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‣ Breast imaging technology: Imaging biochemistry - applications to breast cancer

Ronen, Sabrina M; Leach, Martin O
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
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The use of magnetic resonance spectroscopy (MRS) to investigate breast tumour biochemistry in vivo is reviewed. To this end, results obtained both from patients in vivo and from tumour extracts and model systems are discussed. An association has been observed between transformation and an increase in phosphomonoesters (PMEs) detected in the 31P MRS spectrum, as well as an increase in choline-containing metabolites detected in the 1H spectrum. A decrease in PME content after treatment is associated with response to treatment as assessed by tumour volume. Experiments in model systems aimed at understanding the underlying biochemical processes are presented, as well as data indicating the usefulness of MRS in monitoring the uptake and metabolism of some chemotherapeutic agents.

‣ NEW EMBO MEMBER’S REVIEW: Molecular background of progressive myoclonus epilepsy

Lehesjoki, Anna-Elina
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 15/07/2003 Português
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Research on human inherited diseases provides a powerful tool to identify an intrinsically important subset of genes vital to healthy functioning of the organism. Progressive myoclonus epilepsies (PMEs) are a group of rare inherited disorders characterized by the association of epilepsy, myoclonus and progressive neurological deterioration. Significant progress has been made in elucidating the molecular background of PMEs. Here, progress towards understanding the molecular pathogenesis of PMEs is reviewed using the most common single cause of PME, Unverricht–Lundborg disease, as an example. Mutations in the gene encoding cystatin B (CSTB), a cysteine protease inhibitor, are responsible for the primary defect in Unverricht–Lundborg disease. CSTB-deficient mice, produced by targeted disruption of the mouse Cstb gene, display a phenotype similar to the human disease, with progressive ataxia and myoclonic seizures. The mice show neuronal atrophy, apoptosis and gliosis as well as increased expression of apoptosis and glial activation genes. Although significant advances towards understanding the molecular basis of Unverricht–Lundborg disease have been achieved, the physiological function of CSTB and the molecular pathogenesis of the disease remain unknown.

‣ A phosphorus nuclear magnetic resonance study of metabolites and intracellular pH in rabbit vascular smooth muscle.

Spurway, N C; Wray, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1987 Português
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1. 31P nuclear magnetic resonance (n.m.r.) spectroscopy was used to investigate metabolites, intracellular pH (pHi) and the effects of pHi on tone in rabbit blood vessels. The vessels were bathed in mammalian Ringer solution and maintained at 20 degrees C while inside the spectrometer. 2. Vascular spectra showed relatively low phosphocreatine (PCr) concentrations compared to skeletal muscle. The [PCr]/[ATP] ratio was only 1.32 +/- 0.09 (n = 7). There was also a prominent phosphomonoester (PME) peak. Similar features have been reported for other smooth muscles examined by 31P n.m.r. 3. The [PCr] was higher and the inorganic phosphate (Pi) concentration lower than values deduced from chemical analysis of arterial extracts. However, the [PCr] value fell within the range obtained for other smooth muscles when studied by 31P n.m.r. 4. Measurement of pHi under control conditions (external pH 7.25) gave a mean value of 7.19 +/- 0.03 at 20 degrees C (n = 5). Metabolic inhibition brought about by 0.5 mM-cyanide and 0.2 mM-fluoride did not significantly alter pHi. At higher inhibitor concentrations (3 and 1 mM respectively) there was a significant acidosis. 5. The effects of NH4Cl upon pH were investigated in metabolically inhibited preparations. During 10 min applications of 30 mM-NH4Cl (isosmotically substituted for NaCl) the pHi rose; during subsequent NH4Cl removal it fell below control values. In the least inhibited tissues the total pHi excursion between NH4Cl applications and removals was 0.5 unit. 6. Rabbit ear vessels have been found to increase vascular tone during manoeuvres which were expected to decrease pHi. From the direct measurement of pHi reported in this study...

‣ Prolonged Outbreak of Infection Due to TEM-21-Producing Strains of Pseudomonas aeruginosa and Enterobacteria in a Nursing Home

Dubois, Véronique; Arpin, Corinne; Noury, Patrick; Andre, Catherine; Coulange, Laure; Quentin, Claudine
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Publicado em /08/2005 Português
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Over a 6-year period, 24 extended-spectrum β-lactamase (ESBL)-producing isolates of Pseudomonas aeruginosa were collected from 18 patients living in a nursing home. These isolates had a delayed development of a red pigment and exhibited a similar antibiotype (resistance to all β-lactams except for imipenem and to gentamicin, tobramycin, netilmicin, ciprofloxacin, and rifampin) associated with the production of the TEM-21 β-lactamase and a type II 3′-N-aminoglycoside acetyltransferase [AAC(3)-II] enzyme. Surprisingly, serotyping showed that these isolates belonged to four successive serotypes (P2, P16, P1, and PME), although molecular typing by PCR methods and pulsed-field gel electrophoresis yielded identical or similar profiles. Moreover, in all isolates the blaTEM-21 gene was part of a chromosomally located Tn801 transposon truncated by an IS6100 element inserted within the resolvase gene, and the aac(3)-II gene was adjacent to this structure. During the same period, 17 ESBL-producing isolates of enterobacteria were also collected from 10 of these patients. These isolates harbored a similar large plasmid that contained the blaTEM-21 and the aac(3)-II genes and that conferred additional resistance to sulfonamides and chloramphenicol...

‣ NMR structure refinement and dynamics of the K+-[d(G3T4G3)]2 quadruplex via particle mesh Ewald molecular dynamics simulations.

Strahan, G D; Keniry, M A; Shafer, R H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1998 Português
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The solution structure and dynamical properties of the potassium-stabilized, hairpin dimer quadruplex formed by the oligonucleotide d(G3T4G3) have been elucidated by a combination of high-resolution NMR and molecular dynamics simulations. Refinement calculations were carried out both in vacuo, without internally coordinated K+ cations, and in explicit water, with internally coordinated K+ cations. In the latter case, the electrostatic interactions were calculated using the particle mesh Ewald (PME) method. The NMR restraints indicate that the K+ quadruplex has a folding arrangement similar to that formed by the same oligonucleotide in the presence of sodium, but with significant local differences. Unlike the Na+ quadruplex, the thymine loops found in K+ exhibit considerable flexibility, and appear to interconvert between two preferred conformations. Furthermore, the NMR evidence points toward K+-stabilized guanine quartets of slightly larger diameter relative to the Na+-stabilized structure. The characteristics of the quartet stem are greatly affected by the modeling technique employed: caged cations alter the size and symmetry of the quartets, and explicit water molecules form hydration spines within the grooves. These results provide insight into those factors that determine the overall stability of hairpin dimer quadruplexes and the effects of different cations in modulating the relative stability of the dimeric hairpin and linear...

‣ An atomic model for the pleated beta-sheet structure of Abeta amyloid protofilaments.

Li, L; Darden, T A; Bartolotti, L; Kominos, D; Pedersen, L G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1999 Português
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Synchrotron x-ray studies on amyloid fibrils have suggested that the stacked pleated beta-sheets are twisted so that a repeating unit of 24 beta-strands forms a helical turn around the fibril axis (. J. Mol. Biol. 273:729-739). Based on this morphological study, we have constructed an atomic model for the twisted pleated beta-sheet of human Abeta amyloid protofilament. In the model, 48 monomers of Abeta 12-42 stack (four per layer) to form a helical turn of beta-sheet. Each monomer is in an antiparallel beta-sheet conformation with a turn located at residues 25-28. Residues 17-21 and 31-36 form a hydrophobic core along the fibril axis. The hydrophobic core should play a critical role in initializing Abeta aggregation and in stabilizing the aggregates. The model was tested using molecular dynamics simulations in explicit aqueous solution, with the particle mesh Ewald (PME) method employed to accommodate long-range electrostatic forces. Based on the molecular dynamics simulations, we hypothesize that an isolated protofilament, if it exists, may not be twisted, as it appears to be when in the fibril environment. The twisted nature of the protofilaments in amyloid fibrils is likely the result of stabilizing packing interactions of the protofilaments. The model also provides a binding mode for Congo red on Abeta amyloid fibrils. The model may be useful for the design of Abeta aggregation inhibitors.

‣ Molecular dynamics simulations of solvated yeast tRNA(Asp).

Auffinger, P; Louise-May, S; Westhof, E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1999 Português
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Transfer RNA molecules are involved in a variety of biological processes, implying complex recognition events with proteins and other RNAs. From a structural point of view, tRNAs constitute a reference system for studying RNA folding and architecture. A deeper understanding of their structural and functional properties will derive from our ability to model accurately their dynamical behavior. We present the first dynamical model of a fully neutralized and solvated tRNA molecule over a 500-ps time scale. Starting from the crystallographic structure of yeast tRNA(Asp), the 75-nucleotide molecule was modeled with 8055 water molecules and 74 NH4+ counterions, using the AMBER4.1 program and the particle mesh Ewald (PME) method for the treatment of long-range electrostatic interactions. The calculations led to a dynamically stable model of the tRNA molecule. During the simulation, all secondary and tertiary base pairs are maintained while a certain lability of base triples in the tRNA core is observed. This lability was interpreted as resulting from intrinsic factors associated with the "weaker" hydrogen bonding patterns seen in these base triples and from an altered ionic environment of the tRNA molecule. Calculated thermal factors are used to compare the dynamics of the tRNA in solution and in the crystal. The present molecular dynamics simulation of a complex and highly charged nucleic acid molecule attests to the fact that simulation methods are now able to investigate not only the dynamics of proteins...

‣ The defect seen in the phosphatidylinositol hydrolysis pathway in HIV-infected lymphocytes and lymphoblastoid cells is due to inhibition of the inositol 1,4,5-trisphosphate 1,3,4,5-tetrakisphosphate 5-phosphomonoesterase.

Nye, K E; Riley, G A; Pinching, A J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1992 Português
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Lymphocytes infected in vivo with HIV or lymphoblastoid cells exposed in vitro to either HIV or its envelope glycoprotein (gp120) show a defect in inositol polyphosphate-mediated signal transduction together with an associated abnormality in intracellular calcium regulation. The defect in patients reverses after treatment with the anti-retroviral agent zidovudine (AZT). We present evidence that the defect is at the level of the Ins (1,3,4,5)P4 5-phosphomonoesterase (PME) in these cells and that, though elevation of the intracellular ATP level partially down-regulates the activity of this enzyme, such changes alone are unable to account for the complete inhibition seen in HIV-infected cells.

‣ Inhibitory Activities of Three Classes of Acyclic Nucleoside Phosphonates against Murine Polyomavirus and Primate Simian Virus 40 Strains▿

Lebeau, Ilya; Andrei, Graciela; Krečmerová, Marcela; De Clercq, Erik; Holý, Antonin; Snoeck, Robert
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Português
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Murine polyomavirus and simian virus 40 were used to evaluate the potencies of the compounds of three classes of acyclic nucleoside phosphonates: (i) the original HPMP (3-hydroxy-2-phosphonomethoxypropyl) and PME (2-phosphonomethoxyethyl) derivatives, (ii) the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (DAPy) derivatives, and (iii) a new class of HPMP derivatives containing a 5-azacytosine moiety. The last class showed the highest activities and selectivities against both polyomaviruses.

‣ Letter: Properties of PME.

Bell, J. I.; Yee, R.; Cook, D. A.; Paton, D. M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 07/09/1974 Português
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‣ Energetics of nutrition and polyamine-related tumor growth alterations in experimental cancer.

Westin, T.; Soussi, B.; Idström, J. P.; Lindnér, P.; Edström, S.; Lydén, E.; Gustavsson, B.; Hafström, L.; Lundholm, K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1993 Português
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The aim of this study was to evaluate whether food intake modulates experimental tumour growth by acute alterations in the energy state and blood flow of the tumour, and if so whether such changes are related to alterations in the enzyme ornithinedecarboxylase (ODC) and DNA synthesis. Inbred mice (C57BL/J) bearing a syngeneic undifferentiated and rapidly growing tumour were used. The tumour levels of high energy phosphates were measured in vivo by 31-P-NMR spectroscopy and biochemically following tissue extraction. DNA synthesis was estimated by measuring the incorporation of bromodeoxy-uridine into tumour DNA. Difluoro-methylornithine (DFMO) was used to inhibit ODC-activity. Tumour blood flow was estimated by a 132Xe local clearance technique. Tumour progression was associated with a significant decrease in tumour tissue high energy phosphates. Acute starvation decreased DNA-synthesis and tumour energy charge as well as its PCr/Pi which were rapidly normalised during subsequent refeeding. These changes were related to similar alterations in tumour blood flow. The inorganic phosphate (Pi) resonance and the resonances in the phosphomonoester (PME) region were considerably increased in tumour tissue. Inhibition of ODC-activity by DFMO decreased DNA-synthesis...

‣ 31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply.

Lyng, H.; Olsen, D. R.; Southon, T. E.; Rofstad, E. K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1993 Português
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Six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice were subjected to 31P-nuclear magnetic resonance (31P-NMR) spectroscopy in vivo. The following resonances were detected: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and nucleoside triphosphate gamma, alpha and beta (NTP gamma, alpha and beta). The main purpose of the work was to search for possible relationships between 31P-NMR resonance ratios and tumour pH on the one hand and blood supply per viable tumour cell on the other. The latter parameter was measured by using the 86Rb uptake method. Tumour bioenergetic status [the (PCr + NTP beta)/Pi resonance ratio], tumour pH and blood supply per viable tumour cell decreased with increasing tumour volume for five of the six xenograft lines. The decrease in tumour bioenergetic status was due to a decrease in the (PCr + NTP beta)/total resonance ratio as well as an increase in the Pi/total resonance ratio. The decrease in the (PCr + NTP beta)/total resonance ratio was mainly a consequence of a decrease in the PCr/total resonance ratio for two lines and mainly a consequence of a decrease in the NTP beta/total resonance ratio for three lines. The magnitude of the decrease in the (PCr + NTP beta)/total resonance ratio and the magnitude of the decrease in tumour pH were correlated to the magnitude of the decrease in blood supply per viable tumour cell. Tumour pH decreased with decreasing tumour bioenergetic status...

‣ The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours.

Burney, I. A.; Maxwell, R. J.; Griffiths, J. R.; Field, S. B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1991 Português
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Using 31P NMR spectroscopy, changes in tumour metabolic status were studied in a transplanted rat fibrosarcoma following the administration of vasodilators. Mean Arterial Blood Pressure (MABP) was monitored simultaneously. Two vasodilators were studied, prazosin and CGRP, which altered the NMR parameters Pi/sigma P, beta NTP,Pi, PCr/Pi and PME/Pi in a dose dependent manner. There was a good correlation between the various NMR parameters; for analysis, Pi/sigma P was used for convenience. With increasing doses of vasodilator, Pi/sigma P increased and the MABP decreased. Reduction in pHNMR showed a correlation with decreasing MABP following the administration of prazosin but not after CGRP. Both prazosin and CGRP produced changes in 31P NMR spectra consistent with a reduction in tumour blood flow. The results for prazosin and CGRP were comparable and showed a 15-20% increase in Pi/sigma P for a 20% reduction in MABP. These results were compared with those from hydralazine. With hydralazine an acceptable reduction in blood pressure (up to approximately 25%) has little effect and may even alter NMR parameters consistent with an increase in blood flow, a reduction of approximately 40% is required for a significant decrease in flow. Both prazosin and CGRP are shown to be far more effective than hydralazine in causing tumour hypoxia at a clinically acceptable reduction in blood pressure. CGRP may be the more suitable for clinical use because of its short half life...

‣ Scent evolution in Chinese roses

Scalliet, Gabriel; Piola, Florence; Douady, Christophe J.; Réty, Stéphane; Raymond, Olivier; Baudino, Sylvie; Bordji, Karim; Bendahmane, Mohammed; Dumas, Christian; Cock, J. Mark; Hugueney, Philippe
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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The phenolic methyl ether 3,5-dimethoxytoluene (DMT) is a major scent compound of many modern rose varieties, and its fragrance participates in the characteristic “tea scent” that gave their name to Tea and Hybrid Tea roses. Among wild roses, phenolic methyl ether (PME) biosynthesis is restricted to Chinese rose species, but the progenitors of modern roses included both European and Chinese species (e.g., Rosa chinensis cv Old Blush), so this trait was transmitted to their hybrid progeny. The last steps of the biosynthetic pathways leading to DMT involve two methylation reactions catalyzed by the highly similar orcinol O-methyltransferases (OOMT) 1 and 2. OOMT1 and OOMT2 enzymes exhibit different substrate specificities that are consistent with their operating sequentially in DMT biosynthesis. Here, we show that these different substrate specificities are mostly due to a single amino acid polymorphism in the phenolic substrate binding site of OOMTs. An analysis of the OOMT gene family in 18 species representing the diversity of the genus Rosa indicated that only Chinese roses possess both the OOMT2 and the OOMT1 genes. In addition, we provide evidence that the Chinese-rose-specific OOMT1 genes most probably evolved from an OOMT2-like gene that has homologues in the genomes of all extant roses. We propose that the emergence of the OOMT1 gene may have been a critical step in the evolution of scent production in Chinese roses.

‣ Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice

Ortega-Gutiérrez, Silvia; Leung, Donmienne; Ficarro, Scott; Peters, Eric C.; Cravatt, Benjamin F.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 02/07/2008 Português
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‣ Expression patterns of cell wall-modifying genes from banana during fruit ripening and in relationship with finger drop

Mbéguié-A-Mbéguié, D.; Hubert, O.; Baurens, F. C.; Matsumoto, T.; Chillet, M.; Fils-Lycaon, B.; Sidibé-Bocs, S.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Few molecular studies have been devoted to the finger drop process that occurs during banana fruit ripening. Recent studies revealed the involvement of changes in the properties of cell wall polysaccharides in the pedicel rupture area. In this study, the expression of cell-wall modifying genes was monitored in peel tissue during post-harvest ripening of Cavendish banana fruit, at median area (control zone) and compared with that in the pedicel rupture area (drop zone). To this end, three pectin methylesterase (PME) and seven xyloglucan endotransglycosylase/hydrolase (XTH) genes were isolated. The accumulation of their mRNAs and those of polygalaturonase, expansin, and pectate lyase genes already isolated from banana were examined. During post-harvest ripening, transcripts of all genes were detected in both zones, but accumulated differentially. MaPME1, MaPG1, and MaXTH4 mRNA levels did not change in either zone. Levels of MaPME3 and MaPG3 mRNAs increased greatly only in the control zone and at the late ripening stages. For other genes, the main molecular changes occurred 1–4 d after ripening induction. MaPME2, MaPEL1, MaPEL2, MaPG4, MaXTH6, MaXTH8, MaXTH9, MaEXP1, MaEXP4, and MaEXP5 accumulated highly in the drop zone, contrary to MaXTH3 and MaXTH5...

‣ Noninvasive Detection of Lentiviral-Mediated Choline Kinase Targeting In a Human Breast Cancer Xenograft

Balaji, Krishnamachary; Glunde, Kristine; Wildes, Flonne; Mori, Noriko; Takagi, Tomoyo; Raman, Venu; Bhujwalla, Zaver M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Elevated phosphocholine (PC) and total choline metabolites are widely established characteristics of most cancer cells including breast cancer. Effective silencing of choline kinase (chk), the enzyme that converts choline to phosphocholine, is associated with reduced tumor growth. The functional importance and down regulation of chk using RNAi has been previously established. Here, we report on the preclinical evaluation of lentiviral vector-mediated downregulation of choline kinase (chk) using short hairpin RNA (shRNA), in established tumors derived from human breast cancer cells. Concentrated lentivirus expressing shRNA against chk was injected intravenously in the tail vein of MDA-MB-231 tumor bearing female severe combined immunodeficient (SCID) mice. Transduction efficiency in cells and tumors in vivo, was assessed optically by enhanced green fluorescent protein (EGFP) expression and additionally from chk mRNA and protein levels. An 80% reduction in chk mRNA and protein was achieved following almost 100% transduction efficiency in cells. Post-transduction with chk-shRNA, 1H magnetic resonance spectroscopy (MRS) of cell and tumor extracts showed decreases in PC and total choline levels (P < 0.01 and 0.05 respectively) in comparison to controls. PC levels were monitored non-invasively by 31P MRS in tumors...

‣ Nanoscale Dewetting Transition in Protein Complex Folding

Hua, Lan; Huang, Xuhui; Liu, Pu; Zhou, Ruhong; Berne, Bruce J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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In a previous study, a surprising drying transition was observed to take place inside the nanoscale hydrophobic channel in the tetramer of the protein melittin. The goal of this paper is to determine if there are other protein complexes capable of displaying a dewetting transition during their final stage of folding. We searched the entire protein data bank (PDB) for all possible candidates, including protein tetramers, dimers, and two-domain proteins, and then performed the molecular dynamics (MD) simulations on the top candidates identified by a simple hydrophobic scoring function based on aligned hydrophobic surface areas. Our large scale MD simulations found several more proteins, including three tetramers, six dimers, and two two-domain proteins, which display a nanoscale dewetting transition in their final stage of folding. Even though the scoring function alone is not sufficient (i.e., a high score is necessary but not sufficient) in identifying the dewetting candidates, it does provide useful insights into the features of complex interfaces needed for dewetting. All top candidates have two features in common: (1) large aligned (matched) hydrophobic areas between two corresponding surfaces, and (2) large connected hydrophobic areas on the same surface. We have also studied the effect on dewetting of different water models and different treatments of the long-range electrostatic interactions (cutoff vs PME)...

‣ PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease

Turnbull, Julie; DePaoli-Roach, Anna A.; Zhao, Xiaochu; Cortez, Miguel A.; Pencea, Nela; Tiberia, Erica; Piliguian, Mark; Roach, Peter J.; Wang, Peixiang; Ackerley, Cameron A.; Minassian, Berge A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Lafora disease is the most common teenage-onset neurodegenerative disease, the main teenage-onset form of progressive myoclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. Polyglucosan formation is catalyzed by glycogen synthase, which is activated through dephosphorylation by glycogen-associated protein phosphatase-1 (PP1). Here we remove PTG, one of the proteins that target PP1 to glycogen, from mice with Lafora disease. This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases.

‣ Involvement of TBL/DUF231 proteins into cell wall biology

Bischoff, Volker; Selbig, Joachim; Scheible, Wolf-Rüdiger
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
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Through map-based cloning we determined TRICHOME BIREFRINGENCE (TBR) belongs to a plant-specific, yet anonymous gene family with 46 members in Arabidopsis thaliana. These genes all encode the domain of unknown function 231 (DUF231). TBR and its homolog TRICHOME BIREFRINGENCE-LIKE3 (TBL3) are transcriptionally coordinated with CELLULOSE SYNTHASE (CESA) genes, and loss of TBR or TBL3 results in decreased levels of crystalline secondary wall cellulose in trichomes and stems, respectively. Loss of TBR or TBL3 further results in increased pectin methylesterase (PME) activity and reduced pectin esterification in etiolated Arabidopsis hypocotyls. Together, the results suggest that DUF231 proteins might function in the maintenance of pectin- and probably homogalacturonan esterification, and that this is a requirement for normal secondary wall cellulose synthesis, at least in some tissues and organs. Here we expand the discussion about the role of TBL/DUF231 proteins in cell wall biology based on sequence and structure analyses. Our analysis revealed structural similarities of TBR with a rhamnogalacturonan acetylesterase (RGAE) of Aspergillus aculeatus and the protein LUSTRIN A-LIKE (Oryza sativa). The implications of these findings in regard to TBL functions are discussed.