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PubMed1999

Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila.

CpG methylation is essential for mouse development as well as gene regulation and genome stability. Many features of mammalian DNA methylation are consistent with the action of a de novo methyltransferase that establishes methylation patterns during early development and the post-replicative maintenance of these patterns by a maintenance methyltransferase. The mouse methyltransferase Dnmt1 (encoded by Dnmt) shows a preference for hemimethylated substrates in vitro, making the enzyme a candidate for a maintenance methyltransferase. Dnmt1 also has de novo methylation activity in vitro, but the significance of this finding is unclear, because mouse embryonic stem (ES) cells contain a de novo methylating activity unrelated to Dnmt1 (ref. 10). Recently, the Dnmt3 family of methyltransferases has been identified and shown in vitro to catalyse de novo methylation. To analyse the function of these enzymes, we expressed Dnmt and Dnmt3a in transgenic Drosophila melanogaster. The absence of endogenous methylation in Drosophila facilitates detection of experimentally induced methylation changes. In this system, Dnmt3a functioned as a de novo methyltransferase, whereas Dnmt1 had no detectable de novo methylation activity. When co-expressed, Dnmt1 and Dnmt3a cooperated to establish and maintain methylation patterns. Genomic DNA methylation impaired the viability of transgenic flies, suggesting that cytosine methylation has functional consequences for Drosophila development.

Animals↗

PubMed1995

Predicting coiled coils by use of pairwise residue correlations.

A method is presented that predicts coiled-coil domains in protein sequences by using pairwise residue correlations obtained from a (two-stranded) coiled-coil database of 58,217 amino acid residues. A program called PAIRCOIL implements this method and is significantly better than existing methods at distinguishing coiled coils from alpha-helices that are not coiled coils. The database of pairwise residue correlations suggests structural features that stabilize or destabilize coiled coils.

Algorithms↗

PubMed2000

Characterization of structural features that mediate the tethering of Caenorhabditis elegans protein kinase A to a novel A kinase anchor protein. Insights into the anchoring of PKAI isoforms.

Caenorhabditis elegans protein kinase A (PKAI(CE)) is tethered to organelles in vivo. A unique A kinase anchor protein (AKAP(CE)) avidly binds the RI-like regulatory subunits (R(CE)) of PKAI(CE) and stringently discriminates against RIIalpha and RIIbeta subunits, the preferred ligands for classical AKAPs. We elucidated structural features that stabilize AKAP(CE).R(CE) complexes and confer atypical R isoform specificity on the anchor protein. Three large aliphatic amino acids (Leu(236), Ile(248), and Leu(252)) in the tethering domain of AKAP(CE) (residues 236-255) are crucial for ligation of R(CE). Their side chains apparently generate a precisely configured hydrophobic binding pocket that accommodates an apolar surface on R(CE) dimers. Basic residues (His(254)-Arg(255)-Lys(256)) at the C terminus of the tethering site set an upper limit on affinity for R(CE.) A central dipeptide (Phe(243)-Ser(244)) contributes critical and distinctive properties of the tethering site. Ser(244) is essential for selective binding of R(CE) and exclusion of RII isoforms. The aromatic hydrophobic character of Phe(243) ensures maximal R(CE) binding activity, thereby supporting a "gatekeeper" function of Ser(244). Substitution of Phe(243)-Ser(244) with Leu-Val generated an RII-specific AKAP. R(CE) and RII subunits contain similar dimerization domains. AKAP-binding domains of R(CE) (residues 23-47) and RII differ markedly in size, amino acid sequence, and docking specificity. Four hydrophobic residues (Cys(23), Val(27), Ile(32), and Cys(44)) in R(CE) are crucial for avid binding with AKAP(CE), whereas side chains from Leu(20), Leu(35), Val(36), Ile(40), and Ile(41) have little impact on complex formation. Tyr(26) is embedded in the docking domain, but its aromatic ring is required for R(CE)-R(CE) dimerization. Residues 236-255 in AKAP(CE) also constitute a binding site for mammalian RIalpha. RIalpha (PKAIalpha) is tightly sequestered by AKAP(CE) in vitro (K(D) = approximately 10 nM) and in the environment of intact cells. The tethering domain of AKAP(CE) provides a molecular module for manipulating intracellular localization of RI and elucidating functions of anchored PKAI in eukaryotes.

A Kinase Anchor Proteins↗

PubMed2000

NMR structure of the N-terminal J domain of murine polyomavirus T antigens. Implications for DnaJ-like domains and for mutations of T antigens.

The NMR structure of the N-terminal, DnaJ-like domain of murine polyomavirus tumor antigens (PyJ) has been determined to high precision, with root mean square deviations to the mean structure of 0.38 A for backbone atoms and 0.94 A for all heavy atoms of ordered residues 5-41 and 50-69. PyJ possesses a three-helix fold, in which anti-parallel helices II and III are bridged by helix I, similar to the four-helix fold of the J domains of DnaJ and human DnaJ-1. PyJ differs significantly in the lengths of N terminus, helix I, and helix III. The universally conserved HPD motif appears to form a His-Pro C-cap of helix II. Helix I features a stabilizing Schellman C-cap that is probably conserved universally among J domains. On the helix II surface where positive charges of other J domains have been implicated in binding of hsp70s, PyJ contains glutamine residues. Nonetheless, chimeras that replace the J domain of DnaJ with PyJ function like wild-type DnaJ in promoting growth of Escherichia coli. This activity can be modulated by mutations of at least one of these glutamines. T antigen mutations reported to impair cellular transformation by the virus, presumably via interactions with PP2A, cluster in the hydrophobic folding core and at the extreme N terminus, remote from the HPD loop.

Amino Acid Sequence↗

PubMed2004

Structural and ligand recognition characteristics of an acetylcholine-binding protein from Aplysia californica.

We generated an acetylcholine-binding protein from Aplysia californica by synthesis of a cDNA found in existing data bases and its expression in mammalian cell culture. Its subunit assembly and ligand recognition behavior were compared with the binding protein previously derived from Lymnaea stagnalis. The secreted proteins were purified by elution from columns of attached antibodies directed to the FLAG epitope encoded in the expression construct. Although the sequences of the two proteins from marine and fresh water mollusks exhibit the characteristic features of the extracellular domain of the nicotinic receptor, they only possess 33% amino acid identity. Both assemble as stable pentamers with five binding sites per pentamer, yet they show distinguishing features of stability and sensitivity to epitope tag placement. Both proteins exhibit changes in tryptophan fluorescence upon ligand binding; however, the magnitude of the changes differs greatly. Moreover, certain ligands show marked differences in dissociation constants for the two proteins and can be regarded as distinguishing or signature ligands. Hence, the two soluble proteins from mollusks, which can be studied by a variety of physical methods, become discrete surrogate proteins for the extracellular domains of distinct subtypes of nicotinic acetylcholine receptors.

Amino Acid Sequence↗

PubMed2005

Protein adduct species in muscle and liver of rats following acute ethanol administration.

AIMS: Previous immunohistochemical studies have shown that the post-translational formation of aldehyde-protein adducts may be an important process in the aetiology of alcohol-induced muscle disease. However, other studies have shown that in a variety of tissues, alcohol induces the formation of various other adduct species, including hybrid acetaldehyde-malondialdehyde-protein adducts and adducts with free radicals themselves, e.g. hydroxyethyl radical (HER)-protein adducts. Furthermore, acetaldehyde-protein adducts may be formed in reducing or non-reducing environments resulting in distinct molecular entities, each with unique features of stability and immunogenicity. Some in vitro studies have also suggested that unreduced adducts may be converted to reduced adducts in situ. Our objective was to test the hypothesis that in muscle a variety of different adduct species are formed after acute alcohol exposure and that unreduced adducts predominate. METHODS: Rabbit polyclonal antibodies were raised against unreduced and reduced aldehydes and the HER-protein adducts. These were used to assay different adduct species in soleus (type I fibre-predominant) and plantaris (type II fibre-predominant) muscles and liver in four groups of rats administered acutely with either [A] saline (control); [B] cyanamide (an aldehyde dehydrogenase inhibitor); [C] ethanol; [D] cyanamide+ethanol. RESULTS: Amounts of unreduced acetaldehyde and malondialdehyde adducts were increased in both muscles of alcohol-dosed rats. However there was no increase in the amounts of reduced acetaldehyde adducts, as detected by both the rabbit polyclonal antibody and the RT1.1 mouse monoclonal antibody. Furthermore, there was no detectable increase in malondialdehyde-acetaldehyde and HER-protein adducts. Similar results were obtained in the liver. CONCLUSIONS: Adducts formed in skeletal muscle and liver of rats exposed acutely to ethanol are mainly unreduced acetaldehyde and malondialdehyde species.

Acetaldehyde↗

PubMed2004

Searching for cochlear implant information on the internet maze: implications for parents and professionals.

The present study has three purposes: (a) to determine who disseminates information on cochlear implants on the Web; (b) to describe a representative sample of Web sites that disseminate information on cochlear implants, with a focus on the content topics and their relevance to parents of deaf children; and (c) to discuss the practical issues of Web-based information and its implications for professionals working with parents of deaf children. Using the terms "cochlear implants" and "children," the first 10 sites generated by the four most popular search engines (Google, Yahoo, Microsoft's MSN, and America Online) at two points in time were selected for analysis, resulting in a sample of 31 Web sites. The majority of Web sites represented medically oriented academic departments and government organizations, although a wide variety of other sources containing information about cochlear implants were also located. Qualitative analysis revealed that the content tended to fall into eight categories; however, the important issues of educational concerns, habilitation following surgery, and communication methods were either addressed minimally or neglected completely. Using analytical tools that had been developed to evaluate "user friendliness" in other domains, each Web site was assessed for its stability, service/design features and ease of use. In general, wide variability was noted across the Web sites for each of these factors. The strong recommendation is made that professionals understand and enhance their knowledge of both the advantages and limitations of incorporating the new technology into their work with parents.

Cochlear Implants↗

PubMed1990

Molecular mechanisms underlying the expression of the human HOX-5.1 gene.

The complex mechanisms underlying homeobox genes expression involve regulation at transcriptional, post-transcriptional and translational levels. The multiple transcripts of the human HOX-5.1 gene are expressed differentially in tissue- and stage-specific patterns during embryogenesis, and differentially induced by retinoic acid (RA) in human embryonal carcinoma (EC) NT2/D1 cells. We have sequenced 6.3 Kb of the genomic region containing the HOX-5.1 gene and analyzed its mechanisms of expression. Two alternative promoters underlie the transcription of two classes of HOX-5.1-specific mRNAs. These classes differ in tissue and subcellular distribution, induction by RA, structure of the 5'-UT region and mRNA stability: these features are compatible with a differential function of the two classes of transcripts in embryogenesis.

Amino Acid Sequence↗

PubMed1995

DNA interactions of antitumor platinum(IV) complexes.

Modifications of natural DNA and synthetic double-stranded oligodeoxyribonucleotides by cis-diamminedichloro-trans-dihydroxyplatinum(IV) (oxoplatin) were studied by means of ELISA, Maxam-Gilbert footprinting techniques, HPLC of enzymically digested DNA, and transcription assay. It was found that oxoplatin can bind DNA directly without addition of a reducing agent. In addition, the antibodies elicited against DNA modified by cisplatin were not competitively inhibited by DNA modified by oxoplatin. However, DNA containing the adducts of oxoplatin became a strong inhibitor of these antibodies, if it was subsequently treated with ascorbic acid, which is a reducing agent. These results were interpreted to mean that oxoplatin can form DNA adducts containing the platinum moiety in the quadrivalent state. The direct irreversible binding of the platinum(IV) drug is, however, slow as compared to the reaction of its platinum(II) counterpart. It was also found that oxoplatin preferentially binds to guanine residues and can form DNA intrastrand and interstrand cross-links containing platinum(IV). The DNA adducts containing platinum(IV) can inhibit in vitro transcription by a prokaryotic DNA-dependent RNA polymerase. We find that the platinum(IV) complex binds to DNA at similar sites as its platinum(II) counterpart. On the other hand, the DNA adducts containing the platinum(II) or platinum(IV) analogues differ in the number of ligands and the formal charge on their platinum center. We suggest that these differences could be responsible for distinct conformational features and stability of DNA modified by platinum(II) or platinum(IV) complexes.

Animals↗

PubMed2001

Roles of thiol-redox pathways in bacteria.

Disulfide bonds in proteins play various important roles. They are either formed as structural features to stabilize the protein or are found only transiently as part of a catalytic or regulatory cycle. In vivo, the formation and reduction of disulfide bonds is catalyzed by specialized thiol-disulfide exchanging enzymes that contain an active site with the sequence motif Cys-X-X-Cys. These proteins have structurally evolved to catalyze predominantly either oxidative reactions or reductive steps. There is mounting evidence that, in addition to the thiol redox potential, the spatial distribution within different cell compartments and the overall redox state of the cell are equally important. In the cytoplasm, multiple pathways play overlapping roles in the reduction of disulfide bonds and additionally, the expression of several components of thiol-redox pathways was shown to respond to the changes in the cellular thiol-redox equilibrium. In the periplasm, two systems coexist, one catalyzing thiol oxidation and the other disulfide reduction. Recent results suggest that two different mechanisms are used to translocate reducing power from the cytoplasm or to dissipate the electrons after oxidation.

Bacteria↗

PubMedDate not supplied

Extended suicide attempt: psychopathology, personality and risk factors.

Delinquency among depressed patients plays a minor role in criminal behavior. Among the most tragic associations between depression and criminality are cases of extended suicide or suicide attempt. We studied psychopathology, personality, and psychosocial stressors of 9 Austrian females who committed a serious extended suicide attempt. They were admitted for treatment at a special department of the Justizanstalt Wien-Josefstadt, Aussenstelle Wilhelmshöhe. Patients were diagnosed according to ICD-10 as severely depressed with (n = 6) or without (n = 3) psychotic features. After stabilization we diagnosed the following personality disorders: anxious-avoidant (n = 5), paranoid (n = 1), combined (n = 1) and borderline type (n = 1). Traits of the typus melancholicus were found in 5 patients. Seven females were pretreated before the offence by a psychiatrist or a psychologist; 4 of them had committed at least one suicide attempt in the past. Main psychosocial stressors mentioned by patients in the context of the offence were overstrain, marital and/or financial problems. One female killed her child under the influence of acoustic hallucinations. Patients with traits of the melancholic type showed an altruistic and hypernomic motive for killing as well as a psychotic identification with the victim, whereas in the other cases egocentric motives were in the forefront. Potential risk factors for an extended suicide attempt will be discussed.

Adult↗

PubMed2004

Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature.

POEMS syndrome is characterized by peripheral neuropathy (PN), a clonal plasma cell disorder (PCD), organomegaly, endocrinopathy, skin changes, edema, sclerotic bone lesions, and thrombocytosis. Based on the improved response rates observed with peripheral blood stem cell transplantation (PBSCT) in patients with other PCDs, autologous PBSCT may be an attractive treatment option for this syndrome. Sixteen patients with POEMS syndrome have undergone PBSCT at Mayo. Of these patients, 15 had a severe rapidly progressive sensorimotor PN (9 were wheelchair dependent) and 14 were male. Median age was 51 years (range, 19-62 years). The median number of prior therapies was 3 (range, 0-7). From first symptoms and from diagnosis of POEMS the times to transplantation were 42 months and 5 months (ranges, 8-185 months and 2-149 months), respectively. There were 15 patients who had significantly abnormal pretransplant pulmonary function tests. There was one transplant-related death. During the peritransplant period, 5 patients required intubation for respiratory compromise, including one who required intubation during his stem cell mobilization period. Another patient required noninvasive biphasic positive airway pressure throughout his course. Of the 14 evaluable patients, all have had neurologic improvement or stabilization. Other features have improved substantially. PBSCT for POEMS syndrome is effective therapy but may also be associated with significant morbidity.

Adult↗

PubMed1987

The relative stability of positive and negative features in chronic schizophrenia.

The mental states of 92 inpatients with chronic schizophrenia were assessed on two occasions 4 years apart. The relationship between the two ratings was examined in the 84 patients who were either consistently on or consistently off neuroleptics. Negative features were more stable than positive, but were not irreversible. Every feature examined was shown to resolve in some cases.

Antipsychotic Agents↗

PubMed2004

Neurosarcoidosis: an unusual indication for radiotherapy.

Up to 70% of patients with systemic sarcoidosis developing neurosarcoidosis do so within the first 2 years of their systemic illness. Central nervous system (CNS) involvement as the only manifestation of sarcoidosis can be seen both at first time of disease and at recurrence in a few isolated cases. A young man showed neurological symptoms caused by isolated CNS sarcoidosis after unsuccessful treatment of primary pulmonary sarcoidosis by steroids. MRI scans of the head showed a distinct structural lesion temporodorsal in the left hemisphere and in the left-sided basal ganglia. The diagnosis was proved by neurosurgical resection. Post-operative systemic treatment with long-term corticosteroids was ineffective. After low-dose whole-brain irradiation of the isolated CNS lesion with 20 Gy, partial resolution of the clinical features and stabilization of disease proved by MRI ensued. In neurosarcoidosis the use of radiation therapy remains an appropriate therapy option with minimal adverse sequelae if primary medical treatment fails.

Brain Diseases↗

PubMed2006

Near common-path optical fiber interferometer for potentially fast on-line microscale-nanoscale surface measurement.

We introduce a new surface measurement method for potential online application. Compared with our previous research, the new design is a significant improvement. It also features high stability because it uses a near common-path configuration. The method should be of great benefit to advanced manufacturing, especially for quality and process control in ultraprecision manufacturing and on the production line. Proof-of-concept experiments have been successfully conducted by measuring the system repeatability and the displacements of a mirror surface.

Journal Article↗

PubMed2000

Targeting multi-stranded DNA structures.

The design of agents targeted toward a structure-specific molecular recognition of DNA triplexes or tetraplexes ( quadruplexes ) is discussed, where such structures are relevant to antigene-based chemotherapies and the in situ cellular inhibition of telomerase function, respectively. Using principles that stem from the development of earlier synthetic duplex-binding ligands, together with recent findings that probe structure thermodynamic linkages and kinetic features of stability, a rational approach is developed to exploit the distinct molecular templates offered by these high-order nucleic acid biotarget systems. Such analytical techniques can usefully augment conventional drug design methods, particularly where detailed structural information is unavailable or the mode of binding to form a persistent DNA biotarget ligand complex is not established. Examples from the author s laboratory are used to illustrate structure-specific (or structure-preferential) recognition and subsequent stabilization of DNA triplexes using intercalative or groove-mediated binding mechanisms, and the successful targeting of DNA tetraplexes using planar extended-aromatic ligands. In each case, chemical manipulation of the molecule by exploiting either (i) geometric isomers, (ii) redistribution of charged groups and/or H-bond donors/acceptors, or (iii) optimization of intermolecular pi-overlap can be used to improve the affinity or specificity of the underlying DNA drug binding events.

Animals↗

PubMed1996

A 100 mT-class ELF magnetic field exposure system for cultured cells.

We developed a system for exposure of cultured cells to extremely low frequency (ELF) magnetic fields much stronger than those used in previous in vitro studies. The system consists of an electromagnet, a commercial incubator with a custom-designed door and a custom-designed shelf, and other components, and exposes cells in the incubator to ELF magnetic field. We confirmed that it has good performance characteristics in terms of field intensity, field uniformity, waveform, field stability, temperature uniformity, and temperature stability. Its features include: (1) strong ELF magnetic fields (at most, 170 mTRMS), (2) long-term exposure (at least, 5.5 h), and (3) variable frequencies (10-100 Hz). This exposure system is expected to contribute significantly to research on possible hazards of ELF magnetic fields.

Cells, Cultured↗

PubMed2006

Establishment and characterization of a cholangiocarcinoma cell line (RMCCA-1) from a Thai patient.

AIM: To establish and characterize a new cell line derived from peripheral cholangiocarcinoma of a Thai patient. METHODS: The peripheral cholangiocarcinoma specimen surgically obtained from the patient was aseptically processed by washing and mincing before culturing in Ham's F12 medium containing 10% fetal bovine serum. After 3 mo, when the cell line has become homogeneous and stabilized, several features were investigated, including growth characteristics, immunofluorescence staining for cytokeratins, expression of tumor markers, chromosomal analysis by G-banding and multicolour fluorescence in situ hybridization (mFISH), in vitro migration and invasion characteristics. RESULTS: The RMCCA-1 cell line has been established. These cells proliferated as a monolayer with a population doubling time of 48 h. Immunofluorescence staining showed positive staining for human cytokeratin 7 and 19 verifying the biliary epithelial origin. RMCCA-1 secreted carbohydrate antigen 19-9 (CA19-9), but insignificant levels of carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). Chromosome analysis identified aneuploidy karyotypes with a modal chromosome number of 59. RMCCA-1 exhibited a low level of in vitro invasiveness, but a high degree of motility. The cell line exhibited a significant number of chromosomal aberrations as shown by mFISH and G-banding methods. CONCLUSION: A new cell line derived from peripheral cholangiocarcinoma of a Thai patient has been established. This cell line shows a low level of in vitro invasiveness, but a high degree of motility. It will serve as a valuable tool for further studies on tumor biology, molecular pathogenesis, metastatic mechanism and response to therapeutic drugs of cholangiocarcinoma.

Adult↗