SEARCH · PubMed Health

Results for “TLS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources

PubMed1999

Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation.

Homologous recombination plays a fundamental role in DNA double-strand break repair. Previously, we detected two mammalian nuclear proteins of 100 and 75 kDa (POMp100 and POMp75, respectively) that are able to promote homologous DNA pairing, a key step in homologous recombination. Here we describe the identification of human (h) POMp75 as the pro-oncoprotein TLS/FUS. hPOMp75/TLS binds both single- and double-stranded DNAs and mediates annealing of complementary DNA strands. More important, it promotes the uptake of a single-stranded oligonucleotide into a homologous superhelical DNA to form a D-loop. The formation of a D-loop is an essential step in DNA double-strand break repair through recombination. DNA annealing and D-loop formation catalyzed by hPOMp75/TLS require Mg(2+) and are ATP-independent. Interestingly, the oncogenic fusion form TLS-CHOP is not able to promote DNA pairing. These data suggest a possible role for hPOMp75/TLS in maintenance of genomic integrity.

Base Pairing↗

PubMed2002

Na-ctl-2, a cDNA encoding a C-type lectin expressed exclusively in adult Necator americanus hookworms.

C-type lectins (C-TLs) are carbohydrate-binding proteins central to diverse physiological processes including immunity, venom-induced haemostasis and wound repair. Here we describe the cloning of Na-ctl-2, a cDNA encoding a secreted C-TL from the human hookworm Necator americanus. The transcript was detected in mRNA from adult worms but not infective larvae. The cDNA encoded an N-terminal secretory signal peptide followed by a long-form C-TL domain with sequence similarity to C-TL-like proteins from Caenorhabditis elegans and mammalian antigen presenting cell receptors, suggesting that hookworms might utilise this class of lectin to interrupt anti-parasite immune responses or interfere with host clotting mechanisms. This is the first report of a full-length cDNA encoding a lectin from hookworms. The unusually skewed representation of this protein family within different nematode genera and its subsequent impact on the evolution of nematode parasitism is discussed.

Amino Acid Sequence↗

PubMed2004

Management of hyperuricemia with rasburicase review.

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.

Allopurinol↗

PubMed2006

Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination.

Differential modifications of proliferating cell nuclear antigen (PCNA) determine DNA repair pathways at stalled replication forks. In yeast, PCNA monoubiquitination by the ubiquitin ligase (E3) yRad18 promotes translesion synthesis (TLS), whereas the lysine-63-linked polyubiquitination of PCNA by yRad5 (E3) promotes the error-free mode of bypass. The yRad5-dependent pathway is important to prevent genomic instability during replication, although its exact molecular mechanism is poorly understood. This mechanism has remained totally elusive in mammals because of the lack of apparent RAD5 homologues. We report that a putative tumor suppressor gene, SHPRH, is a human orthologue of yeast RAD5. SHPRH associates with PCNA, RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2) and promotes methyl methanesulfonate (MMS)-induced PCNA polyubiquitination. The reduction of SHPRH by stable short hairpin RNA increases sensitivity to MMS and enhances genomic instability. Therefore, the yRad5/SHPRH-dependent pathway is a conserved and fundamental DNA repair mechanism that protects the genome from genotoxic stress.

Amino Acid Sequence↗

PubMed1996

Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex.

The feasibility of producing a visual prosthesis for the blind using intracortical microstimulation (ICMS) of the visual cortex was studied in a 42-year-old woman who had been totally blind for 22 years secondary to glaucoma. Thirty-eight microelectrodes were implanted in the right visual cortex, near the occipital pole, for a period of 4 months. Percepts reported as small spots of light, called phosphenes, were produced with 34 of the 38 implanted microelectrodes. Threshold currents for phosphene generation with trains of biphasic pulses were as low as 1.9 microA, and most of the microelectrodes had thresholds below 25 microA. Phosphene brightness could be modified with stimulus amplitude, frequency and pulse duration. Repeated stimulation over a period of minutes produced a gradual decrease in phosphene brightness. Phosphenes did not flicker. The apparent size of phosphenes ranged from a "pin-point' to a "nickel' (20 mm diameter coin) held at arm's length. Phosphene size usually decreased as stimulation current was increased but increased slightly as the train length (TL) was increased. At levels of stimulation near threshold, the phosphenes were often reported to have colours. As the stimulation level was increased, the phosphenes generally became white, greyish or yellowish. Individual phosphenes appeared at different distances from the subject. When two phosphenes were simultaneously generated, the apparent distances of the individual phosphenes sometimes changed to make them appear to be at about the same distance. When three or more phosphenes were simultaneously generated, they became coplanar. Except for rare occasions, phosphenes extinguished rapidly at the termination of the stimulation train. When stimulation TLs were increased beyond 1 s, phosphenes usually disappeared before the end of the train. The duration of phosphene perception could be increased by interrupting a long stimulation train with brief pauses in stimulation. Intracortical microelectrodes spaced 500 microns apart generated separate phosphenes, but microelectrodes spaced 250 microns typically did not. This two-point resolution was about five times closer than has typically been achieved with surface stimulation. With some individual microelectrodes, a second closely spaced phosphene was sometimes produced by increasing the stimulation current. Phosphenes moved with eye movements. When up to six phosphenes were simultaneously elicited, they all moved with the same relative orientation during eye movements. All phosphenes were located in the left hemi-field with the majority above the horizontal meridian. There was a clustering of most of the phosphenes within a relatively small area of visual space. The potentially greater microelectrode density and lower power requirements of ICMS compared with surface stimulation appears encouraging for a visual prosthesis. However, further studies with blind subjects are required to optimize stimulation parameters and test complex image recognition before the feasibility of a visual prosthesis based on ICMS can be established.

Adult↗

PubMed1998

TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis.

The leukemogenic potential of BCR/ABL oncoproteins depends on their tyrosine kinase activity and involves the activation of several downstream effectors, some of which are essential for cell transformation. Using electrophoretic mobility shift assays and Southwestern blot analyses with a double-stranded oligonucleotide containing a zinc finger consensus sequence, we identified a 68 kDa DNA-binding protein specifically induced by BCR/ABL. The peptide sequence of the affinity-purified protein was identical to that of the RNA-binding protein FUS (also called TLS). Binding activity of FUS required a functional BCR/ABL tyrosine kinase necessary to induce PKCbetaII-dependent FUS phosphorylation. Moreover, suppression of PKCbetaII activity in BCR/ABL-expressing cells by treatment with the PKCbetaII inhibitor CGP53353, or by expression of a dominant-negative PKCbetaII, markedly impaired the ability of FUS to bind DNA. Suppression of FUS expression in myeloid precursor 32Dcl3 cells transfected with a FUS antisense construct was associated with upregulation of the granulocyte-colony stimulating factor receptor (G-CSFR) and downregulation of interleukin-3 receptor (IL-3R) beta-chain expression, and accelerated G-CSF-stimulated differentiation. Downregulation of FUS expression in BCR/ABL-expressing 32Dcl3 cells was associated with suppression of growth factor-independent colony formation, restoration of G-CSF-induced granulocytic differentiation and reduced tumorigenic potential in vivo. Together, these results suggest that FUS might function as a regulator of BCR/ABL leukemogenesis, promoting growth factor independence and preventing differentiation via modulation of cytokine receptor expression.

Amino Acid Sequence↗

PubMed2003

Results of a high-resolution genome screen of 437 Alzheimer's disease families.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Aged↗

PubMed2002

Structural variation and functional importance of a D-loop-T-loop interaction in valine-accepting tRNA-like structures of plant viral RNAs.

Valine-accepting tRNA-like structures (TLSs) are found at the 3' ends of the genomic RNAs of most plant viruses belonging to the genera Tymovirus, Furovirus, Pomovirus and Pecluvirus, and of one Tobamovirus species. Sequence alignment of these TLSs suggests the existence of a tertiary D-loop-T-loop interaction consisting of 2 bp, analogous to those in the elbow region of canonical tRNAs. The conserved G(18).Psi(55) pair of regular tRNAs is found to covary in these TLSs between G.U (possibly also modified to G.Psi) and A.G. We have mutated the relevant bases in turnip yellow mosaic virus (TYMV) and examined the mutants for symptom development on Chinese cabbage plants and for accumulation of genetic reversions. Development of symptoms is shown to rely on the presence of either A.G or G.U in the original mutants or in revertants. This finding supports the existence and functional importance of this tertiary interaction. The fact that only G.U and A.G are accepted at this position appears to result from steric and energetic limitations related to the highly compact nature of the elbow region. We discuss the implications of these findings for the various possible functions of the valine-accepting TLS.

Base Sequence↗

PubMed2004

Biological consequences of oxidative stress-induced DNA damage in Saccharomyces cerevisiae.

Reactive oxygen species (ROS), generated by endogenous and exogenous sources, cause significant damage to macromolecules, including DNA. To determine the cellular effects of induced, oxidative DNA damage, we established a relationship between specific oxidative DNA damage levels and biological consequences produced by acute H2O2 exposures in yeast strains defective in one or two DNA damage-handling pathways. We observed that unrepaired, spontaneous DNA damage interferes with the normal cellular response to exogenous oxidative stress. In addition, when base excision repair (BER) is compromised, there is a preference for using recombination (REC) over translesion synthesis (TLS) for handling H2O2-induced DNA damage. The global genome transcriptional response of these strains to exogenous H2O2 exposure allowed for the identification of genes responding specifically to induced, oxidative DNA damage. We also found that the presence of DNA damage alone was sufficient to cause an increase in intracellular ROS levels. These results, linking DNA damage and intracellular ROS production, may provide insight into the role of DNA damage in tumor progression and aging. To our knowledge, this is the first report establishing a relationship between H2O2-induced biological endpoints and specific oxidative DNA damage levels present in the genome.

DNA Damage↗

PubMed2004

The post-replication repair RAD18 and RAD6 genes are involved in the prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae.

7,8-dihydro-8-oxoguanine (8-oxoG) is an abundant and mutagenic lesion produced in DNA exposed to free radicals and reactive oxygen species. In Saccharomyces cerevisiae, the OGG1 gene encodes the 8-oxoG DNA N-glycosylase/AP lyase (Ogg1), which is the functional homologue of the bacterial Fpg. Ogg1-deficient strains are spontaneous mutators that accumulate GC to TA transversions due to unrepaired 8-oxoG in DNA. In yeast, DNA mismatch repair (MMR) and translesion synthesis (TLS) by DNA polymerase eta also play a role in the prevention of the mutagenic effect of 8-oxoG. In the present study, we show the RAD18 and RAD6 genes that are required to initiate post-replication repair (PRR) are also involved in the prevention of mutations by 8-oxoG. Consistently, a synergistic increase in spontaneous CanR and Lys+ mutation rates is observed in the absence of Rad6 or Rad18 proteins in ogg1 mutant strains. Spectra of CaR mutations in ogg1 rad18 and ogg1 rad6 double mutants show a strong bias in the favor of GC to TA transversions, which are 137- and 189-fold higher than in the wild-type, respectively. The results also show that Poleta (RAD30 gene product) plays a critical role on the prevention of mutations at 8-oxoG, whereas Polzeta (REV3 gene product) does not. Our current model suggests that the Rad6-Rad18 complex targets Poleta at DNA gaps that result from the MMR-mediated excision of adenine mispaired with 8-oxoG, allowing error-free dCMP incorporation opposite to this lesion.

Base Pair Mismatch↗

PubMed1994

Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature.

Tumor lysis syndrome (TLS), resulting from massive necrosis of neoplastic cells after chemotherapy, is a rare complication in nonhematologic malignancies. A 32-year-old woman suffering from a rapidly progressing breast adenocarcinoma metastatic to the liver and bones received a course of single-agent chemotherapy with mitoxanthrone and 4 days later developed the tumor lysis syndrome, and subsequently acute renal failure. The patient responded well to appropriate treatment. This case report points out that breast cancer can be extremely sensitive to chemotherapy and suggests that prophylaxis for tumor lysis syndrome should be considered in the subset of patients with breast carcinoma who have hepatic metastases and large tumor burdens.

Adult↗

PubMed2003

Spontaneous tumor lysis syndrome in solid tumors: really a rare condition?

Acute tumor lysis syndrome (ATLS), which occurs spontaneously, without cytotoxic therapy, is a rare condition. Spontaneous TLS (STLS) has been seen most commonly in lymphoma and leukemia. We report a series of 3 cases of STLS in patients with solid tumors who were hospitalized in our department during a 9-month period and suggest that STLS is probably more frequent than previously thought.

Adrenal Gland Neoplasms↗

PubMed1995

The emerging molecular genetics of sarcoma translocations.

Many types of sarcomas are characterized by specific chromosomal translocations which are likely to be of etiologic significance. The recent elucidation of the molecular structure of the several of these translocations has revealed some striking similarities. Nearly all appear to result in the production of novel, tumor-specific chimeric transcription factors. Furthermore, six of the translocations, namely the t(11;22), t(21;22), and t(7;22) of Ewing's sarcoma, the t(12;22) of clear cell sarcoma, the t(12;16) of myxoid liposarcoma, and the t(11;22) of desmoplastic small round cell tumor, achieve this following a peculiar pattern, consisting in the fusion of a gene with an RNA-binding domain (EWS or TLS) with a transcription factor gene (FLI1, ERG, ETV1, ATF-1, CHOP, or WT1). The observation that the different translocation partners of the EWS gene are specifically associated with several distinct types of primitive sarcomas suggests a model in which the translocation partner supplying the DNA-binding domain confers the target specificity of the transcriptional activation mediated by these chimeric proteins, whereas the partner supplying the N-terminal domain and promoter region determines their transactivation potential and expression level. Further analysis of the normal functions and expression patterns of these genes should yield insights into the histogenesis of these different tumor types and into normal tissue development and differentiation. Clinically, our new understanding of the molecular structure of these translocations opens new avenues for molecular diagnosis and investigative therapeutics.

Base Sequence↗

PubMed2004

Myxoid liposarcoma with adipocytic maturation: detection of TLS/CHOP fusion gene transcript.

This report describes a 49-year-old woman with a well-circumscribed nodule of liposarcoma. The patient noticed a soft, slowly growing mass at the right sural region. Both axial computed tomography and magnetic resonance imaging revealed a soft tissue tumor consisting of nonfatty lesion measuring 5 x 3 x 3 cm circumscribed by a 1-cm thickened fatty area. Histologically, the tumor was made of 2 distinct components: the inner component of the tumor was a classic myxoid liposarcoma with numerous lipoblasts; the outer component was a lipoma-like lesion consisting of mature adipocytes without atypical nuclei. Immunohistochemically, MDM2 overexpression was observed and p53 immunophenotype was negative in both components. Molecular analysis revealed that type 1 TLS/ CHOP fusion gene transcript, characteristic of myxoid/round cell liposarcoma, was detected in both areas.

Adipocytes↗

PubMed2001

Electronic energy relaxation and transition frequency jumps of single molecules at 30 mK.

Transition frequency jumps for single terrylene molecules in a polyethylene matrix caused by resonant laser irradiation are investigated at 30 mK. These jumps are not accompanied by substantial sample heating. A model for the effect is proposed, based on the interaction of tunneling two-level systems (TLSs) surrounding the single molecule with high-energy nonthermal phonons emitted by the molecule during electronic energy relaxation. The radius of the effective interaction volume is estimated to be r(m) approximately 12.5 nm, and the interaction cross section for nonequilibrium phonon-TLS scattering is estimated as approximately 10(-22) cm2.

Journal Article↗

PubMed2004

Modeling of the nuclear parameters for H atoms in X-ray charge-density studies.

Extensive and precise X-ray diffraction data for xylitol have been used to test different approaches to estimate nuclear parameters for H atoms in charge-density studies. The parameters from a neutron diffraction study of the same compound were taken as a reference. The resulting static charge densities obtained for the different approaches based on a multipole model were subjected to a topological analysis. The comparative analysis led to the following results. The procedure of extending the X-H bond to match bond lengths from neutron diffraction studies provides the best agreement with the neutron positional parameters. An isotropic model for the atomic displacements of H atoms is highly unsatisfactory and leads to significant deviations for the properties of the bond critical points including those that only involve non-H atoms. Anisotropic displacement parameters for H atoms can be derived from the X-ray data that are in agreement with the values from the neutron study, and the resulting charge-density models are in good agreement with the reference model. The anisotropic displacement parameters for H atoms are derived from the X-ray data as a sum of the external (rigid-body) and internal vibrations. The external vibrations are obtained from a TLS analysis of the ADPs of the non-H atoms and the internal vibrations from analysis of neutron diffraction studies of related compounds. The results from the analysis of positional and thermal parameters were combined to devise a 'best anisotropic' model, which was employed for three other systems where X-ray and neutron data were available. The results from the topological analysis of these systems confirm the success of the 'best anisotropic' model in providing parameters for the H atoms that give charge densities in agreement with the reference models based on H-atom parameters derived from neutron diffraction.

Journal Article↗

PubMed2006

Contributions to the application of the transferability principle and the multipolar modeling of H atoms: electron-density study of L-histidinium dihydrogen orthophosphate orthophosphoric acid. I.

The electron density of L-histidinium dihydrogen orthophosphate orthophosphoric acid has been determined from X-ray and neutron diffraction data at low temperature (120 K). Topological analysis of the electron density has been used to analyse the effect of the multipolar refinement strategy on the electron-density model in the hydrogen-bonding regions. The electron density at low temperature has also been used to acquire high-quality experimental thermal parameters at room temperature using the transferability principle. Molecular vibrations, TLS and normal mode analysis are discussed and studied at both temperatures.

Journal Article↗

PubMed2001

Anisotropic thermal expansion of potassium dinitramide: a variable-temperature crystallographic study.

The structure of potassium dinitramide (KDN), KN(3)O(4), has been refined in the temperature range 85-298 K from single-crystal X-ray diffraction data. The unit-cell axial lengths and the cell volume decrease linearly on cooling with the b axis being the most sensitive to the change of temperature. The beta cell angle increases with decreasing temperature. The thermal expansion of KDN is significantly anisotropic, expanding along the b axis [010] more than three times the amount parallel to any other crystallographic direction. Other eigenvectors of the thermal expansion tensor lie approximately parallel to the diagonals of the ac plane. A rigid-body analysis of the dinitramide ion using the TLS formalism was performed and shows that the thermal motion of the anion is well represented by the rigid-body model. The eigenvalues of the libration tensor show significant anisotropy, whereas the translation tensor is close to isotropic. The variation of all descriptions of the thermal motion with respect to temperature indicates an anharmonic contribution to the mean field potential. The direction of greatest unit-cell expansion coincides with the largest components of the displacement tensor of the potassium ions and the direction of the largest atomic amplitudes due to the libration of the dinitramide anions.

Journal Article↗