of Myc-induced tumorigenesis, we demonstrate that each lesion cooperates with Myc in vivo by a distinct mechanism. While Bcl-xL blocks Myc-induced apoptosis, inactivation of p19 ARF enhances it. However, this increase in apoptosis is matched by increased Myc-induced proliferation. p53 inactivation shares features of both lesions, partially suppressing apoptosis while augmenting proliferation. Bcl-xL and p19 ARF loss together synergize to further accelerate Myc oncogenesis. Thus, differing lesions cooperate oncogenically with Myc by discrete mechanisms that can themselves synergize with each other.

Animals↗
PubMed2005

Mutational analysis of the Arf1*GTP/Arf GAP interface reveals an Arf1 mutant that selectively affects the Arf GAP ASAP1.

Arf1 is a GTP binding protein that functions at a number of cellular sites to control membrane traffic and actin remodeling. Arf1 is regulated by site-specific GTPase-activating proteins (GAPs). The combined results of crystallographic and biochemical studies have led to the proposal that Arf1 GAPs differ in the specific interface formed with Arf1. To test this hypothesis, we have used mutagenesis to examine the interaction of three Arf GAPs (ASAP1, AGAP1, and ArfGAP1) with switch 1, switch 2, and alpha helix3 of Arf1. The GAPs were similar in being affected by mutations in switch 1 and 2. However, effects of a mutation within alpha helix3 and specific mutations within switch 1 and 2 differed among the GAPs. The largest differences were observed with a change of isoleucine 46 to aspartate ([I46D]Arf1), which reduced ASAP1-induced catalysis by approximately 10,000-fold but had a 3-fold effect on AGAP1. The reduction was due to an isolated effect on the catalytic rate, k(cat). In vivo [I46D]Arf1 had no detectable effect on the Golgi apparatus but, instead, functioned as a constitutively active mutant in the cell periphery, affecting the localization of ASAP1 and paxillin. Based on our results, we conclude that the contribution of specific residues within switch 1 of Arf to binding and achieving a transition state toward GTP hydrolysis differs among Arf GAPs.

ADP-Ribosylation Factor 1↗
PubMed2006

Expression of the cell cycle regulators p14(ARF) and p16(INK4a) in chronic myeloid leukemia.

Expression of p14(ARF) and p16(INK4a) tumor suppressor genes was investigated in 109 patients with chronic myeloid leukemia (CML). The p14(ARF) and p16(INK4a) mRNA levels were significantly low in patients in chronic phase (CP) at presentation and high in patients treated with interferon-alpha (IFN-alpha), especially in non-responders. A moderate overexpression of p14(ARF) with a normal expression of p16(INK4a) was observed in imatinib-resistant patients. Although protein expression did not consistently match mRNA levels, a role for the two cell cycle regulators in the IFN-alpha signaling pathway is suggested as well as a relation with the resistance to IFN-alpha or imatinib therapy.

Cell Cycle↗
PubMed2005

Membrane recruitment of effector proteins by Arf and Rab GTPases.

In their GTP-bound form, Arf and Rab family GTPases associate with distinct organelle membranes, to which they recruit specific sets of effector proteins that regulate vesicular transport. The Arf GTPases are involved in the formation of coated carrier vesicles by recruiting coat proteins. On the other hand, the Rab GTPases are involved in the tethering, docking and fusion of transport vesicles with target organelles, acting in concert with the tethering and fusion machineries. Recent structural studies of the Arf1-GGA and Rab5-Rabaptin-5 complexes, as well as other effector structures in complex with the Arf and Rab GTPases, have shed light on the mechanisms underlying the GTP-dependent membrane recruitment of these effector proteins.

ADP-Ribosylation Factor 1↗
PubMed2002

Dominant-negative mutant of BIG2, an ARF-guanine nucleotide exchange factor, specifically affects membrane trafficking from the trans-Golgi network through inhibiting membrane association of AP-1 and GGA coat proteins.

BIG2 is one of the guanine nucleotide exchange factors (GEFs) for the ADP-ribosylation factor (ARF) family of small GTPases, which regulate membrane association of COPI and AP-1 coat protein complexes and GGA proteins. Brefeldin A (BFA), an ARF-GEF inhibitor, causes redistribution of the coat proteins from membranes to the cytoplasm and membrane tubulation of the Golgi complex and the trans-Golgi network (TGN). We have recently shown that BIG2 overexpression blocks BFA-induced redistribution of the AP-1 complex but not TGN membrane tubulation. In the present study, we constructed a dominant-negative BIG2 mutant and found that when expressed in cells it induced redistribution of AP-1 and GGA1 and membrane tubulation of the TGN. By contrast, the mutant did not induce COPI redistribution or Golgi membrane tubulation. These observations indicate that BIG2 is involved in trafficking from the TGN by regulating membrane association of AP-1 and GGA through activating ARF.

ADP-Ribosylation Factors↗
PubMed2005

Cytohesin-1: structure, function, and ARF activation.

Mammalian cytohesins are a family of very similar guanine nucleotide-exchange proteins (GEPs) that activate ADP-ribosylation factors (ARFs). Cytohesins are multifunctional molecules comprising a Sec7 domain that is responsible for the GEP activity, a PH domain that binds specific phosphatidylinositol phosphates, and a coiled-coil domain responsible for homodimerization and interaction with other proteins. Cytohesin proteins are ubiquitous and have been implicated in several functions including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. Unlike the GEP activity of BIG1 and BIG2, the acceleration by cytohesins of guanine nucleotide exchange to generate active ARF-GTP is not inhibited by the fungal metabolite brefeldin, A (BFA). This chapter is concerned for the most part with cytohesin-1 and the assay of its GEP activity.

Animals↗
PubMed1998

Structure of the guanine nucleotide exchange factor Sec7 domain of human arno and analysis of the interaction with ARF GTPase.

Sec7-related guanine nucleotide exchange factors (GEFs) initiate vesicle budding from the Golgi membrane surface by converting the GTPase ARF to a GTP-bound, membrane-associated form. Here we report the crystal structure of the catalytic Sec7 homology domain of Arno, a human GEF for ARF1, determined at 2.2 angstroms resolution. The Sec7 domain is an elongated, all-helical protein with a distinctive hydrophobic groove that is phylogenetically conserved. Structure-based mutagenesis identifies the groove and an adjacent conserved loop as the ARF-interacting surface. The sites of Sec7 domain interaction on ARF1 have subsequently been mapped, by protein footprinting experiments, to the switch 1 and switch 2 GTPase regions, leading to a model for the interaction between ARF GTPases and Sec7 domain exchange factors.

ADP-Ribosylation Factor 1↗
PubMed2003

Endosome-specific localization and function of the ARF activator GNOM.

ARF GTPases act at multiple steps of the secretory and vacuolar/lysosomal trafficking pathways, but little is known about the spatial regulation of ARF activation. In this issue of Cell, Geldner et al. demonstrate that the Arabidopsis ARF activator GNOM localizes to endosomes where it controls the polarized trafficking of the auxin efflux carrier PIN1 to the basal plasma membrane.

Arabidopsis↗