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PubMed2002

Tissue selectivity of interferon-stimulated gene expression in mice infected with Dam(+) versus Dam(-) Salmonella enterica serovar Typhimurium strains.

The host interferon (IFN) system plays an important role in protection against microbial infections. Salmonella enterica serovar Typhimurium is highly virulent in the mouse model, whereas mutants that lack DNA adenine methylase (Dam(-)) are highly attenuated and elicit fully protective immune responses against murine typhoid fever. We examined the expression of IFN-responsive genes in several mouse tissues following infection with Dam(+) or Dam(-) Salmonella. Infection of mice with Dam(+) Salmonella resulted in the induction of host genes known to be indicators of IFN bioactivity and regulated by either IFN-alpha/beta (Mx1) or IFN-gamma (class II transactivator protein [CIITA] and inducible nitric oxide synthase [iNOS]) or by both IFN-alpha/beta and IFN-gamma (RNA-specific adenosine deaminase [ADAR1] and RNA-dependent protein kinase [PKR]) in a tissue-specific manner compared to uninfected animals. Since the Mx1 promoter is IFN-alpha/beta specific and the Mx1 gene is not inducible directly by IFN-gamma, these data suggest a role of IFN-alpha/beta in the host response to Salmonella infection. Mice infected with Dam(-) Salmonella showed reduced expression of the same set of IFN-stimulated genes (ISGs) as that observed after infection with wild-type Salmonella. The reduced capacity to induce ISGs persisted in Dam(-)-vaccinated mice after challenge with the virulent (Dam(+)) strain. Finally, although no Dam(-) organisms were recovered from the liver or spleen after oral infection of mice, ADAR, PKR, Mx, and CIITA expression levels were elevated in these tissues relative to those in uninfected mice, suggestive of the distant action of a signaling molecule(s) in the activation of ISG expression.

Adenosine Deaminase↗

PubMed2004

Contribution of immunological memory to protective immunity conferred by a Bacillus anthracis protective antigen-based vaccine.

Protective antigen (PA)-based vaccination is an effective countermeasure to anthrax infection. While neutralizing anti-PA antibody titers elicited by this vaccine serve as good correlates for protection against anthrax (S. Reuveny, M. D. White, Y. Y. Adar, Y. Kafri, Z. Altboum, Y. Gozes, D. Kobiler, A. Shafferman, and B. Velan, Infect. Immun. 69:2888-2893, 2001), no data are available on the contribution of the immunological memory for PA itself to protection. We therefore developed a guinea pig model in which a primary immunization with threshold levels of PA can induce a long-term T-cell immunological memory response without inducing detectable anti-PA antibodies. A revaccination of primed animals with the same threshold PA levels was effective for memory activation, yielding a robust and rapid secondary response. A challenge with a lethal dose (40 50% lethal doses; 2,000 spores) of spores after the booster vaccinations indicated that animals were not protected at days 2, 4, and 6 postboosting. Protection was achieved only from the 8th day postboosting, concomitant with the detection of protective levels of neutralizing antibody titers in the circulation. The practical implications from the studies reported herein are that, as expected, the protective capacity of memory depends on the PA dose used for the primary immunization and that the effectiveness of booster immunizations for the postexposure treatment of anthrax may be very limited when no detectable antibodies are present in primed animals prior to Bacillus anthracis spore exposure. Therefore, to allow for the establishment of memory-dependent protection prior to the expected onset of disease, booster immunizations should not be used without concomitant antimicrobial treatment in postexposure scenarios.

Animals↗

PubMed2002

RNA editing in hepatitis delta virus genotype III requires a branched double-hairpin RNA structure.

RNA editing at the amber/W site plays a central role in the replication scheme of hepatitis delta virus (HDV), allowing the virus to produce two functionally distinct forms of the sole viral protein, hepatitis delta antigen (HDAg), from the same open reading frame. Editing is carried out by a cellular activity known as ADAR (adenosine deaminase), which acts on RNA substrates that are at least partially double stranded. In HDV genotype I, editing requires a highly conserved base-paired structure that occurs within the context of the unbranched rod structure characteristic of HDV RNA. This base-paired structure is disrupted in the unbranched rod of HDV genotype III, which is the most distantly related of the three known HDV genotypes and is associated with the most severe disease. Here I show that RNA editing in HDV genotype III requires a branched double-hairpin structure that deviates substantially from the unbranched rod structure, involving the rearrangement of nearly 80 bp. The structure includes a UNCG RNA tetraloop, a highly stable structural motif frequently involved in the folding of large RNAs such as rRNA. The double-hairpin structure is required for editing, and hence for virion formation, but not for HDV RNA replication, which requires the unbranched rod structure. HDV genotype III thus relies on a dynamic conformational switch between the two different RNA structures: the unbranched rod characteristic of HDV RNA and a branched double-hairpin structure that is required for RNA editing. The different mechanisms of editing in genotypes I and III underscore their functional differences and may be related to pathogenic differences as well.

Base Sequence↗

PubMed2005

New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1.

While many clinical hepatitis C virus (HCV) infections are resistant to alpha interferon (IFN-alpha) therapy, subgenomic in vitro self-replicating HCV RNAs (HCV replicons) are characterized by marked IFN-alpha sensitivity. IFN-alpha treatment of replicon-containing cells results in a rapid loss of viral RNA via translation inhibition through double-stranded RNA-activated protein kinase (PKR) and also through a new pathway involving RNA editing by an adenosine deaminase that acts on double-stranded RNA (ADAR1). More than 200 genes are induced by IFN-alpha, and yet only a few are attributed with an antiviral role. We show that inhibition of both PKR and ADAR1 by the addition of adenovirus-associated RNA stimulates replicon expression and reduces the amount of inosine recovered from RNA in replicon cells. Small inhibitory RNA, specific for ADAR1, stimulated the replicon 40-fold, indicating that ADAR1 has a role in limiting replication of the viral RNA. This is the first report of ADAR's involvement in a potent antiviral pathway and its action to specifically eliminate HCV RNA through adenosine to inosine editing. These results may explain successful HCV replicon clearance by IFN-alpha in vitro and may provide a promising new therapeutic strategy for HCV as well as other viral infections.

Adenosine↗

PubMed1998

Hepatitis delta virus RNA editing is highly specific for the amber/W site and is suppressed by hepatitis delta antigen.

RNA editing at adenosine 1012 (amber/W site) in the antigenomic RNA of hepatitis delta virus (HDV) allows two essential forms of the viral protein, hepatitis delta antigen (HDAg), to be synthesized from a single open reading frame. Editing at the amber/W site is thought to be catalyzed by one of the cellular enzymes known as adenosine deaminases that act on RNA (ADARs). In vitro, the enzymes ADAR1 and ADAR2 deaminate adenosines within many different sequences of base-paired RNA. Since promiscuous deamination could compromise the viability of HDV, we wondered if additional deamination events occurred within the highly base paired HDV RNA. By sequencing cDNAs derived from HDV RNA from transfected Huh-7 cells, we determined that the RNA was not extensively modified at other adenosines. Approximately 0.16 to 0.32 adenosines were modified per antigenome during 6 to 13 days posttransfection. Interestingly, all observed non-amber/W adenosine modifications, which occurred mostly at positions that are highly conserved among naturally occurring HDV isolates, were found in RNAs that were also modified at the amber/W site. Such coordinate modification likely limits potential deleterious effects of promiscuous editing. Neither viral replication nor HDAg was required for the highly specific editing observed in cells. However, HDAg was found to suppress editing at the amber/W site when expressed at levels similar to those found during HDV replication. These data suggest HDAg may regulate amber/W site editing during virus replication.

Base Sequence↗

PubMed2001

CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain.

RNA editing of specific residues by adenosine deamination is a nuclear process catalyzed by adenosine deaminases acting on RNA (ADAR). Different promoters in the ADAR1 gene give rise to two forms of the protein: a constitutive promoter expresses a transcript encoding (c)ADAR1, and an interferon-induced promoter expresses a transcript encoding an N-terminally extended form, (i)ADAR1. Here we show that (c)ADAR1 is primarily nuclear whereas (i)ADAR1 encompasses a functional nuclear export signal in the N-terminal part and is a nucleocytoplasmic shuttle protein. Mutation of the nuclear export signal or treatment with the CRM1-specific drug leptomycin B induces nuclear accumulation of (i)ADAR1 fused to the green fluorescent protein and increases the nuclear editing activity. In concurrence, CRM1 and RanGTP interact specifically with the (i)ADAR1 nuclear export signal to form a tripartite export complex in vitro. Furthermore, our data imply that nuclear import of (i)ADAR1 is mediated by at least two nuclear localization sequences. These results suggest that the nuclear editing activity of (i)ADAR1 is modulated by nuclear export.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

Juvenile arteritis revisited. Buerger's disease-Takayasu's disease.

Thromboangiitis obliterans is defined as an inflammatory disease involving small and medium sized arteries and veins. As no clinical symptoms, signs, radiological or laboratory abnormalities nor pathological features are specific, the diagnosis is usually made according the criteria proposed by Adar in a young smoker, male or female, with distal arterial occlusions sometimes associated with thrombophlebitis and with negative aetiological investigations. Recently, rheumatic manifestations were identified in about 10% of patients. If new developments in vascular medicine, as ultrasound explorations or CT scan limit the indications for angiography, others, especially in the field of thrombophilia, make more difficult the differential diagnosis. If the strong link between the disease activity and smoking habits is confirmed, medical or surgical approach remain disappointing. Takayasu's disease or non specific aorto-arteritis is an inflammatory disease of young women that primarily affects the aorta its main branches and the pulmonary arteries. The disease often start in children. The prevalence of the disease as the arterial lesions show geographical variations. That and the different associations with infectious, rheumatic or systemic diseases could justify to consider Takayasu's disease as a syndrome. B-mode ultrasonography and electron beam computed tomography are usually sufficient to characterize the arterial involvement and are essential for the follow up of patients. In some rare cases arterial biopsy is necessary to confirm the diagnosis. The surgical treatment concerns specific lesions with ischemic symptoms and failure of the medical approach, however endovascular techniques are often discussed in first intention. During inflammatory phases with evolutive lesions corticosteroids are often used. In case of failure cyclophosphamide or methotrexate have been used.

Child↗

PubMed2005

SINEs point to abundant editing in the human genome.

Recent bioinformatic analyses suggest that almost all human transcripts are edited by adenosine deaminases (ADARs), converting adenosines to inosines. Most of this editing is in Alu element transcripts, which are unique to primates. This editing might have no function or might be involved in functions such as the regulation of splicing, chromatin or nuclear localization of transcripts.

Adenosine Deaminase↗

PubMed2005

The mRNA expression differences of RNA editing enzymes in differentiated and undifferentiated NG108-15 cells.

The alteration of the editing pattern of serotonin 2C receptor (5-HT2CR) mRNA has been reported during cell differentiation. Since editing of 5-HT2CR mRNA is regulated by adenosine deaminases acting on RNA (ADARs), it is of interest to investigate if the expression of these enzymes changes during cell differentiation. The level of ADAR1 mRNA in NG108-15 cells was decreased by cell differentiation. These results suggest that the decrease of ADAR1 expression during cell differentiation may play an important role in the differentiation-induced alteration of the 5-HT2CR editing pattern in NG108-15.

Adenosine Deaminase↗

PubMed2006

RNA aptamers binding the double-stranded RNA-binding domain.

Specific RNA recognition of proteins containing the double-strand RNA-binding domain (dsRBD) is essential for several biological pathways such as ADAR-mediated adenosine deamination, localization of RNAs by Staufen, or RNA cleavage by RNAse III. Structural analysis has demonstrated the lack of base-specific interactions of dsRBDs with either a perfect RNA duplex or an RNA hairpin. We therefore asked whether in vitro selections performed in parallel with individual dsRBDs could yield RNAs that are specifically recognized by the dsRBD on which they were selected . To this end, SELEX experiments were performed using either the second dsRBD of the RNA-editing enzyme ADAR1 or the second dsRBD of Xlrbpa, a homolog of TRBP that is involved in RISC formation. Several RNA families with high binding capacities for dsRBDs were isolated from either SELEX experiment, but no discrimination of these RNAs by different dsRBDs could be detected. The selected RNAs are highly structured, and binding regions map to two neighboring stem-loops that presumably form stacked helices and are interrupted by mismatches and bulges. Despite the lack of selective binding of SELEX RNAs to individual dsRBDS, selected RNAs can efficiently interfere with RNA editing in vivo.

Adenosine Deaminase↗

PubMed2003

Coordination of editing and splicing of glutamate receptor pre-mRNA.

Adenosine deaminase that acts on RNA, ADAR, catalyzes the conversion of adenosine into inosine within double-stranded RNA. This type of editing has mainly been found in genes involved in neurotransmission. Site-specific A to I modifications often require intronic sequences to create the double-stranded structure necessary for editing. A system was developed to investigate if editing and splicing of pre-mRNA are coordinated. We have focused on a selectively edited site (R/G) in the glutamate receptor subunit B pre-mRNA. This editing site is situated in close proximity to a 5' splice site. To ensure efficient splicing, the editing site, together with its natural 5' splice site, was fused to a 3' splice site of the major late transcript from adenovirus. In vitro, on a premade transcript, ADAR2 editing and splicing were found to interfere with each other. The stable stem-loop required for ADAR2 editing had a negative effect on in vitro splicing, possibly by sequestering the 5' splice site. Further, RNA helicase A was shown to overcome the splicing inhibition caused by ADAR2. In vivo, allowing cotranscriptional processing, the same construct was found to efficiently edit and splice without interference, suggesting that the two RNA processing events are coordinated.

Adenosine Deaminase↗

PubMed2004

Evidence for auto-inhibition by the N terminus of hADAR2 and activation by dsRNA binding.

Adenosine deaminases that act on RNA (ADARs) catalyze adenosine to inosine conversion in RNA that is largely double stranded. Human ADAR2 (hADAR2) contains two double-stranded RNA binding motifs (dsRBMs), separated by a 90-amino acid linker, and these are followed by the C-terminal catalytic domain. We assayed enzymatic activity of N-terminal deletion constructs of hADAR2 to determine the role of the dsRBMs and the intervening linker peptide. We found that a truncated protein consisting of one dsRBM and the deaminase domain was capable of deaminating a short 15-bp substrate. In contrast, full-length hADAR2 was inactive on this short substrate. In addition, we observed that the N terminus, which was deleted from the truncated protein, inhibits editing activity when added in trans. We propose that the N-terminal domain of hADAR2 contains sequences that cause auto-inhibition of the enzyme. Our results suggest activation requires binding to an RNA substrate long enough to accommodate interactions with both dsRBMs.

Adenosine Deaminase↗

PubMed2004

Methods for the analysis of adenosine-to-inosine editing in RNA.

In this work we describe methods for the analysis of RNAs that have been edited by the double-strand RNA-specific adenosine deaminase, ADAR. These RNAs contain inosine residues that can be detected and quantified by a variety of approaches, including base hydrolysis and thin-layer chromatography, reverse transcription polymerase chain reaction, primer extension, and inosine-specific base cleavage. The most common method for the analysis of editing will be described here. This method involves complete hydrolysis of edited RNAs to nucleoside monophosphates, followed by separation of the products using thin-layer chromatography.

Adenosine↗

PubMed2006

Adenosine-to-inosine RNA editing: perspectives and predictions.

Adenosine-to-Inosine RNA editing introduces changes in RNA transcripts via a post-transcriptional mechanism, the hydrolytic deamination of adenosine (A) to inosine (I) which is interpreted as guanosine by cellular machineries. Adenosine deaminases that act on RNA (ADAR) enzymes catalyze editing in double-stranded (ds) RNA substrates.

Adenosine↗

PubMed2006

Genetic predisposition of responsiveness to therapy for chronic hepatitis C.

BACKGROUND: A combination of interferon-alpha (IFN-alpha) and ribavirin has been the choice for treating chronic hepatitis C (CHC) patients. It achieves an overall sustained response rate of approximately 50%; however, the treatment takes 6-12 months and often brings significant adverse reactions to some patients. It would therefore be beneficial to include a pretreatment evaluation in order to maximize the efficacy. In addition to viral genotypes, we hypothesize that patient genotypes might also be useful for the prediction of treatment response. METHODS: We retrospectively analyzed the genetic differences of CHC patients that are associated with IFN/ribavirin responses. The DNA polymorphisms among 195 sustained responders and 122 nonresponders of CHC patients of Taiwanese origin were compared. Statistical and algorithmic methods were used to select the genes associated with drug response and single nucleotide polymorphisms (SNPs) that permitted the construction of a predictive model. RESULTS: Association studies and haplotype reconstruction revealed selection of seven genes: adenosine deaminase, RNA-specific (ADAR), caspase 5, apoptosis-related cysteine peptidase (CASP5), fibroblast growth factor 1 (FGF1), interferon consensus sequence binding protein 1 (ICSBP1), interferon-induced protein 44 (IFI44), transporter 2, ATP-binding cassette, subfamily B (TAP2) and transforming growth factor, beta receptor associated protein 1 (TGFBRAP1) for the responsiveness trait. Based on confirmed linkage disequilibrium block in the population, a minimal set of 26 SNPs in the seven selected genes was inferred. To predict treatment outcome, a multiple logistic regression model was constructed using susceptible genotypes of SNPs. The performance of the resultant model had a sensitivity of 68.2% and specificity of 60.7% on 317 CHC patients treated with IFN-combined therapy. In addition, a prediction model with both the host genetic and viral genotype information was also constructed which enhanced the performance with a sensitivity of 80.7% and specificity of 67.2%. CONCLUSIONS: A genetic model was constructed to predict outcomes of the combination therapy in CHC patients with high sensitivity and specificity. Results also provide a possible process of selecting targets for predicting treatment outcomes and the basis for developing pharmacogenetic tests.

Adult↗

PubMed1982

Malabsorption syndrome, coccidiosis, combined immune deficiency, and fulminant lymphoproliferative disease.

Coccidia were found in a patient suffering from malabsorption syndrome. In addition, immunologic investigation showed combined humoral and cellular immunodeficiency. Treatment with metronidazole induced the disappearance of coccidia from the stool and clinical remission. Six months later, the patient was seen with acute lymphoproliferative disease and died thereafter. The possible relationship between malabsorption, immunodeficiency, coccidiosis, metronidazole, and malignancy is reviewed.

Adult↗

PubMed1977

Gustatory phenomena after upper dorsal sympathectomy.

In a series of 100 bilateral upper dorsal sympathectomies performed for palmar hyperhidrosis, gustatory sweating and other gustatory phenomena were reported by 68 of 93 patients (73%), followed up for an average of 1 1/2 years. These gustatory phenomena were quite different from physiologic gustatory sweating: a wide range of gustatory stimuli caused a variety of phenomena in varied locations. There was a negative correlation between the incidence of these phenomena and the occurrence of Horner's syndrome after sympathectomy. Analysis of our observations, and of clinical and experimental work of others, leads to the conclusion that gustatory phenomena after upper dorsal sympathectomy are the result of preganglionic sympathetic regeneration or collateral sprouting with aberrant synapses in the superior cervical ganglion.

Adult↗

PubMed1991

Vascular insufficiency quantitatively aggravates diabetic neuropathy.

The effect of lower-limb ischemia on the severity of neuropathy was examined in 48 diabetic patients with peripheral vascular disease. The severity of the vascular disease, as determined by medical history, physical findings, and laboratory data, was scored for each leg. Neuropathy was rated clinically and based on the results of nerve conduction studies of the common peroneal, posterior tibial, and sural nerves. A significant correlation was found between the vascular scores and neurologic variables of the two legs, most strikingly so in electrophysiologic data, with coefficients of .6 to .7. Nondiabetic control patients showed no evidence of neuropathy, regardless of the severity of ischemia, whereas diabetic controls without limb ischemia showed symmetrical neuropathy. These findings support the hypoxic theory in the pathogenesis of diabetic neuropathy.

Adult↗