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PubMed2005

Sexuality and parasitism share common regulatory pathways in the fungus Parasitella parasitica.

Parasitella parasitica, a facultative mycoparasite of zygomycetous fungi, forms cytoplasmic fusions with its hosts during infection. Thus, the organism is an efficient donor of genetic material in parasexual host-parasite interactions. Recognition between parasite and host is mediated by trisporoids, which are also responsible for sexual communication. The TDH gene for one of the key enzymes of trisporic acid biosynthesis, 4-dihydromethyl-trisporate dehydrogenase, was cloned and its transcription analysed. TDH was cloned on a 6175-bp insert and was found to map in a complex cluster of genes that suggest post-transcriptional antisense regulation. Histochemical TDH analysis in developing parasitic or sexual structures shows high enzymatic activity in Parasitella. TDH is linked to a gene for a putative acyl-CoA thioesterase (ACT). Two ORFs were identified in the 5'-region of the TDH gene, a third one, coding for 176 amino acids overlaps the ACT gene in antisense direction completely. Expression levels of ACT and ORF1 depend on parasitic and sexual interactions.

Amino Acid Sequence↗
PubMed2005

Phylogenetic relationships of Irkut and West Caucasian bat viruses within the Lyssavirus genus and suggested quantitative criteria based on the N gene sequence for lyssavirus genotype definition.

The nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) genes of Irkut and West Caucasian bat viruses (WCBV) were sequenced and compared with those of other lyssaviruses. N gene nucleotide identities provided unequivocal separation of all lyssavirus genotypes with an identity threshold of 82%. On this basis, Irkut virus should be considered as a new genotype with particular relatedness to genotypes 4 and 5 (78.0-78.6% identity for N gene nucleotides and 90.4-92.6% for amino acids). Furthermore, genotypes 4-6, together with Aravan, Khujand and Irkut viruses, present a solid phylogroup of Old World bat lyssaviruses. This relationship is apparent using all three viral genes, and causes overlap between intragenotype and intergenotype identities for the P gene (Aravan, Khujand viruses and genotype 6) and for the G gene (Aravan, Khujand, genotypes 5 and 6). WCBV is the most divergent of known lyssaviruses with only limited relatedness to genotypes 2 and 3.

Amino Acid Sequence↗
PubMed2002

mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether.

The antimalarial artemisinin derivatives artesunate (ART), arteether (ARE), and artemether (ARM) reveal remarkable antineoplastic activity. In the present investigation, we identified mRNA expression profiles associated with the response of tumor cells to ART, ARE, and ARM. We performed correlation and hierarchical cluster analyses of inhibition concentration 50% (IC(50)) values and basal mRNA expression levels of 464 genes deposited in the database of the National Cancer Institute, USA. Correlating IC(50) values of ART, ARE, and ARM and of 16 established antineoplastic drugs revealed that the artemisinin derivatives could not be assigned with a known class of drugs with defined mode(s) of action. The basal mRNA expression of 208 out of 464 genes (45%) correlated significantly with IC(50) values of at least one artemisinin derivative. These genes were from different classes (drug resistance genes, DNA damage and repair genes, apoptosis-regulating genes, proliferation-associated genes, oncogenes, tumor suppressor genes and cytokines). We identified two different gene clusters by hierarchical cluster analysis. One cluster contained predominately genes significantly correlated to all three artemisinin derivatives. This overlapping set of genes points to common molecular mechanisms of tumor inhibition by all three drugs in which genes affecting cellular proliferation may play an important role. The second cluster contained genes differentially associated with the response of artemisinin derivatives to cancer cells. The number of correlating drug resistance genes in this cluster increased in the order ART<ARE<ARM and was paralleled by increasing IC(50) values of the three drugs in the same order. The higher activity of ART in comparison to ARE and ARM may, thus, be explained by a lower number of drug resistance genes affecting ARTs action. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of artemisinin derivatives in tumor cells.

Antimalarials↗
PubMed1997

Molecular cloning of the gene encoding the 83 kDa amastigote surface protein and its identification as a member of the Trypanosoma cruzi sialidase superfamily.

Amastigote surface proteins of Trypanosoma cruzi are likely targets of both humoral and cell-mediated immune responses, however, few such molecules have been well studied. In this study, we have used modified RACE (rapid amplification of cDNA ends) and SOE (gene splicing by overlap extension) polymerase chain reaction strategies to clone the gene for the previously described 83 kDa amastigote surface protein of T. cruzi. Of the several clones obtained, only one clone, clone 4, was found to encode the 20 amino acid sequence originally reported by Pan and McMahon-Pratt (J Immunol 1989;143:1001-1008). The identity of the cloned gene with the 83 kDa amastigote surface protein was further confirmed by the reactivity of polyclonal antisera against the purified 83 kDa protein with the gene product expressed in E. coli. Sequence analyses revealed that this amastigote surface protein (ASP-2) has two conserved aspartic acid box motifs and the highly conserved VTVxNVxLYNR motif characteristic of bacterial and viral sialidases and the type III module of fibronectin, respectively. ASP-2 thus joins ASP-1 as a member of the amastigote surface expressed family of sialidase-like molecules having strong homology with family 2 of the sialidase/trans-sialidase gene superfamily of T. cruzi.

Amino Acid Sequence↗
PubMed1989

Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus.

The gene encoding human adrenal steroid 21-hydroxylase (P450c21) and its highly similar pseudogene are duplicated in tandem with the two genes encoding the fourth component of human serum hemolytic complement (C4). This 60-kilobase gene complex, which lies within the major histocompatibility complex on the short arm of human chromosome 6, has been studied in considerable detail because genetic disorders in steroid 21-hydroxylation and in C4 are common. We have cloned a cDNA encoded by a previously unidentified gene in this region. This gene lies on the strand of DNA opposite from the strand containing the P450c21 and C4 genes, and it overlaps the last exon of P450c21. The newly identified gene encodes mRNAs of 3.5 and 1.8 kilobases that are expressed in the adrenal and in a Leydig cell tumor but are not expressed in nonsteroidogenic tissues. The sequence of the longest cDNA (2.7 kilobases) shows no similarity to known sequences available in two computerized data bases. The 5' end of this sequence is characterized by three repeats, each encoding about 100 amino acids flanked by potential sites for proteolytic cleavage. Although numerous studies have shown that gene deletions causing congenital adrenal hyperplasia occur in this region, none of these gene deletions extends into this newly identified gene, suggesting that it encodes an essential function.

Amino Acid Sequence↗
PubMed2005

Gene expression profiling of 17beta-estradiol and genistein effects on mouse thymus.

Estrogen regulates thymic development and involution and modulates immune function. Despite its critical role in thymus, as well as in autoimmune disorders, the mechanism by which estrogen affects the thymus is not well understood. We previously reported that the estrogenic soy isoflavone genistein, as well as 17beta-estradiol (E2), could induce thymic involution, but genistein effects were only partially mediated through estrogen receptors. To provide insights into mechanisms of estrogenic effects in the thymus, we investigated thymic gene expression changes induced by E2 (125 ng/day) and genistein (1500 ppm in feed) in weanling mice using high-density DNA arrays. We identified several E2-responsive genes involved in thymic development and thymocyte signaling during selection and maturation. Functional characterization indicated effects on genes involved in transcription, apoptosis, and the cell cycle. This study also identified changes in several E2-regulated transcripts essential to maintain immune self-tolerance. E2 upregulated more genes than genistein, while genistein downregulated more genes than E2. Though each treatment regulated several genes not altered by the other, there was considerable overlap in the genes regulated by E2 and genistein. Changes in transcription factors and cell cycle factors were consistent with decreases in cell proliferation induced by both genistein and E2. As indicated by the regulation of non-E2-responsive genes, genistein also induced unique effects through non-estrogenic mechanisms. The specific downregulation of the CD4 coreceptor transcript by genistein was consistent with the decline of CD4+ thymocytes in genistein-treated mice in our previous study. This is the first study identifying E2 and genistein target genes in the thymus. These findings provide new mechanistic insights toward explaining estrogen action on thymocyte development, selection, and maturation, as well as the effects of genistein on prenatal and neonatal thymic development and function.

Animals↗
PubMed2026

Whole Genome Characterization of Klebsiella Strains in European Hedgehogs and Human Nosocomial Settings Identified Shared Sequence Types, Antimicrobial Resistance Genes and Plasmids.

INTRODUCTION: Klebsiella pneumoniae is a pathogen associated with healthcare-acquired infections and antimicrobial resistance (AMR) to beta-lactams and carbapenems. Although wild animals are not typically exposed to antibiotics, they can harbour resistant strains. The European hedgehog (Erinaceus europaeus) is increasingly found in urban areas, where it interacts with humans and livestock. Studies have identified concerning levels of AMR in hedgehogs, including Extended-Spectrum &#x3b2;-Lactam (ESBL) and carbapenems-resistant Klebsiella pneumoniae strains. METHODS: This study focuses on Klebsiella spp. isolated in hedgehogs from urban areas, using whole-genome sequencing (WGS). We compared these isolates with openly available strains isolated from humans in the same region with the objective to have a thorough understanding of ST, AMR gene, and plasmid overlap between human and environmental compartments. RESULTS: High AMR gene levels, including the carbapenemase blaOXA-48, were found in the hedgehog population. Notably, human nosocomial clones, including ST307 and ST392, globally distributed sequence types also found in wildlife, were identified in both hedgehogs and humans. The presence of conjugative plasmids, including IncFIB(K) and IncL1 types, was identified in both hedgehogs and humans, highlighting plasmid dissemination as a significant factor in AMR spread. CONCLUSIONS: Although no direct transmission from wildlife to hospital settings has been conclusively demonstrated, our findings suggest that hedgehogs may play a role in bridging environmental and healthcare environments. The study underscores the need for further investigation into multidrug-resistant Klebsiella spp. and other resistant bacteria in wildlife to better understand their potential role in the dissemination of resistance genes across ecosystems.

Animals↗
PubMed1991

A herpes simplex virus type 1 mutant lacking the ICP0 introns reactivates with normal efficiency.

Previous evidence suggests that the latency-associated transcript (LAT) gene of herpes simplex virus type 1 appears to have a role during reactivation of latent virus because viruses which are null mutants in this gene reactivate slowly or less efficiently than wild-type viruses. Mapping studies have shown that the LAT gene covers a region of about 8.5 kb that overlaps the ICP0 gene in the repeat long region of the herpes simplex virus genome. Previously, we had constructed a mutant with a deletion in the region of the LAT gene encoding a stable 2-kb RNA species (that accumulates to high levels in latently infected cells) and had shown that it reactivates normally (T.M. Block, J.G. Spivack, I. Steiner, S. Deshmane, M.T. McIntosh, R.P. Lirette, and N.W. Fraser, J. Virol. 64:3417-3426, 1990). We now show that a mutant which has two deletions downstream of this region (deleted in both ICP0 introns) reactivates normally in explant cocultivation assays. Thus, the slow or inefficient reactivation phenotype of herpes simplex virus type 1 LAT null mutants is not assignable to this region of the LAT gene.

Animals↗
PubMed2004

Genomics of preconditioning.

Brief episodes of ischemia can protect against subsequent damaging ischemic events; however, the molecular mechanisms responsible for protection are poorly understood. Identifying genes involved in this process could provide insight into cell survival and treatment of stroke. We developed a murine model of ischemic preconditioning and subsequent stroke and used gene expression profiling to identify genes that may be involved in neuroprotective pathways. Middle cerebral artery occlusions were performed in mice for 15 minutes. (preconditioning), 60 minutes (stroke), or 15 minutes, followed 72 hours later with 60 minutes (preconditioning plus stroke) of middle cerebral artery occlusions. RNA from a region of cortex that is protected by ischemic preconditioning was hybridized to oligonucleotide microarrays. Follow-up experiments used patch clamp to examine cell conductance in cultured neurons exposed to oxygen-glucose deprivation. Stroke, ischemic preconditioning, and ischemic preconditioning plus stroke all induced gene changes that overlapped little among conditions. Stroke induced robust upregulation of gene expression whereas preconditioning followed by stroke resulted in a marked downregulation. Genes upregulated by stroke suggested activation of stress/inflammatory pathways and increased metabolism and ion channel function. Preconditioning tended to decrease genes involved in these pathways. Follow-up experiments show that preconditioning decreased voltage-gated potassium currents in vitro and increased bleeding time. Preconditioning reprograms the response to ischemic injury via transcriptional changes that may suppress metabolic pathways and immune responses, reduce ion channel activity, and decrease blood coagulation. These changes resemble evolutionarily conserved responses to decreased blood flow and oxygen availability that occur during hibernation.

Animals↗
PubMed1997

Genomic organization of the human DDX13 gene located between RD and RP1 in the class III MHC complex.

Recently we cloned a novel human cDNA homologous to yeast SKI2, reported a partial cDNA sequence, and mapped the gene to human chromosome 6p21 (Lee et al., 1995). It was a member of the DEAD/DExH family gene with seven conserved helicase domains; thus, it was named DDX13 consequently. We determined the complete genomic organization of the DDX13 gene. It consisted of 28 exons distributed over 11 kb of genomic DNA. An Alu element was present in introns 17 and 18, respectively. The major transcription start site was located 390 bp upstream from the translation initiation codon. The DDX13 gene was located in the class III region of the MHC between the genes coding for two other nuclear proteins, RD and RP1. The RD and DDX13 genes were oppositely oriented, and their first exons were overlapped. The distance between their first methionine codons was only 745 bp. It was of note that DDX13 and RD are in such proximity that their 5' regulatory regions overlap. The RP1 gene was located immediately downstream from the DDX13 gene in the same transcriptional orientation, and the distance between the stop codon of DDX13 and the translation initiation codon of RP1 was 2,272 bp.

Base Sequence↗
PubMed1983

Structure and function of the yeast URA3 gene. Differentially regulated expression of hybrid beta-galactosidase from overlapping coding sequences in yeast.

Expression of the URA3 gene of Saccharomyces cerevisiae was studied by analysis of URA3-lacZ gene fusions constructed in vitro. Synthesis of hybrid beta-galactosidase by fusions in frame with the coding sequence for orotidine-5'-phosphate decarboxylase (OMPdecarboxylase) was found to be normally regulated even when only 11 nucleotides of URA3 coding sequence remained, indicating that all transcription initiation and regulatory sites are present at the beginning of the URA3 gene. An upstream initiator codon that begins a short overlapping coding sequence in another reading frame was also found to be active in producing hybrid beta-galactosidase. However this beta-galactosidase synthesis showed little or no regulation. Nuclease protection experiments revealed numerous species of URA3 mRNA. The regulation of these is consistent with the idea that the URA3 protein and the overlapping peptide are translated from differentially regulated mRNAs of different lengths.

Base Sequence↗
PubMed2000

The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium.

We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a approximately 630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this approximately 630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of approximately 370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal approximately 120-kb segment and 11 genes lying in the distal approximately 250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/alpha2delta-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (+/-) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA, Analysis of the approximately 630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Naturally occurring antisense: transcriptional leakage or real overlap?

Naturally occurring antisense transcription is associated with the regulation of gene expression through a variety of biological mechanisms. Several recent genome-wide studies reported the identification of potential antisense transcripts for thousands of mammalian genes, many of them resulting from alternatively polyadenylated transcripts or heterogeneous transcription start sites. However, it is not clear whether this transcriptional plasticity is intentional, leading to regulated overlap between the transcripts, or, alternatively, represents a "leakage" of the RNA transcription machinery. To address this question through an evolutionary approach, we compared the genomic organization of genes, with or without antisense, between human, mouse, and the pufferfish Fugu rubripes. Our hypothesis was that if two neighboring genes overlap and have a sense-antisense relationship, we would expect negative selection acting on the evolutionary separation between them. We found that antisense gene pairs are twice as likely to preserve their genomic organization throughout vertebrates' evolution compared to nonantisense pairs, implying an overlap existence in the ancestral genome. In addition, we show that increasing the genomic distance between pairs of genes having a sense-antisense relationship is selected against. These findings indicate that, at least in part, the abundance of antisense transcripts observed in expressed data represents real overlap rather than transcriptional leakage. Moreover, our results imply that natural antisense transcription has considerably affected vertebrate genome evolution.

Animals↗
PubMed1994

Study of the Huntington's disease (HD) gene CAG repeats in schizophrenic patients shows overlap of the normal and HD affected ranges but absence of correlation with schizophrenia.

The CAG repeats in the Huntington's disease gene were investigated in chromosomes from 71 unrelated schizophrenic persons and 18 patients with schizoaffective disorder in order to determine if any of these patients had abnormal expansions. All of the probands had repeat sizes in the normal range (< 35 repeats) and there was no significant difference between the allele distributions of these patients and the normal controls. The families of two patients with 32 repeats and one patient with 34 repeats were investigated further and showed no uniform segregation of the disease with the large repeat alleles. The proband with 34 repeats inherited a chromosome that originally had 36 repeats in her father. The presence of 36 CAG repeats in members of her family and in HD patients suggests that there is an overlap between the normal and Huntington's disease CAG repeat size ranges. The more recently described CCG polymorphism in this gene was also examined in the schizophrenic and schizoaffective persons. All patients had alleles in the normal range.

Alleles↗
PubMed1997

The chicken caudal genes establish an anterior-posterior gradient by partially overlapping temporal and spatial patterns of expression.

The caudal genes in vertebrates as in invertebrates assume a posterior position along the anterior-posterior axis and they appear to regulate the expression of the Hox genes. The third chicken caudal gene, Cdx-C, was cloned. Extensive comparisons of the sequence of this protein to the other known members of this homeobox family has lead to the suggestion that vertebrate genomes contain three members of the caudal homeobox family. A comparative study of the chicken Cdx-A and Cdx-C genes during gastrulation and neurulation revealed the differences between the genes. The caudal genes exhibit sequential activation in the newly formed neural plate and sequential extinction in axial midline structures during the primitive streak regression along the anterior-posterior axis. This pattern of expression suggests that the number and identity of caudal genes expressed along the anterior-posterior axis changes dynamically.

Amino Acid Sequence↗
PubMed1996

Molecular analysis of the DLA DR region.

The dog is an important model for studying organ transplantation. In order to develop a DNA-based typing system, a genomic analysis of the canine DR region of the MHC was undertaken. Southern analysis suggests the presence of two DRB genes in most dogs and all have one DRA gene. One dog out of 200 examined contains only one DRB gene. The DRA gene was mapped in one lambda phage clone. One DRB gene (DRBB1) was localized to two overlapping phage clones. Another DRB gene (DRBB2) was localized to two overlapping phage clones. Sequence analysis of the two DRB genes suggests that one gene is intact (DRBB1) and one gene is a pseudogene (DRBB2) because it lacks a splice acceptor signal for exon 3 and lacks exons 2 and exon 4. Intron 1 and 2 sequence data from DRBB1 allow amplification of the polymorphic exon 2 which, in turn, can serve as a basis for developing a typing system for DRB.

Amino Acid Sequence↗
PubMed1997

Dlx genes encode DNA-binding proteins that are expressed in an overlapping and sequential pattern during basal ganglia differentiation.

The Dlx gene family encodes homeodomain proteins that are required for forebrain and craniofacial development. Towards elucidating the roles for each of these genes, we have isolated cDNA clones encoding the full-coding sequence for murine Dlx-5 and partial coding sequence for murine Dlx-6. Three different classes of sense Dlx-5 cDNA clones were characterized, two of which lack the homeobox. We also identified an antisense Dlx-6 transcript. Genomic analysis shows that the Dlx-5 and -6 genes are linked. Biochemical analysis using gel shift assays demonstrate that DLX-1, -2 and -5 have very similar DNA-binding properties. The expression of Dlx-1, -2, -5, -6 and antisense Dlx-1 and -6 was studied in the midgestation mouse brain. We found that the Dlx genes are expressed in overlapping patterns at different stages of differentiation within the primordia of the basal ganglia. Dlx-1 and -2 are expressed in the least mature cells (in the ventricular and subventricular zones). Dlx-5 appears to be co-expressed with Dlx-1 and -2 in the SVZ, but is also expressed in the postmitotic cells of the mantle. Dlx-6 expression is strongest in the mantle. Antisense Dlx-1 and -6 have their highest expression in the SVZ. These results suggest that each of these Dlx genes may have a distinct role in different steps of differentiation in the basal ganglia.

Amino Acid Sequence↗
PubMed2003

GALA, a database for genomic sequence alignments and annotations.

We have developed a relational database to contain whole genome sequence alignments between human and mouse with extensive annotations of the human sequence. Complex queries are supported on recorded features, both directly and on proximity among them. Searches can reveal a wide variety of relationships, such as finding all genes expressed in a designated tissue that have a highly conserved noncoding sequence 5' to the start site. Other examples are finding single nucleotide polymorphisms that occur in conserved noncoding regions upstream of genes and identifying CpG islands that overlap the 5' ends of divergently transcribed genes. The database is available online at http://globin.cse.psu.edu/ and http://bio.cse.psu.edu/.

5' Untranslated Regions↗