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PubMed1999

Expression of mouse semaphorin H mRNA in the inner ear of mouse fetuses.

Semaphorins constitute a large family of secreted and cell-surfaced proteins that appear to function as chemorepellents to guide axons. We examined the expression pattern of M-semaH mRNA in the inner ear of mouse fetuses by in situ hybridization histochemistry. M-semaH mRNA expression was high in the endolymphatic sac involved in endolymph homeostasis. It was also high in the semicircular ducts except for the crista ampullaris, whereas no expression was detected in the epithelium of cochlear ducts.

Animals↗

PubMed2000

Phenotypic testing predicts virological response in successive protease inhibitor-based regimens.

OBJECTIVE: To evaluate the importance of the number of active drugs, as determined by phenotypic resistance testing, in achieving virological response in successive salvage regimens. DESIGN: Phenotypic study of 57 plasma samples corresponding to 24 patients who had sequentially received three protease inhibitor-containing regimens. Phenotypic susceptibility to a drug (active drug) was defined as less than a four-fold-increase in the IC50 in comparison with the wild type. MAIN OUTCOME MEASURE: Virological response according to the number of active drugs (three versus two or fewer), HIV load, length of antiretroviral exposure, and line of protease inhibitor-based therapy (first, second and third regimen). RESULTS: Before the first protease inhibitor-based therapy, the median time on antiretroviral treatment was 42 months, and before the second and third protease inhibitor-salvage regimens it was 10 and 8 months, respectively. The number of patients receiving three active drugs simultaneously was 24, 35 and 31% in each line of therapy. At week 12, a close correlation was found between the presence of three active drugs in the antiretroviral regimen and the rate of virological response, in comparison with those patients receiving two or fewer active drugs [76 versus 45%, relative risk (RR), 1.7; 95% confidence interval (CI) 1.1-2.6; P = 0.028]. In a multivariate analysis, the use of two or fewer active drugs was an independent predictor of lack of response, regardless of HIV load, length of previous antiretroviral exposure and line of salvage therapy (RR, 4.5; 95%CI, 1.1-18.3; P = 0.03). Of note, a higher rate of response was observed in patients receiving the first protease inhibitor-containing regimen in comparison with those in subsequent protease inhibitor-based salvage regimens (83 versus 50 versus 28%, P < 0.01), even when only those patients receiving three active drugs were included (100 versus 71 versus 60%). CONCLUSIONS: This data confirm the usefulness of phenotypic testing in guiding antiretroviral therapy in heavily pretreated patients. The number of active drugs and the line of salvage therapy are independent predictors of virological response, regardless of HIV load and the length of antiretroviral exposure.

Anti-HIV Agents↗

PubMed1998

Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval.

Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p. Here we describe the isolation from within this interval of the human Semaphorin F (SEMAF) gene, a member of a family of proteins that has been implicated in axonal pathfinding. The human SEMAF gene covers at least 10% of the deleted region and defines a new class within this large gene family characterized by the presence of seven type 1 thrombospondin repeats. Prominent expression of murine semaphorin F (Semaf) was observed in the mouse brain, consistent with a role for semaphorin F as a signaling molecule that guides axons or migrating neuronal precursors during development. The known functions of semaphorins and the interesting pattern of expression for Semaf suggest that haploinsufficiency for SEMAF may disrupt normal brain development and might lead to some of the features of Cri-du-chat.

Amino Acid Sequence↗

PubMed2005

15,16-dihydrotanshinone I suppresses the activation of BV-2 cell, a murine microglia cell line, by lipopolysaccharide.

Microglial activation has been implicated in neurodegenerative diseases. Therefore, inhibition of inflammation mediated by microglia is a strategy in neurodegenerative disease therapy. In this study, we isolated cryptotanshinone and 15,16-dihydrotanshinone I from Salvia miltiorrhiza, a traditional Korean herb medicine, by bioactivity-guided fractionation based on inhibitory effect on nitric oxide in a lipopolysaccharide-stimulated BV-2 cells, a murine microglial cell line. 15,16-Dihydotanshinoe I suppressed the expression of not only inducible nitric oxide synthase but also of interleukin-1beta, tumor necrosis factor-alpha, and of TNF-alpha converting enzyme.

Animals↗

PubMed1993

An alternative helix in the 26S rRNA promotes excision and integration of the Tetrahymena intervening sequence.

A highly conserved ribosomal stem-loop immediately upstream of the Tetrahymena splice junction can inhibit both forward and reverse self-splicing by competing with base pairing between the 5' exon and the guide sequence of the intervening sequence. Formation of this unproductive hairpin is preferred in precursor RNAs with short exons and results in a lower rate of splicing. Inhibition of self-splicing is not observed in longer precursors, suggesting that additional interactions in the extended exons can influence the equilibrium between the productive and unproductive hairpins at the 5' splice site. An alternative pairing upstream of the 5' splice site has been identified and is proposed to stabilize the active conformer of the pre-rRNA. Nucleotide changes that alter the ability to form this additional helix were made, and the self-splicing rates were compared. Precursors in which the proposed stem is stabilized splice more rapidly than the wild type, whereas RNAs that contain a base mismatch splice more slowly. The ability of DNA oligomers to bind the RNA, as detected by RNase H digestion, correlates with the predicted secondary structure of the RNA. We also show that a 236-nucleotide RNA containing the natural splice junction is a substrate for intervening sequence integration. As in the forward reaction, reverse splicing is enhanced in ligated exon substrates in which the alternative rRNA pairing is more stable.

Animals↗

PubMed2001

In situ hybridization to mRNA: from black art to guiding light.

In situ hybridization to mRNA in embryo sections or wholemount embryos is one of the most powerful analytical tools available to the molecular developmental biologist. For many workers, this procedure provides the first insights into the function of newly isolated genes, allowing the formulation of hypotheses and setting the course for further research. This paper presents a personal historical perspective of the development of in situ hybridization, looks at the theory and practice of the technique, summarizes the current state of the art, and speculates on possible directions for the future as a tool in functional genomics.

Animals↗

PubMed2004

Molecular cloning and characterization of gene for Golgi-localized syntaphilin-related protein on human chromosome 8q23.

Loci for several human genetic diseases including glaucoma have been mapped to q23 region on chromosome 8. We carried out homology search analysis of the genomic sequence of a bacterial artificial chromosome (BAC) clone, KB1590E11, on 8q23 region, and mapped a previously described cDNA, KIAA1472, to this BAC clone. In this study, we determined the complete genomic structure of the KIAA1472 gene and its expression in various tissues and cell lines. Four mRNA species (types 1a, 1b, 1c, and 2) were produced from this gene by use of alternative transcription start sites and alternative-splicing events. These mRNAs were expressed in various tissues, except for type 1a, which was found only in the brain. Further, type 1 mRNA could be translated into two protein isoforms with different N-terminal sequences; and type 2 mRNA, into another type of isoform. All three of these KIAA1472 gene products were localized in Golgi apparatus and contained a C-terminal hydrophobic segment characteristic of a transmembrane domain, thus indicating them to be Golgi membrane-bound proteins. Furthermore, these proteins were homologous to syntaphilin, a molecule involved in guiding vesicular transport. These results indicate that KIAA1472 gene products may play an important role in vesicular traffic in various tissues including the brain.

Alternative Splicing↗

PubMed2006

Centrosomal proteins Nde1 and Su48 form a complex regulated by phosphorylation.

The centrosome modulates spindle formation and plays a critical role in guiding proper segregation of chromosomes during cell division. Centrosome aberrations, frequently seen in human tumors, may cause abnormal chromosome segregation and contribute to malignant transformation. To explore the components of the centrosomes, we previously identified a novel centrosomal protein called Su48. To further characterize the Su48-containing protein ensemble in the centrosome, we performed yeast two-hybrid screens and isolated a number of Su48-interacting molecules, including the centrosomal protein Nde1. Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. Ablation of Nde1 by gene specific small interfering RNA causes mitotic delay and cell death, coupled with a modest decrease in the incidence of the cells that harbor excessive centrosomes. Collectively, our findings indicate that Nde1 can form a protein complex with Su48 in the centrosome and plays an important role for successful mitosis.

Carrier Proteins↗

PubMed2006

Functions of microRNAs and related small RNAs in plants.

MicroRNAs (miRNAs) and short interfering RNAs (siRNAs), 20- to 27-nt in length, are essential regulatory molecules that act as sequence-specific guides in several processes in most eukaryotes (with the notable exception of the yeast Saccharomyces cerevisiae). These processes include DNA elimination, heterochromatin assembly, mRNA cleavage and translational repression. This review focuses on the regulatory roles of plant miRNAs during development, in the adaptive response to stresses and in the miRNA pathway itself. This review also covers the regulatory roles of two classes of endogenous plant siRNAs, ta-siRNAs and nat-siRNAs, which participate in post-transcriptional control of gene expression.

Adaptation, Physiological↗

PubMed1995

An intramolecular recombination mechanism for the formation of the rRNA gene palindrome of Tetrahymena thermophila.

Large palindromic DNAs are found in a wide variety of eukaryotic cells. In Tetrahymena thermophila, a large palindrome is formed from a single rRNA gene (rDNA) during nuclear differentiation. We present evidence that a key step in the formation of the rDNA palindrome of T. thermophila involves homologous intramolecular recombination. Heteroduplex micronuclear rDNA molecules were constructed in vitro and microinjected into developing macronuclei, where they formed palindromes. Analysis of the resulting palindromes indicated that both strands of the microinjected rDNA are used to form the same palindrome. This study, together with a previous study (L. F. Yasuda and M.-C. Yao, Cell 67:505-516, 1991), is the first to define a molecular pathway of palindrome formation. The process is initiated by chromosome breakage at sites flanking the micronuclear rDNA. An intramolecular recombination reaction, guided by a pair of short inverted repeats located at the 5' end of the excised rDNA, covalently joins the two strands of micronuclear rDNA in a giant hairpin molecule. Bidirectional DNA replication converts the giant hairpin molecule to a palindrome. We suggest that the general features of this pathway are applicable to palindrome formation in other cell types.

Animals↗

PubMed2000

Use of CMV transcripts for monitoring of CMV infections in transplant recipients.

The development of the nucleic acid sequence-based amplification (NASBA) technology has allowed qualitative determination of human cytomegalovirus (HCMV) immediate-early (IE) and late (pp67) transcripts for monitoring of HCMV infections in the post transplantation period. pp67-mRNA NASBA was shown to be less sensitive than pp65 antigenemia and leukoDNAemia, yet more sensitive than viremia in (i) detecting HCMV infection in both patients and blood samples and (ii) anticipating diagnosis of HCMV infection in solid organ (heart, lung) transplant recipients (SOTR). Use of pp67-mRNA NASBA, as a parameter for initiation of pre-emptive therapy, could be employed as an alternative to detecting antigenemia or DNAemia in SOTR, whereas in bone marrow transplant recipients (BMTR) its use would be too risky because of the delayed detection of HCMV infection. On the other hand, IE-mRNA NASBA was shown to be largely superior to the other assays both in detecting HCMV infection in patients and blood samples and in anticipating diagnosis of HCMV infection. This appears particularly useful in BMTR, where early initiation of antiviral treatment is mandatory in order to prevent the appearance of HCMV interstitial pneumonia. Pre-emptive therapy in BMTR, however, if based upon IE-mRNA NASBA would imply treatment of a greater number of patients as compared with antigenemia- or DNAemia-guided treatment. The clinical usefulness of this approach should be evaluated in prospective trials in the near future, pp67-mRNA NASBA in SOTR with reactivated HCMV infections and IE-mRNA NASBA in BMTR could represent two new virologic parameters to be used as a cutoff for pre-emptive therapy control of HCMV infections in the post-transplant period. Viral transcripts are more direct markers of viral replication in vivo and their disappearance indicates block of the replication process.

Antiviral Agents↗

PubMed2001

Maternal hypothyroidism selectively affects the expression of neuroendocrine-specific protein A messenger ribonucleic acid in the proliferative zone of the fetal rat brain cortex.

Thyroid hormone is essential for mammalian brain development, but the mechanisms by which thyroid hormone exerts its effects, the developmental processes affected, and the timing of thyroid hormone effects are poorly understood. An important question is whether thyroid hormone of maternal origin is essential in guiding fetal brain development. In both humans and rats, thyroid hormone of maternal origin reaches the fetus before the onset of fetal thyroid function. Moreover, receptors for thyroid hormone (TRs) are present in the fetal brain and are occupied by thyroid hormone. Finally, a recent report strongly indicates that transient undiagnosed maternal hypothyroidism can lead to measurable neurological deficits in the offspring despite the lack of neonatal hypothyroidism. Considering that TRs are ligand-activated transcription factors, we recently initiated a project to identify thyroid hormone-responsive genes in the fetal cortex before the onset of fetal thyroid function. One of the thyroid hormone-responsive genes we identified, neuroendocrine-specific protein (NSP), is expressed as two separate transcripts, NSP-A and NSP-C. Only NSP-A is affected by maternal thyroid hormone. We now demonstrate that the messenger RNA encoding NSP-A is expressed exclusively in the proliferative zone of the fetal cortex, and that its expression is affected by maternal hypothyroidism. Moreover, as development proceeds, NSP-A becomes selectively expressed in Purkinje cells of the cerebellum, a well known thyroid hormone-responsive cell. These findings strongly support the concept that thyroid hormone of maternal origin exerts specific receptor-mediated effects on fetal brain development.

Animals↗

PubMedDate not supplied

Practical use of hepatitis C and B molecular tools: Belgian guidelines.

This article discusses the use of virologic assays in the diagnosis and management of hepatitis C virus (HCV) and hepatitis B (HBV) infection. The use of virologic tests has become essential in the management of HCV and HBV infection to diagnose viral infection, guide treatment decisions, and assess the virologic response to antiviral therapy. The continuing development of test systems accompanied by new antiviral drugs and novel therapeutic approaches should lead to an optimization of the treatment of HCV infection. Molecular methods for viral testing have become an integral part of the diagnostic and therapeutic management of infections with hepatitis C virus (HCV) and hepatitis B virus (HBV).

Belgium↗

PubMed2002

Functional role of the prokaryotic proline-tRNA synthetase insertion domain in amino acid editing.

Aminoacyl-tRNA synthetases catalyze the attachment of specific amino acids to cognate tRNAs in a two-step process that is critical for the faithful translation of genetic information. During the first chemical step of tRNA aminoacylation, noncognate amino acids that are smaller than or isosteric with the cognate substrate can be misactivated. Thus, to maintain high accuracy during protein translation, some synthetases have evolved an editing mechanism. Previously, we showed that class II Escherichia coli proline-tRNA synthetase (ProRS) is capable of (1) weakly misactivating Ala, (2) hydrolyzing the misactivated Ala-AMP in a reaction known as pretransfer editing, and (3) deacylating a mischarged Ala-tRNA(Pro) variant via a post-transfer editing pathway. In contrast to most systems where an editing function has been established, pretransfer editing by E. coli ProRS occurs in a tRNA-independent fashion. However, neither the pre- nor the post-transfer editing active site(s) has been identified. Sequence analyses revealed that most prokaryotic ProRSs possess a large insertion domain (INS) between class II conserved motifs 2 and 3. The function of the approximately 180-amino acid INS in E. coli ProRS is the subject of this investigation. Alignment-guided Ala scanning mutagenesis was carried out to test conserved amino acid residues present in the INS for their role in pre- and post-transfer editing. Our biochemical data and modeling studies suggest that the prokaryotic INS plays a critical role in editing and that this activity resides in a domain that is functionally and structurally distinct from the aminoacylation active site.

Alanine↗

PubMed2006

A guide through present computational approaches for the identification of mammalian microRNA targets.

Computational microRNA (miRNA) target prediction is a field in flux. Here we present a guide through five widely used mammalian target prediction programs. We include an analysis of the performance of these individual programs and of various combinations of these programs. For this analysis we compiled several benchmark data sets of experimentally supported miRNA-target gene interactions. Based on the results, we provide a discussion on the status of target prediction and also suggest a stepwise approach toward predicting and selecting miRNA targets for experimental testing.

3' Untranslated Regions↗

PubMed2004

Mass spectrometry in drug discovery: a current review.

Drug discovery in the pharmaceutical industry has shown great demands for screening absorption, distribution, metabolism, excretion (ADME) and pharmacokinetics (PK) in guiding the selection of lead candidate compounds. Determination of ADME/PK properties of new chemical entities (NCE) in early drug discovery should allow defects to be corrected prior to time-consuming and expensive preclinical and clinical development stages. Mass spectrometry has evolved to become an irreplaceable technology in all types of drug discovery applications because of its high sensitivity, speed, selectivity, versatility, and ease of automation. This review will include current mass spectrometric techniques and applications in drug discovery, as well as future prospects.

Combinatorial Chemistry Techniques↗

PubMed2005

Genome-wide analyses of two families of snoRNA genes from Drosophila melanogaster, demonstrating the extensive utilization of introns for coding of snoRNAs.

Small nucleolar RNAs (snoRNAs) are an abundant group of noncoding RNAs mainly involved in the post-transcriptional modifications of rRNAs in eukaryotes. In this study, a large-scale genome-wide analysis of the two major families of snoRNA genes in the fruit fly Drosophila melanogaster has been performed using experimental and computational RNomics methods. Two hundred and twelve gene variants, encoding 56 box H/ACA and 63 box C/D snoRNAs, were identified, of which 57 novel snoRNAs have been reported for the first time. These snoRNAs were predicted to guide a total of 147 methylations and pseudouridylations on rRNAs and snRNAs, showing a more comprehensive pattern of rRNA modification in the fruit fly. With the exception of nine, all the snoRNAs identified to date in D. melanogaster are intron encoded. Remarkably, the genomic organization of the snoRNAs is characteristic of 8 dUhg genes and 17 intronic gene clusters, demonstrating that distinct organizations dominate the expression of the two families of snoRNAs in the fruit fly. Of the 267 introns in the host genes, more than half have been identified as host introns for coding of snoRNAs. In contrast to mammals, the variation in size of the host introns is mainly due to differences in the number of snoRNAs they contain. These results demonstrate the extensive utilization of introns for coding of snoRNAs in the host genes and shed light on further research of other noncoding RNA genes in the large introns of the Drosophila genome.

Animals↗

PubMed1992

Neurons and neuroblastoma as a source of macrophage colony-stimulating factor.

Accumulation of macrophages in brain tissue as observed in nervous system injury may be due to local production of hematopoietic colony-stimulating factors (CSF). The present work shows human neuroblastoma cells and murine neurons, namely granule cells of the cerebellum, to produce macrophage (M)-CSF which guides expansion and differentiation of macrophage lineage cells. The mRNA-encoding M-CSF but not the respective protein is present in mouse brain including cerebellum. Neither granulocyte M-CSF nor IL-3 is produced by cerebellar neurons or neuroblastoma. By their production of M-CSF, neurons may regulate the macrophage response and lead to local expansion and enhanced function of macrophages in inflammatory diseases of the central nervous system.

Animals↗