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PubMed1984

Murine forebrain anomalies induced by coxsackievirus B3 variants.

Neonatal or 7-day-old mice inoculated intracranially with either of two temperature-sensitive mutants (ts1, ts6) or the parent coxsackievirus B3 (CVB3) subsequently developed porencephaly or hydranencephaly. The forebrain anomaly induced depended upon age of the animal at inoculation and virus variant inoculated. Sections of brains from hydranencephalic mice revealed severe meningeal reactions, necrotizing encephalitis, and liquifactive necrosis in the cerebrum. No pathology was found in the pons, medulla, or cerebellum. Immunofluorescence studies with hyperimmune anti-CVB3 antiserum showed a random distribution of virus-infected cells in the cerebrum. Virus was recovered from several organs but little to no interferon and no anti-CVB3 neutralizing antibody were present in brain tissues. Availability of cells for replication of virus at the time of inoculation and replicative properties of each virus likely contributed to the outcome. Thus, forebrain anomalies resembling those found in infants can be induced in a murine model by select variants of coxsackievirus B3.

Animals↗
PubMed2004

Pruning of motor neuron branches establishes the DLM innervation pattern in Drosophila.

During the Drosophila life-cycle two sets of neuromuscular junctions are generated: the embryonic/larval NMJs develop during the first half, followed by the period of metamorphosis during which the adult counterpart is generated. Development of the adult innervation pattern is preceded by a withdrawal of larval NMJs, which occurs at the onset of metamorphosis, and is followed by adult-specific motor neuron outgrowth to innervate the newly developing adult fibers. Establishment of the adult innervation pattern occurs in the context of a broader restructuring of the nervous system, which results in the development of neural circuits that are necessary to carry out behaviors specific to the adult. In this article, we follow development of the dorsal longitudinal muscle (DLM) innervation pattern through metamorphosis. We find that the initial period of motor neuron elaboration is followed by a phase of extensive pruning resulting in a threefold reduction of neuromuscular contacts. This event establishes the adult pattern of second order branching. Subsequent higher order branching from the second order "contact" points generates the characteristic multiterminal innervation pattern of the DLMs. Boutons begin to appear after the pruning phase, and are much smaller than their larval counterparts. Additionally, we demonstrate that the DLM innervation is altered in the hyperexcitable double mutant, ether a go-go Shaker, and that the phenotype is suppressed by the hypoexcitable mutant, nap(ts1). Our results demonstrate that electrical activity regulates the patterning of DLM innervation during metamorphosis.

Animals↗
PubMed2006

Differential roles of two major brain structures, mushroom bodies and central complex, for Drosophila male courtship behavior.

Drosophila male courtship is a complex and robust behavior, the potential for which is genetically built into specific neural circuits in the central nervous system. Previous studies using male-female mosaics and the flies with defects in particular brain structures implicated the critical central regions involved in male courtship behavior. However, their acute physiological roles in courtship regulation still largely remain unknown. Using the temperature-sensitive Dynamin mutation, shibire(ts1), here we demonstrate the significance of two major brain structures, the mushroom bodies and the central complex, in experience-independent aspects of male courtship. We show that blocking of synaptic transmission in the mushroom body intrinsic neurons significantly delays courtship initiation and reduces the courtship activity by shortening the courtship bout length when virgin females are used as a sexual target. Interestingly, however, the same treatment affects neither initiation nor maintenance of courtship toward young males that release courtship-stimulating pheromones different from those of virgin females. In contrast, blocking of synaptic transmission in a central complex substructure, the fan-shaped body, slightly but significantly reduces courtship activity toward both virgin females and young males with little effect on courtship initiation. Taken together, our results indicate that the neuronal activity in the mushroom bodies plays an important role in responding to female-specific sex pheromones that stimulate initiation and maintenance of male courtship behavior, whereas the fan-shaped body neurons are involved in maintenance of male courtship regardless of the nature of courtship-stimulating cues.

Animals↗
PubMed2005

QM/MM modeling the Ras-GAP catalyzed hydrolysis of guanosine triphosphate.

The mechanism of the hydrolysis reaction of guanosine triphosphate (GTP) by the protein complex Ras-GAP (p21(ras) - p120(GAP)) has been modeled by the quantum mechanical-molecular mechanical (QM/MM) and ab initio quantum calculations. Initial geometry configurations have been prompted by atomic coordinates of a structural analog (PDBID:1WQ1). It is shown that the minimum energy reaction path is consistent with an assumption of two-step chemical transformations. At the first stage, a unified motion of Arg789 of GAP, Gln61, Thr35 of Ras, and the lytic water molecule results in a substantial spatial separation of the gamma-phosphate group of GTP from the rest of the molecule (GDP). This phase of hydrolysis process proceeds through the low-barrier transition state TS1. At the second stage, Gln61 abstracts and releases protons within the subsystem including Gln61, the lytic water molecule and the gamma-phosphate group of GTP through the corresponding transition state TS2. Direct quantum calculations show that, in this particular environment, the reaction GTP + H(2)O --> GDP + H(2)PO(4) (-) can proceed with reasonable activation barriers of less than 15 kcal/mol at every stage. This conclusion leads to a better understanding of the anticatalytic effect of cancer-causing mutations of Ras, which has been debated in recent years.

Catalysis↗
PubMed2007

Mechanisms of guanosine triphosphate hydrolysis by Ras and Ras-GAP proteins as rationalized by ab initio QM/MM simulations.

The hydrolysis reaction of guanosine triphosphate (GTP) by p21(ras) (Ras) has been modeled by using the ab initio type quantum mechanical-molecular mechanical simulations. Initial geometry configurations have been prompted by atomic coordinates of the crystal structure (PDBID: 1QRA) corresponding to the prehydrolysis state of Ras in complex with GTP. Multiple searches of minimum energy geometry configurations consistent with the hydrogen bond networks have been performed, resulting in a series of stationary points on the potential energy surface for reaction intermediates and transition states. It is shown that the minimum energy reaction path is consistent with an assumption of a two-step mechanism of GTP hydrolysis. At the first stage, a unified action of the nearest residues of Ras and the nearest water molecules results in a substantial spatial separation of the gamma-phosphate group of GTP from the rest of the molecule (GDP). This phase of hydrolysis process proceeds through the low barrier (16.7 kcal/mol) transition state TS1. At the second stage, the inorganic phosphate is formed in consequence of proton transfers mediated by two water molecules and assisted by the Gln61 residue from Ras. The highest transition state at this segment, TS3, is estimated to have an energy 7.5 kcal/mol above the enzyme-substrate complex. The results of simulations are compared to the previous findings for the GTP hydrolysis in the Ras-GAP (p21(ras)-p120(GAP)) protein complex. Conclusions of the modeling lead to a better understanding of the anticatalytic effect of cancer causing mutation of Gln61 from Ras, which has been debated in recent years.

Amino Acid Sequence↗
PubMed1997

Neural activity affects distribution of glutamate receptors during neuromuscular junction formation in Drosophila embryos.

Changes in the distribution and density of transmitter receptors in the postsynaptic cell are required steps for functional synapse formation. We raised antibodies against Drosophila glutamate receptors (DGluR-II) and visualized the distribution of receptors during neuromuscular junction formation in embryos. In wild-type embryos, embryonic development is complete within 22 hr after egg lying (AEL) and neuromuscular junction (NMJ) formation begins at 13 hr AEL. At the time of initial synapse formation, DGluR-IIs appeared as clusters closely associated with some muscle nuclei. Subsequently, these nonjunctional clusters dispersed while DGluR-IIs accumulated at the junctional region. In a paralytic temperature-sensitive mutant, para(ts1), neural activity decreases drastically at restrictive temperatures. When neural activity was blocked throughout synaptogenesis by rearing embryos at a restrictive temperature prior to the beginning of synaptogenesis, 12 hr AEL, the dispersal of extrajunctional clusters was significantly suppressed and no accumulation of receptors at the junction was observed at 22 hr AEL. However, when neural activity was blocked later, by rearing embryos at a restrictive temperature from 13 hr AEL, DGluR-IIs did not accumulate at the NMJ, although extrajunctional clusters dispersed normally. These findings suggest that the neural activity differentially regulates dissipation of receptor clusters in the nonjunctional region and accumulation of receptors at the junctional region.

Amino Acid Sequence↗
PubMed1996

New stimulation ligand of the adenovirus 2 protease.

The catalytic activity of the adenovirus cysteine peptidase is increased by a specific 11-amino-acid peptide adduct (GVQSLKRRRCF, referred to as pVIc). To identify additional peptides which might bind and alter the activity of the protease, a cysteine-constrained random peptide phage library was screened. Of 29 different phages which were isolated, 7 contained the consensus sequence VEGGS. Despite a superficial similarity to the substrate cleavage site of the protease, the peptide was not digested by the enzyme. VEGGS and pVIc altered protease activity similarly without sharing sequence similarity. To similar degrees, pVIc and VEGGS (a) stimulated the activity of the recombinant protease, (b) had no effect on viral protease, (c) increased the fluorescence emission of tryptophan residues in the protease, suggesting a conformational change, and (d) inhibited wt virus infection, but rescued ts1 infection at the nonpermissive temperature. The experiments also suggest that once the protease has been stimulated by one peptide, the other peptide has no further activity on the recombinant adenovirus cysteine protease, suggesting that the two peptides bring about the same change on the protease via different binding sites.

Adenoviruses, Human↗
PubMed1986

Shedding of plasma membrane fragments. Neoplastic and developmental importance.

The phenomenon of shedding of cell surface macromolecules and their importance in the cancer process has been reviewed with particular emphasis on tumor membrane fragments. With cell activation (during growth or stimulation of normal cells), there is an increase in synthesis, processing, insertion, and eventual, intact release of certain membrane proteins, some of which are proteases. In cancer, these events occur spontaneously and without the temporal, physiological, or hormonal control apparent in normal cells. In a previous review (Black, 1980), many of the consequences of shedding tumor products were described, but the nature of the shed material was not clear. It now seems likely that some proteolytic, procoagulant, and immunosuppressive activities of shed material are contained within membrane particulate material (vesicles). Under normal conditions, shed membrane material (particularly proteolytic activity) may be necessary for cell movement and tissue remodeling which occur during embryogenesis. In cancer, shedding of plasma membrane fragments may be responsible for the key features of the malignant phenotype by the presence and release of proteolytic activity producing the separation of tumor cells from the primary site, invasion of the surrounding tissues by tumor cells, and formation of distinct metastases. Shed plasma membrane fragments may play a central role in tumor progression by enhancing the steps of the metastatic cascade, in particular by increasing tumor embolus formation (by enhanced fibrin deposition and platelet aggregation) and vascular permeability, as well as increasing basement membrane degradation. Shed membrane fragments (containing tumor antigens) either alone or complexed with antibody, may be responsible for blocking the cell-mediated immune reaction by the formation of "blocking factors" or by suppressing the formation of cytotoxic immune pathways. The suppression of immune response formation may be due to blocking of antigen presentation by macrophages (due to inhibition of Ia) or by the induction of Ts1 cells.

Animals↗
PubMed2006

Influence of proinflammatory cytokines and chemokines on the neuropathogenesis of oncornavirus and immunosuppressive lentivirus infections.

Retroviral infection of the CNS can lead to severe debilitating neurological diseases in humans and other animals. Four general types of pathogenic effects with various retroviruses have been observed including: hemorrhage (TR1.3), spongiform encephalopathy (CasBrE, FrCasE, PVC211, NT40, Mol-ts1), demyelination with inflammatory lesions (HTLV-1, visna, CAEV), and encephalopathy with gliosis and proinflammatory chemokines and cytokines, usually with microglial giant cells and nodules [human immunodeficiencyvirus (HIV), feline immunodeficiencyvirus (FIV), simian immunodeficiency virus (SIV), Fr98]. This review focuses on this fourth group of retroviruses. In this latter group, proinflammatory cytokine and chemokine upregulation accompanies the disease process, and may influence pathogenesis by direct effects on resident CNS cells. The review first discusses the Fr98 murine polytropic virus system with particular reference to the roles of cytokines and chemokines in the pathogenic process. The Fr98 data are then compared and contrasted to the cytokine and chemokine data in the lentivirus systems, HIV, SIV, and FIV. Finally, various mechanisms are presented by which tumor necrosis factor (TNF) and several chemokines may alter the pathogenesis of retrovirus infection of the CNS.

Animals↗
PubMed1976

A transducing bacteriophage lambda carrying the structural gene for elongation factor Ts.

A specialized transducing bacteriophage lambdadpolCdap D-9 has been isolated that carries the structural gene for EF-Ts1 (tsf). The presence of EF-Ts among the proteins synthesized under the direction of this phage in UVL-inactivated cells has been detected by two-dimensional gel electrophoresis and has been verified by antibody precipitation. In an induced lysogen of this phage the relative rate of synthesis of EF-Ts is increased 4-fold. Evidence is presented which suggest that the structural genes for ribosomal protein S2 (rpsB) and RNA polymerase sigma factor (sit) also lies on lambdadpolCdap D-9.

Coliphages↗
PubMed1980

High efficiency temperature-sensitive amber suppressor strains of Escherichia coli K12: construction and characterization of recombinant strains with suppressor-enhancing mutations.

A set of eight strains combining the supD43,74 ts1 suppressor gene with alleles of three suppressor-enhancing (sue) genes have been constructed and characterized. The sue mutations work cooperatively to raise suppressor activity and together raise the activity of the supD43,74-encoded suppressor 40-fold. These strains further expand the utility of the ts suppressor system by providing as much as 100% suppressor activity at temperatures at or below 20 degrees C to as little as 0.015% suppressor activity at 43 degrees C.

Cold Temperature↗
PubMed1980

The role of the HCR system in the repair of lethal lesions of Bacillus subtilis phages and their transfecting DNA damaged by radiation and alkylating agents.

The role of the HCR system in the repair of prelethal lesions induced by UV-light, gamma-rays and alkylating agents was studied in the Bacillus subtilis SPP1 phage, its thermosensitive mutants (N3, N73 and ts1) and corresponding infectious DNA. The survival of phages and their transfecting DNA after treatment with UV light is substantially higher in hcr+ cells than in hcr cells, the differences being more striking in intact phages than in their transfecting DNA's. Repair inhibitors reduce the survival in hcr+ cells: caffeine lowers the survival of UV-irradiated phage SPP1 in exponentially growing hcr+ cells but has no effect on its survival in competent hcr+ cells; acriflavin and ethidium bromide decrease the survival of UV-irradiated SPP1 phage in both exponentially growing and competent hcr+ cells to the level of survival observed in hcr cells; moreover, ethidium bromide lowers the number of infective centres in hcr+ cells of UV-irradiated DNA of the SPP1 phage. Repair inhibitors do not lower the survival of UV-irradiated phages or their DNA in hcr cells. The repair mechanism under study repairs also lesions induced by polyfunctional alkylating agents in transfecting DNA's of B. subtilis phages but is not functional with lesions induced by these agents in free phages and lesions caused in phages and their DNA by ethyl methanesulphonate or gamma-rays.

Alkylating Agents↗
PubMed2001

The cytochrome b gene as a phylogenetic marker: the limits of resolution for analyzing relationships among cichlid fishes.

The mitochondrial cytochrome b (cyt-b) gene is widely used in systematic studies to resolve divergences at many taxonomic levels. The present study focuses mainly on the utility of cyt-b as a molecular marker for inferring phylogenetic relationship at various levels within the fish family Cichlidae. A total of 78 taxa were used in the present analysis, representing all the major groups in the family Cichlidae (72 taxa) and other families from the suborders Labroidei and Percoidei. Gene trees obtained from cyt-b are compared to a published total evidence tree derived from previous studies. Minimum evolution trees based on cyt-b data resulted in topologies congruent with all previous analyses. Parsimony analyses downweighting transitions relative to transversions (ts1:tv4) or excluding transitions at third codon positions resulted in more robust bootstrap support for recognized clades than unweighted parsimony. Relative rate tests detected significantly long branches for some taxa (LB taxa) which were composed mainly by dwarf Neotropical cichlids. An improvement of the phylogenetic signal, as shown by the four-cluster likelihood mapping analysis, and higher bootstrap values were obtained by excluding LB taxa. Despite some limitations of cyt-b as a phylogenetic marker, this gene either alone or in combination with other data sets yields a tree that is in agreement with the well-established phylogeny of cichlid fish.

Animals↗
PubMed2004

The roles of endoscopic ultrasonography in the diagnosis of pancreatic tumors.

BACKGROUND: Over 20 years have passed since the development of endoscopic ultrasonography (EUS), and this technique is now widely used for the diagnosis of digestive and pancreaticobiliary diseases. EUS plays a number of roles in the clinical diagnosis of pancreatic tumors including detection of small tumors, differential diagnosis of tumors, and evaluation of tumor extent. METHODS: We evaluated the ability of EUS to detect pancreatic carcinoma in comparison with ultrasonography (US) and computed tomography (CT). RESULTS: The overall tumor detection rates were: US, 69%; CT, 79%; and EUS, 97%. With a tumor size smaller than 2 cm (TS1), the detection rate by EUS was as high as 100%, in contrast to 60% and 50% for US and CT, respectively, except for carcinoma in situ. However, EUS has some pitfalls. The EUS imaging technique is not always easy, EUS has limited penetration, and EUS alone cannot accurately differentiate malignancy from inflammation. CONCLUSIONS: The following points are the future themes of EUS. (1) It will be necessary to foster a large number of operators and to establish a standard EUS scanning technique. (2) Development of a new instrument with high resolution and deep penetration is anticipated. (3) Development of a new medium that can be infused into a vein and that allows diagnosis from B-mode images is much anticipated.

Diagnosis, Differential↗
PubMed1983

Transfer of tyrosinase to melanosomes in Harding-Passey mouse melanoma.

The transfer of tyrosinase from microsomes into melanosomes, without passing through the cytosol in the Harding-Passey mouse melanoma cell, was confirmed by experiments carried out using a combination of radioisotope tracer techniques and immunoprecipitation. 3H-Labeled amino acid incorporation into tyrosinase present in the microsome, melanosome, and soluble fractions confirmed the precursor-product relationship of the enzyme in the microsome fraction and in the melanosome fraction. However, two forms of the enzyme, Ts1- and Ts2-tyrosinase, separated from the soluble fraction by polyacrylamide gel electrophoresis, were shown to play no role in the transfer since little or no incorporation of radioactivity into tyrosinase in this fraction was found. It is suggested that most tyrosinase observed in the soluble fraction does not leak from the melanosomes or the microsomes during homogenization, but comes from necrotic tumor cells. It appears that melanosomal and microsomal tyrosinase might be released from the membrane of necrotic cells modified by various degradation enzymes, considering the data on the recovery of tyrosinase from the soluble fraction, where one-third of total enzyme activity in the postnuclear fraction could not be increased, even when the postnuclear fraction of the tumor was further homogenized radically.

Animals↗
PubMed1983

Localization of the two free thiol groups in the porcine pancreatic alpha-amylase I sequence.

Porcine pancreatic alpha-amylase I, a single 496 residue long polypeptide chain, contains 5 disulfide bridges and 2 free -SH groups. The conditions for specific blocking of native amylase either with radioactive N-ethyl maleimide or with labeled iodoacetic acid were determined. Under these conditions 2 moles of blocking reagent are incorporated per mole of amylase. [14C]-S-succinimido amylase was cleaved by CNBr and the resulting peptides were purified. Only one of them the CNBr 2 + 3 peptide (178 residues) was found labeled. Ts1 a 33-residue peptide containing the whole radioactivity was purified from the tryptic digest of this large fragment. After reduction and carboxymethylation Ts1A, (22 residues) was obtained which contains 2 moles of succinyl-Cys and one mole of CM-Cys per mole of peptide. Chymotryptic digestion of Ts1A yielded 2 equally labeled peptides: C1 (16 residues) and C2 (6 residues). Automated sequencing of both peptides and counting of the PTH-amino acids shows that the free cysteines are only 15 residues apart in the sequence.

Amino Acid Sequence↗
PubMed1992

RNA hydrolysis via an oxyphosphorane intermediate.

From calculations of a model reaction scheme for base-catalyzed RNA hydrolysis, a pentacoodinate dianionic intermediate 2a (Storer, et al., J. Am. Chem. Soc., 1991, 113, 5216-5219) as well as two transition states, TS1 and TS2, to the intermediate have been located by ab initio calculations at the 3-21G* level. Although the intermediate, which has the well depth on the order of kBT, is unlikely to be kinetically significant, the overall rate-limiting transition state structure TS2 obtained at 3-21G* level is very close to the corresponding structure at the STO-3G level; it has an extended P-O(5') bond breaking character. These gas-phase calculation results are used to qualitatively interpret mutagenesis results of Barnase and RNase T1 where water molecules are absent from the active site.

Bacterial Proteins↗
PubMed1985

Splenic I-J-bearing antigen-presenting cells in activation of suppression: further characterization.

A set of I-J-bearing murine splenic antigen-presenting cells (APC) has been found to be responsible for first order suppressor cell (Ts1, afferent suppressor cell) activation in the azobenzenearsonate (ABA) hapten system after intravenous administration. Suppressor cells induced by this set of hapten-coupled cells do not function in the efferent phase of the delayed hypersensitivity (DTH) response. The functional activity of this novel APC to activate afferent suppressor cells was resistant to a dose of ultraviolet radiation (UVR) sufficient to largely abrogate the ability of splenic APC to immunize for a DTH response. It was also found that the previously described splenic I-J-bearing APC needed for third-order suppressor cell (Ts3, effector-suppressor cell) activation is adherent and UVR resistant. The sets of I-J-bearing APC appear to be crucial elements in the activation of suppression and thus in determining the balance between immunologic reactivity and unresponsiveness. Furthermore, the UVR resistance of this set of novel APC may be relevant to the in vivo effects of UVR exposure to mice.

Animals↗