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PubMed1995

Syndromal mental retardation due to mutations in a regulator of gene expression.

Mental handicap is a common clinical problem that has been a relatively neglected area of research. Though the causes are varied and complex, molecular biologists are making progress in understanding the mechanisms in some cases, particularly where there are distinguishing phenotypic or genetic markers. The fortuitous association of alpha thalassaemia with a form of mental retardation has allowed us to define a specific X-linked syndrome (ATR-X). Positional cloning was used to define a disease interval and examination of candidate genes demonstrated that mutations in a gene, XH2, showing homology to the SNF2 superfamily were responsible for this syndrome. The complex ATR-X phenotype suggests that this gene, when mutated, down-regulates the expression of several genes including the alpha-globin genes indicating that it could be a global transcriptional regulator. It is conceivable that this mechanism is involved in other forms of syndromal mental retardation.

Child↗
PubMed1998

Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein.

Mutations in the XNP gene result in different inherited disorders, including the ATR-X syndrome which is characterized by mental retardation (MR) associated with alpha-thalaessemia. Amino acid sequence analysis revealed that the XNP protein is a new member of the SNF2-like family, which comprises numerous members involved in a broad range of biological functions: transcriptional regulation, DNA repair and chromosome segregation. Since experiments on fibroblasts from ATR-X patients have provided no evidence for either a DNA repair defect or abnormal chromosome breakage or segregation, it seems more likely that the XNP protein is somehow involved in regulation of gene expression. Recent genetic and biochemical studies have led to the emerging concept that SNF2-like proteins are components of a large protein complex which may exert its functions by modulating chromatin structure. To investigate whether XNP could mediate the activity of gene-specific activators through chromatin remodelling, we performed a yeast two-hybrid analysis using XNP and several human heterochromatin-associated proteins. We found a specific interaction between the XNP and the EZH2 proteins. In light of these observations, we discuss how the XNP protein may regulate gene transcription at the chromatin level.

Animals↗
PubMed2004

ATM is required for the cellular response to thymidine induced replication fork stress.

Genetically distinct checkpoints, activated as a consequence of either DNA replication arrest or ionizing radiation-induced DNA damage, integrate DNA repair responses into the cell cycle programme. The ataxia-telangiectasia mutated (ATM) protein kinase blocks cell cycle progression in response to DNA double strand breaks, whereas the related ATR is important in maintaining the integrity of the DNA replication apparatus. Here, we show that thymidine, which slows the progression of replication forks by depleting cellular pools of dCTP, induces a novel DNA damage response that, uniquely, depends on both ATM and ATR. Thymidine induces ATM-mediated phosphorylation of Chk2 and NBS1 and an ATM-independent phosphorylation of Chk1 and SMC1. AT cells exposed to thymidine showed decreased viability and failed to induce homologous recombination repair (HRR). Taken together, our results implicate ATM in the HRR-mediated rescue of replication forks impaired by thymidine treatment.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

SMC1 involvement in fragile site expression.

Common fragile sites have been involved in neoplastic transformation, although their molecular basis is still poorly understood. Here, we demonstrate that inhibition of the SMC1 by RNAi is sufficient to induce fragile site expression. By investigating normal, ATM- and ATR-deficient cell lines, we provide evidence that the contribution of SMC1 in preventing the collapse of stalled replication fork is an Atr-dependent pathway. Using a fluorescent antibody specific for gamma-H2AX, we show that very rare discrete nuclear foci appear 1 and 2 h after exposure to aphidicolin and/or RNAi-SMC1, but became more numerous and distinct after longer treatment times. In this context, fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of a stalled DNA replication that lasted too long to be managed by physiological rescue acting through the Atr/Smc1 axis. We propose that in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation.

Aphidicolin↗
PubMed1991

Analysis of the interactions of functional domains of a nuclear origin of replication from Saccharomyces cerevisiae.

We have determined that ARS121 is an efficient origin of replication on chromosome X of Saccharomyces cerevisiae. This origin is comprised of at least three distinct functional domains. One of these domains is the ARS121 core sequence (approximately 35 bp-long), which is essential for origin activity. This essential core contains an 11 bp sequence resembling (2 bp mismatch) the ARS consensus. Another important domain is an enhancer of DNA replication, which binds the OBF1 protein. The third domain, ATR (A/T-rich, approximately 72 bp), is auxiliary and works in either orientation, but only when located 3' to the essential core. When fused to the ARS121 core both the enhancer and the ATR domain act synergistically to enhance the activity of the origin. Furthermore, when fused to the essential core sequences of heterologous ARSs, ARS1 and ARS307, the auxiliary domains also appeared to stimulate synergistically origin function. These results suggest that (i) in order to elicit maximal origin activity all three domains have to interact and (ii) activation of the essential core sequences at different origins of replication may share a common mechanism.

Base Sequence↗
PubMed2004

Selective inhibition of the DNA-dependent protein kinase (DNA-PK) by the radiosensitizing agent caffeine.

Caffeine inhibits cell cycle checkpoints, sensitizes cells to ionizing radiation-induced cell killing and inhibits the protein kinase activity of two cell cycle checkpoint regulators, Ataxia-Telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR). In contrast, caffeine has been reported to have little effect on the protein kinase activity of the DNA-dependent protein kinase (DNA-PK), which is essential for the repair of DNA double-strand breaks. Previously, we reported that DNA-PK phosphorylates Thr21 of the 32 kDa subunit of replication protein A (RPA32) in response to camptothecin. In this report we demonstrate that the camptothecin-induced phosphorylation of RPA32 on Thr21 is inhibited by 2 mM caffeine. In addition, we show that caffeine inhibits immunoprecipitated and purified DNA-PK, as well as DNA-PK in cell extracts, with an IC50 of 0.2-0.6 mM. Caffeine inhibited DNA-PK activity through a mixed non-competitive mechanism with respect to ATP. In contrast, 10-fold higher concentrations of caffeine were required to inhibit DNA-PK autophosphorylation in vitro and caffeine failed to inhibit DNA-PKcs dependent double-strand break repair in vivo. These data suggest that while DNA-PK does not appear to be the target of caffeine-induced radiosensitization, caffeine cannot be used to differentiate between ATM, ATR and DNA- PK-dependent substrate phosphorylation in vivo.

Animals↗
PubMed2003

Genotoxic stress response gene expression in the mid-organogenesis rat conceptus.

The ability of the conceptus to respond to genotoxic stress may be critical for normal development, particularly after exposure to genotoxic teratogens. Members of the phosphatidylinositol 3-kinase (PI3K) superfamily are involved in controlling cell cycle activity and maintaining genomic stability. The expression of PI3K family members ATM, ATR, and DNA-PKcs, and downstream genes p53, GADD45, and p21, was examined in the mid organogenesis rat conceptus in vivo on gestational days (GD) 10 through 12 and in vitro following exposure to genotoxic stress. ATM was the most highly expressed PI3K family member in both yolk sac and embryo proper, with transcript levels increasing ~fourfold in the embryo from GD 10 to 12. Transcript concentrations for ATR, DNA-PKcs, and downstream genes were low in both tissues; all genes had increased transcript levels exclusively in the GD 12 embryo. Transient oxidative stress, induced by short-term, in vitro embryo culture, had no effect on transcript levels in either tissue. Culture for 24 or 44 h significantly decreased ATM transcript levels in both embryo and yolk sac, but downstream genes were unaffected compared to GD-11 and -12 in vivo levels, respectively. Exposure to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated form of the nitrogen mustard cyclophosphamide (CPA), had no effect on transcript levels for any of the genes examined. Therefore, while transcripts for genotoxic stress-response genes are present in the mid organogenesis rat conceptus, their expression is not regulated by exposure in culture to either transient oxidative stress or a genotoxic alkylating agent. The inability of the conceptus to upregulate transcripts in response to insult may contribute to an increased susceptibility to stressors during organogenesis.

Animals↗
PubMedDate not supplied

Glucose-sensitive membrane and infrared absorption spectroscopy for potential use as an implantable glucose sensor.

The applicability of using infrared absorption spectroscopy for an implantable glucose sensor was tested by measuring absorbance at 9.66 microns for glucose in aqueous solution at known concentrations. A commercial Fourier transform infrared spectrometer was used with an attenuated total reflection technique (ATR). Absorbance measurements were reproducible and linearity was excellent (coefficient of correlation: 0.996), in spite of pH and temperature changes over values that span the human physiologic ranges (pH 6.8-7.8, temperature, 32-43 degrees C) and 18-34% decreases in incident infrared energy. The minimum detectable concentration of glucose, however, was 31 mmol/L (560 mg/d) and, to use infrared sources and detectors compatible with an implantable device, an absorbance peak between 1 and 3 microns must be used. To solve the detection sensitivity and wavelength problems, the ATR prism was coated with a hydrophobic liquid membrane. The absorbance of water varied at 2.95 microns in inverse linear proportion to glucose concentration between 2-31 mmol/L (35-560 mg/dL, r = -0.992). Estimated incident infrared energy at 2.95 microns (0.2 micron bandwidth) was low enough to theoretically allow the use of a lithium battery small enough for implantation. These findings support the concept of using infrared absorption spectroscopy for an implantable glucose sensor.

Biosensing Techniques↗
PubMed1998

Endothelin-1 selectively potentiates the purinergic component of sympathetic neurotransmission in rat seminal vesicle.

Endothelin-1 (ET-1; 3-100 nM) caused graded tonic contractions and enhanced neurogenic contractions in rat field-stimulated seminal vesicle. At 100 nM, ET-1 increased nerve-mediated responses by 350 +/- 74 mg/100 mg wet tissue (almost 100% potentiation), whereas sarafotoxin S6c was ineffective. The potentiation of neurogenic responses by ET-1 was virtually abolished by the ETA receptor antagonist BQ-123 (1 microM; c. 95% inhibition) but was not modified by the ETB receptor antagonist BQ-788 (1 microM). Responses to field stimulation were inhibited by tetrodotoxin (0.1 microM; 100%), guanethidine (GTD; 5 microM, 75%), prazosin (PRA; 0.1 microM, 90%), desensitization of P2x purinoceptors with alpha,beta-methylene-ATP (mATP; 10 microM, 50%), or atropine (ATR; 0.1 microM, 40%). ET-1-induced potentiation of neurogenic contractions was not modified by prior incubation with indomethacin (5.6 microM), ATR, or PRA, but mATP and GTD reduced the effects of 100 nM ET-1 to 189 +/- 76 and 5 +/- 7 mg/100 mg wet tissue, respectively (n = 6-8). Therefore, ET-1 enhances nerve-mediated responses of this tissue by selectively potentiating the purinergic component of sympathetic neurotransmission. This action, which is independent of the eicosanoid-cycloxygenase pathway, is mediated via ETA receptors and, at least in part, by enhancement of motor responses to ATP.

Animals↗
PubMed1997

Training adaptation and biological changes among well-trained male triathletes.

The distinction between training and overtraining responses is an important prerequisite for any potential marker for monitoring overtraining in athletes. In this study, eight well-trained male triathletes undertook physical performance assessments, at 6 weekly intervals, throughout a 9-month intensive training season. At each assessment, a resting blood sample was obtained for determination of a number of biological parameters previously associated with overtraining. All athletes produced significant (P < 0.05) improvements in running speed at anaerobic threshold (ATRS) from 15.6 +/- 0.2 k.h-1 at the start of the season to 16.6 +/- 0.6 k.h-1 at the time of major competitions. This improvement in performance was taken as evidence of well balanced training programs. Significant changes (P < 0.05) in plasma glutamine and plasma uric acid concentrations were observed during the training season, and both correlated moderately with ATRS (r = 0.365 and r = -0.328, respectively). None of the other parameters measured showed any significant changes during the training season. The elevations in plasma glutamine concentration observed in response to long-term balanced training may be distinguishable from previous reports of decreased glutamine concentrations in overtrained athletes, making it a potentially valuable tool in the monitoring of overtraining in athletes.

Adult↗
PubMed2000

ABO blood groups and achilles tendon rupture in the Grampian Region of Scotland.

OBJECTIVE: To test whether the association between blood groups and Achilles tendon rupture (ATR) reported in some Scandinavian countries and in Hungary was present in our region. METHODS: We studied 78 patients treated at Aberdeen Royal Infirmary from 1990 to 1996, and compared their distribution of ABO blood groups with that found in 24.501 blood donors typed at the Blood Transfusion Centre during the same period. RESULTS: Overall, 47 of 78 (60%) of patients with an Achilles tendon rupture belonged to blood group O, compared with 51% of the population as a whole. Only 22 (28%) of the Achilles tendon rupture patients belonged to blood group A, whereas 35% of the general population were members of this group (NS). The A/O ratio was 0.47 for the tendon rupture patients, compared with 0.68 for the general population (NS). CONCLUSIONS: We could not demonstrate any significant association between the proportions of ABO blood groups and ATR in the Grampian Region of Scotland. The findings in other studies could be due to peculiarities in the distribution of the ABO groups in genetically segregated populations.

ABO Blood-Group System↗
PubMed1997

Alaska's statewide trauma registry: a useful surveillance tool for injury prevention planning and evaluation.

The state of Alaska is unique because it is one of a small number of states with a surveillance system that collects trauma information from every hospital in the state. The Alaska Trauma Registry (ATR) collects up to 144 data elements for every injured patient. Information from the ATR is useful as an injury surveillance tool for federal, state, and local governments and other agencies and organizations when planning and evaluating injury prevention programs. Combining trauma registry data with Bureau of Vital Statistics cause of death data provides complete, statewide, population-based data on all injuries serious enough to result in death or hospitalization.

Adolescent↗
PubMed2005

The effect of monocularly and binocularly induced astigmatic blur on depth discrimination is orientation dependent.

PURPOSE: Naturally occurring astigmatism varies according to the age of the person. Although uncorrected astigmatism may be associated with meridional amblyopia, there is little information of its effect on stereopsis. The purpose of this study was to determine the effect of astigmatism on depth discrimination and whether this was dependent on the axis of the astigmatism. METHODS: Astigmatic blur was induced in four healthy subjects (mean age, 31.5 years; range, 22 to 42 years) using plain cylinders (-8.75 D to +11.5 D) for orientation control and Jackson cross-cylinders (0 to 12 D) for spherical neutrality. Horizontal, vertical, and oblique astigmatism was induced with five monocular and three binocular axis steps. Depth discrimination was recorded at near using Frisby, TNO, and Titmus stereoacuity tests and at distance (4 m) using the variable distance stereoacuity test. Visual acuity was recorded at 0.4 m and 4 m. RESULTS: Visual acuity and depth discrimination degraded with increasing astigmatic blur. The effect of monocular astigmatic blur on depth discrimination and visual acuity was not dependent on the axis of orientation. For binocular astigmatic blur, the reduction in depth discrimination was dependent on the axis of the induced astigmatism (p < 0.01). The maximum effect occurred with orthogonal-oblique orientations (x45 left; x135 right), followed by against-the-rule (ATR) astigmatism; with-the-rule (WTR) astigmatism had the least effect (p < 0.001). CONCLUSIONS: The lesser effect of WTR compared with ATR astigmatic blur on depth discrimination may reflect the contribution of horizontal compared with nonhorizontal disparity processing in stereopsis. The pronounced effect of oblique astigmatic blur may be because of the effects on horizontal and nonhorizontal disparity and interocular differential image blur.

Adult↗
PubMed2005

Transcriptional analysis of the acid tolerance response in Streptococcus pneumoniae.

Streptococcus pneumoniae, one of the major causes of morbidity and mortality in humans, faces a range of potentially acidic conditions in the middle and late stages of growth in vitro, in diverse human fluids during the infection process, and in biofilms present in the nasopharynx of carriers. S. pneumoniae was shown to develop a weak acid tolerance response (ATR), where cells previously exposed to sublethal pHs (5.8-6.6) showed an increased survival rate of up to one order of magnitude after challenge at the lethal pH (4.4, survival rate of 10(-4)). Moreover, the survival after challenge of stationary phase cells at pH 4.4 was three orders of magnitude higher than that of cells taken from the exponential phase, due to the production of lactic acid during growth and increasing acidification of the growth medium until stationary phase. Global expression analysis after short-term (5, 15 and 30 min, the adaptation phase) and long-term (the maintenance phase) acidic shock (pH 6.0) was performed by microarray experiments, and the results were validated by real-time RT-PCR. Out of a total of 126 genes responding to acidification, 59 and 37 were specific to the adaptation phase and maintenance phase, respectively, and 30 were common to both periods. In the adaptation phase, both up- and down-regulation of gene transcripts was observed (38 and 21 genes, respectively), whereas in the maintenance phase most of the affected genes were down-regulated (34 out of 37). Genes involved in protein fate (including those involved in the protection of the protein native structure) and transport (including transporters of manganese and iron) were overrepresented among the genes affected by acidification, 8.7 and 24.6 % of the acid-responsive genes compared to 2.8 % and 9.6 % of the genome complement, respectively. Cross-regulation with the response to oxidative and osmotic stress was observed. Potential regulatory motifs involved in the ATR were identified in the promoter regions of some of the regulated genes.

Acids↗
PubMed2005

PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints.

The ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases respond to DNA damage by phosphorylating cellular target proteins that activate DNA repair pathways and cell cycle checkpoints in order to maintain genomic integrity. Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. These homeostatic functions may be partially responsible for the oncogenic effects of PPM1D when it is amplified and overexpressed in human tumors.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures.

The checkpoint mediator protein Claspin is indispensable for the ATR-dependent phosphorylation of Chk1 in response to stalled DNA replication forks in Xenopus egg extracts. We show that Claspin also participates in the detection of chromosomal double-stranded DNA breaks (DSBs) in this system. Significantly, removal of Claspin from egg extracts only partially abrogates the activation of Chk1 in response to chromatin with DSBs, whereas depletion of both Claspin and BRCA1 completely abolishes this activation. The function of Claspin in this DSB-triggered pathway depends on phosphorylation of T817 and S819 by ATR. Conversely, neither phosphorylation of Claspin on these sites nor the presence of BRCA1 is necessary for activation of Chk1 in response to stalled replication forks. Thus, site-specific phosphorylation of a checkpoint mediator protein is a crucial determinant in the discrimination between various checkpoint-inducing structures. Furthermore, checkpoint mediator proteins exhibit functional overlap that varies depending on the nature of the checkpoint-triggering DNA signal.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Differential recognition of highly divergent downy mildew avirulence gene alleles by RPP1 resistance genes from two Arabidopsis lines.

The perception of downy mildew avirulence (Arabidopsis thaliana Recognized [ATR]) gene products by matching Arabidopsis thaliana resistance (Recognition of Peronospora parasitica [RPP]) gene products triggers localized cell death (a hypersensitive response) in the host plant, and this inhibits pathogen development. The oomycete pathogen, therefore, is under selection pressure to alter the form of these gene products to prevent detection. That the pathogen maintains these genes indicates that they play a positive role in pathogen survival. Despite significant progress in cloning plant RPP genes and characterizing essential plant components of resistance signaling pathways, little progress has been made in identifying the oomycete molecules that trigger them. Concluding a map-based cloning effort, we have identified an avirulence gene, ATR1NdWsB, that is detected by RPP1 from the Arabidopsis accession Niederzenz in the cytoplasm of host plant cells. We report the cloning of six highly divergent alleles of ATR1NdWsB from eight downy mildew isolates and demonstrate that the ATR1NdWsB alleles are differentially recognized by RPP1 genes from two Arabidopsis accessions (Niederzenz and Wassilewskija). RPP1-Nd recognizes a single allele of ATR1NdWsB; RPP1-WsB also detects this allele plus three additional alleles with divergent sequences. The Emco5 isolate expresses an allele of ATR1NdWsB that is recognized by RPP1-WsB, but the isolate evades detection in planta. Although the Cala2 isolate is recognized by RPP1-WsA, the ATR1NdWsB allele from Cala2 is not, demonstrating that RPP1-WsA detects a novel ATR gene product. Cloning of ATR1NdWsB has highlighted the presence of a highly conserved novel amino acid motif in avirulence proteins from three different oomycetes. The presence of the motif in additional secreted proteins from plant pathogenic oomycetes and its similarity to a host-targeting signal from malaria parasites suggest a conserved role in pathogenicity.

Amino Acid Sequence↗
PubMed2000

Assessment of explanted PTCA balloons.

The data presented here are part of a on-going study to define the surface characteristics and properties of explanted PTCA catheters in a further effort to address some of the ramifications of the re-use issue. PTCA balloon catheter were examined after angioplasty in one hundred and sixty-eight patients (n = 168). This series included six balloon types from three manufacturers. The fresh fixed and dehydrated balloons were examined at first with light microscopy and then in a scanning electron microscope. X-ray semiquantitative microanalysis and FT-IR-ATR analysis were also performed on the balloons. Because most blood proteins are water soluble, we examined unfixed balloons with a protein silver staining kit for detection of adhered proteins described by Heukeshoven. A further method for protein detection is the Lowry-analysis. With this method water insoluble proteins can be observed. Our study has shown convincingly that all deployed angioplasty catheters were coated with adherent protein layers. Plaque particles were found embedded in the surfaces of most of the balloons examined. Fissuring and micro tearing of balloon surfaces was noted. FT-IR-ATR analyses of the blood contacted balloon surfaces did not show any peaks indicative of proteins on the balloon surface. The silver staining method also did not show any evidence of protein adsorption on the balloons. On the other hand, the Lowry-analysis yielded clear evidence that water insoluble proteins were adherent to the balloon surfaces. The average measured protein concentration was 17 microg/ml.

Angioplasty, Balloon, Coronary↗