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PubMed2005

Interspecies comparison of gene structure and computational analysis of gene regulation of 17beta-hydroxysteroid dehydrogenase type 1.

17Beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) is a key enzyme of 17beta-estradiol biosynthesis, and in rodents is additionally involved in testosterone biosynthesis. The human HSD17B1 gene, located on chromosome 17q12-21, is duplicated in tandem, with the 3'-copy being the functional gene. Here we show by sequencing the gene from a diverse set of related species that this duplication is of very recent evolutionary origin, having occurred in the common ancestor of Hominoidae (apes and humans) while being absent in the closely related Old World monkeys (Macaca) and the outgroup species Tupaia belangeri and Mus musculus. By computational analysis of the conserved regulatory elements in the 5'-untranslated (5'-UTR) and putative promoter region of the HSD17B1 gene and, where present, pseudogene, across our broad sample of species we can show significant differences that might point to the origin of the divergent substrate specificity of human and rodent HSD17B1 and highlight potential functionally relevant differences in regulatory patterns in different evolutionary lineages.

5' Untranslated Regions↗
PubMed2006

The Drosophila microtubule associated protein Futsch is phosphorylated by Shaggy/Zeste-white 3 at an homologous GSK3beta phosphorylation site in MAP1B.

The Drosophila homologue of the microtubule associated protein MAP1B is encoded by the futsch locus. The deduced protein Futsch is about twice the size of MAP1B and shows high homology in the N- and C-terminal domains. The central part of Futsch is characterized by a highly repetitive structure based on a 37 amino acid motif. Futsch, like MAP1B, colocalizes with microtubules and is necessary for the organization of the microtubule cytoskeleton during axonal growth and synaptogenesis. To further analyze the functional relevance of Futsch as a MAP1B-like protein, we performed a molecular analysis of the conserved protein domains. Using a number of antisera, we show that, unlike the MAP1B polyprotein, which is cleaved to generate a heavy and light chain, Futsch is expressed as a single protein. The function of MAP1B is in part regulated by phosphorylation mediated by kinases that include casein kinase 2 and glycogen synthase kinase 3beta (GSK3beta). We show here that at least one GSK3beta phosphorylation site of MAP1B is conserved in Futsch and that this site can be phosphorylated by GSK3beta and its Drosophila homologue, Shaggy/Zeste-white 3. To test the functional relevance of these findings we generated a number of minigenes and assayed their ability to rescue the phenotype of futsch mutants. Our data highlight some differences between MAP1B and Futsch but demonstrate that important structural and functional aspects are conserved between fly and vertebrate members of this protein family.

Amino Acid Sequence↗
PubMed2004

Leptospiral immunoglobulin-like proteins elicit protective immunity.

The identification of new vaccine candidates for leptospirosis is of great interest. This paper describes the identification of two homologous immunogenic proteins, LigA-m and LigB-m, of Leptospira interrogans serovar manilae strain UP-MMC-NIID, which show strong similarity with LigA found recently in L. interrogans serovar pomona. Southern blot analysis indicated the conservation of the lig genes among pathogenic leptospires. LigA-m protein was shown to be a surface-exposed lipoprotein expressed during in vitro culture. Both LigA-m and LigB-m induced protective immunity against a challenge with a homologous serovar of L. interrogans in mice. Furthermore, patients' sera infected with heterologous serovars' strains contained antibodies against LigA-m and LigB-m. Our results suggest that LigA-m and LigB-m proteins are new vaccine candidates for the prevention of leptospirosis.

Animals↗
PubMed2005

Development of the polymerase chain reaction assay based on the canine genome database for detection of monoclonality in B cell lymphoma.

From the canine genome database and its bioinformatic analysis, we identified conserved sequences within the vast majority of 61 variable segments and 1 joining segment of the immunoglobulin heavy chain (IgH) gene, and designed optimal primers for polymerase chain reaction (PCR) amplification directed at these conserved sequences to evaluate the monoclonality of IgH in canine B cell lymphoma. Using the primers, a PCR-based assay was performed on fine-needle aspiration samples of normal, hyperplasia, and malignant lymph nodes and lymphoma cell lines. All fine-needle aspiration samples of five B cell lymphoma cases and the B cell lymphoma line GL-1 exhibited clonal amplification, whereas no amplification was observed in the samples from normal and hyperplasia lymph nodes, cases of T cell lymphoma, and the T cell lymphoma line CL-1. The primers we designed clearly distinguished malignant B lymphocytes from normal, reactive, and malignant T lymphocytes, indicating a potential utility of the primers for PCR-based routine clinical examination for canine B cell lymphoma.

Animals↗
PubMed2005

Virus evolution during a severe dengue epidemic in Cuba, 1997.

Full-length genomic sequences from six DENV-2 isolates sampled at different times during a dengue outbreak that occurred in Cuba in 1997 were determined. Phylogenetic analysis indicated that these isolates fall into the "American/Asian" genotype. Genome analysis revealed strong conservation of the structural proteins and the non-coding regions (5' NCR and 3' NCR). Nucleotide substitutions were observed in non-structural genes and most notably in the NS5 gene. There was a clear pattern of virus evolution during the epidemic; the earliest isolates sampled differed from those sampled later by amino acid replacements in the NS1 and NS5 proteins, although there was no evidence that these represented escape mutants. Further studies are therefore required to define the functional role of amino acid replacements observed and their possible relation to disease severity.

Aedes↗
PubMed2026

Genetic dissection of cardiac iron regulation using transcriptome network analysis and systems genetics in BXD mice.

Cardiac iron homeostasis is essential for myocardial energy metabolism and contractile function, yet the genetic and molecular mechanisms governing iron levels within the heart remain poorly understood. We used a systems genetics approach to dissect the transcriptional regulation of cardiac iron homeostasis. Myocardial iron level varies substantially across BXD strains (40-112 μg/g) and is under heritable genetic control (H2 = 0.38). Elevated cardiac iron is associated with reduced ventricular mass, increased ventricular ectopy, and prolonged atrioventricular conduction in the BXD population. Weighted gene co-expression network analysis of the BXD heart transcriptome identified a co-expression module that was significantly and negatively correlated with cardiac iron levels in both young and old BXD mice and enriched for pathways related to metabolic regulation, cyclic AMP (cAMP) signaling, circadian entrainment, and cardiovascular physiology. The module showed substantial overlap with a curated cardiac iron gene set, and cross-species enrichment analysis confirmed its conservation in human cardiomyopathy differentially expressed genes (enrichment ratio = 1.49; false discovery rate [FDR] = 0.0342). Quantitative trait locus (QTL) mapping of the first principal component of the overlapping module iron genes (n = 38), corroborated by individual gene mapping, identified trans-eQTL hotspots on multiple chromosomes, implicating Fcho2, Gcc2, and Rmdn1 as candidate upstream regulators operating through sequential steps of intracellular iron trafficking. Together, these findings establish a systems-level map of cardiac iron gene regulation, identify candidate genetic regulators, and provide a molecular framework linking disruption of iron-related transcriptional networks to structural and electrical cardiac dysfunction with implications for iron-related heart diseases.

BXD mouse population↗
PubMed2004

Three modules of zebrafish Mind bomb work cooperatively to promote Delta ubiquitination and endocytosis.

Precise regulation of Notch signaling activity is critical for development of many different tissues. Here, we show that the zebrafish insertional mutation Hi904 attenuates Notch signaling, and is allelic to mind bomb. We show that Mind bomb protein displays E3 ubiquitin ligase activity in vitro and that it is associated with Delta and enhances its ubiquitination and internalization in transfected cells. Furthermore, by functional analysis of three conserved regions of Mind bomb, we show that the N-terminal half is required for Delta association, the ankyrin repeats are important for Delta internalization, and the ring fingers are required for Delta ubiquitination. Thus, the three functionally distinct modules of Mind bomb work cooperatively to regulate Notch signaling by associating with, ubiquitinating, and internalizing Delta.

Amino Acid Sequence↗
PubMed2002

Molecular characterization and expression of an alternate proliferating cell nuclear antigen homologue, PfPCNA2, in Plasmodium falciparum.

The malaria parasite Plasmodium falciparum genome sequencing has revealed the existence of a second gene for proliferating cell nuclear antigen (PCNA), a key factor in a variety of DNA metabolic events. The alternate copy of PCNA (PfPCNA2) shows only 23% identity to an earlier reported P. falciparum PCNA homologue (PfPCNA1). Our analysis indicated structural conservation of PfPCNA2 compared to eukaryotic PCNAs. PfPCNA1 and 2 polypeptides showed differential expression in the intraerythrocytic cell cycle of the malaria parasite. PfPCNA1 expression slowly increases about threefold from the ring to the late schizont stage. In contrast PfPCNA2 showed robust expression in trophozoites and early schizonts with a sudden drop in expression in the late schizont stage, suggesting that the two PfPCNAs may function under different physiological conditions. Chemical cross-linking indicated the presence of a trimeric PfPCNA2 protein, indicating the possible existence of a functional ring-like PfPCNA2 structure.

Amino Acid Sequence↗
PubMed1992

Cloning and structural characterization of a rabbit genomic DNA for alpha 1 acid glycoprotein.

The gene for rabbit alpha 1 acid glycoprotein (AGP) has been isolated from a lambda EMBL3 genomic DNA library. Isolated clone contains a 12 Kbp fragment of rabbit genomic DNA. Restriction endonuclease mapping has localized the gene within a 4.2 Kbp fragment spanning two EcoRI sites. Southern blot analysis of the rabbit genomic DNA and its comparison with the cloned gene indicates that there is only one gene for AGP present per genome. DNA sequence analysis of the cloned gene indicates that the entire gene, TATA box to the polyadenylation signal, is located within the 4.2 Kbp region and contains six exons representing the full-length cDNA described earlier (1). The 5'-end of alpha 1-AGP gene sequences from rabbit, human, rat and mouse have been compared. Such analysis reveals two conserved regions located between -63 bp and -36 bp and -29 bp and -1 bp of putative transcription start site, which may play a role in transcriptional induction of this gene during acute response. In addition to this conserved domain, DNA sequence upstream of the major transcription start site contains a potential element for Sp1 binding and a 18 bp long palindrome sequence followed by a short repeating dinucleotide sequence, which may be important in the regulation of AGP gene induction.

Animals↗
PubMed2000

Membrane topology of the N-terminus of the Escherichia coli FtsK division protein.

The Escherichia coli FtsK protein targets the septum, is essential for cell division and may play a role in DNA partitioning. Computer modelling suggests that the first 180 amino acids of the protein are embedded in the cytoplasmic membrane by up to six transmembrane domains. We demonstrate, using gene fusions, that the N-terminus contains four transmembrane helices that link two periplasmic domains. The first periplasmic domain contains an HEXXH amino acid sequence characteristic of zinc metalloproteases. We show by mutation analysis that the conserved glutamic acid of the HEXXH sequence is essential for FtsK function during septation.

Alkaline Phosphatase↗
PubMed2003

Molecular identification of wheat endoxylanase inhibitor TAXI-I1, member of a new class of plant proteins.

Triticum aestivum endoxylanase inhibitors (TAXIs) are wheat proteins that inhibit family 11 endoxylanases commonly used in different (bio)technological processes. Here, we report on the identification of the TAXI-I gene which encodes a mature protein of 381 amino acids with a calculated molecular mass of 38.8 kDa. When expressed in Escherichia coli, the recombinant protein had the specificity and inhibitory activity of natural TAXI-I, providing conclusive evidence that the isolated gene encodes an endoxylanase inhibitor. Bioinformatical analysis indicated that no conserved domains nor motifs common to other known proteins are present. Sequence analysis revealed similarity with a glycoprotein of carrot and with gene families in Arabidopsis thaliana and rice, all with unknown functions. Our data indicate that TAXI-I belongs to a newly identified class of plant proteins for which a molecular function as glycoside hydrolase inhibitor can now be suggested.

Amino Acid Sequence↗
PubMed2003

DNA target sequence and FNR-dependent gene expression.

FNR proteins are global transcription regulators that respond to fluctuations in environmental oxygen. They recognise a DNA target consisting of an inverted repeat, TTGATN(1)N(2)N(3)N(4)ATCAA (where N(1-4) represents a non-conserved tetrad, NCT). Analysis of 68 known and predicted FNR sites from the Escherichia coli K12 genome revealed a bias toward A or T at positions N(2) and N(3) of the NCT. The effect of the NCT sequence on FNR-dependent transcription in vivo was assessed using a series of class II and class I model promoters with different NCT sequences. Changing the NCT sequence did not affect basal activity but altered anaerobic induction by as much as an order of magnitude. Thus, the NCT sequence is a fundamental component in setting the dynamic range of the FNR switch.

Base Sequence↗
PubMed1997

Temporal stability of node-based internal bone adaptation simulations.

Jacobs et al. (1995, J. Biomechanics 28, 449-459) introduced a new implementation of the remodeling theory developed by Beaupre et al. (1990, J. Orthop. Res. 8, 651-661) that eliminates certain spurious spatial instabilities of previous implementations. Due to the highly nonlinear, coupled nature of multi-dimensional adaptation simulations, direct stability analyses of this method are not practical. In this manuscript, a linearized stability analysis was used to derive an expression for the critical time step for the stability of a simple model problem. In addition to accurately predicting the temporal response of the single degree-of-freedom problem, the analysis provided a conservative estimate of the critical time step for a more realistic, multiple degree-of-freedom adaptation simulation.

Adaptation, Physiological↗
PubMed1997

Coexistent Hirschsprung's disease and esophageal achalasia in male siblings.

Achalasia of the esophagus developed in two male siblings soon after birth, and they were successfully treated by surgery. Persistent signs resulted in the later diagnosis of Hirschsprung's disease. One required subtotal colectomy and ileoanal anastomosis, and the other is managing well on conservative treatment. Genetic analysis of the genes encoding the RET protooncogene, endothelin-3, and the endothelin-3 receptor did not show any defect. Familial achalasia of the esophagus in combination with Hirschsprung's disease has never been reported.

Colectomy↗
PubMed2002

Cloning and expression of the ovine CD40 molecule and the inhibition of the mixed lymphocyte reaction by the ovine CD40(e)-EGFP fusion protein.

The CD40 molecule is a member of the tumour necrosis factor receptor (TNFR)-like supergene family and plays a major role as a co-stimulatory molecule in the activation of T cells in response to antigens presented by dendritic cells. In this study, reverse transcription-PCR cloning was used to derive the sequence encoding ovine CD40. The ovine CD40 sequence demonstrated a similarity of 97, 76 and 64% with the bovine, human and murine sequences, respectively, at the nucleic acid level. The cysteine residues characteristic of the TNFR family and N-linked glycosylation sites are conserved. Furthermore, RNA analysis confirmed expression of CD40 mRNA in both ovine dendritic cells from lymphatic drainage and dermal fibroblasts in culture. In addition, cDNA encompassing the extracellular region of ovine CD40 (CD40(e)) was fused 'in-frame' with the enhanced green fluorescent protein (EGFP) to generate a fusion protein upon the transfection of Chinese hamster ovary (CHO) cells. Immunoprecipitation with an anti-GFP monoclonal antibody of a 78 kD a protein from conditioned medium of CHO transfectants confirmed that the CD40(e)-EGFP was secreted in the supernatant. All experiments were controlled with a pEGFP-N1 vector-blank construct. Moreover, the biological activity of ovine CD40(e)-EGFP was demonstrated by its ability to inhibit a two-way mixed lymphocyte reaction. Thus these observations confirm that ovine CD40 blockade inhibits co-stimulation mediated by CD40-CD40L (CD154) interactions as has been reported in murine and human studies.

Amino Acid Sequence↗
PubMed1997

Cloning and cross-species comparison of the thrombospondin-related anonymous protein (TRAP) gene from Plasmodium knowlesi, Plasmodium vivax and Plasmodium gallinaceum.

To examine the structure of the Plasmodium sporozoite micronemal protein, thrombospondin-related anonymous protein (TRAP) we have isolated TRAP genes from three species of Plasmodium: P. gallinaceum (PgTRAP), P. knowlesi (PkTRAP) and P. vivax (PvTRAP). Thus it is now possible to compare the TRAP gene from a total of six species of Plasmodium. The overall structure of TRAP is conserved in all species; specifically, an amino-terminal A-domain similar to magnesium-binding domains of mammalian integrins; a thrombospondin-like sulfatide-binding domain similar to region II in Plasmodium circumsporozoite protein; an acidic asparagine/proline-rich repeat region; a trans-membrane domain and a short acidic cytoplasmic region with a highly conserved carboxy terminus. The overall structure of TRAP from P. gallinaceum and P. falciparum (PfTRAP) is conserved and phylogenetic analysis suggests a monophyletic relationship of avian P. gallinaceum and human P. falciparum. Comparison of the amino acid sequences of the A-domain of PgTRAP and PfTRAP indicates a more rapid divergence of this domain with respect to the rest of the protein in these two species. The structural differences of PgTRAP and PfTRAP may relate to the distinct invasion pathways, macrophage and endothelial cell invasion of P. gallinaceum sporozoites versus hepatocyte invasion of P. falciparum.

Amino Acid Sequence↗
PubMed1996

Isolation and characterization of a human heart cDNA encoding a new member of the small heat shock protein family--HSPL27.

A novel cDNA clone was isolated from a human adult heart cDNA library. This cDNA clone is similar to the small heat shock protein (smhsp) in both DNA and amino acid sequences, especially in the conserved region. Sequence analysis has shown that the putative novel smhsp, named 27 kDa heat-shock-protein-like protein (HSPL27) is a protein of 241 amino acids with a deduced molecular mass of 26.7 kDa and a deduced pI of 8.0. We have expressed the HSPL27 in E. coli and the expressed protein was found to be present in the soluble fraction of the bacterial cell lysate. Chromosomal mapping data shows that the HSPL27 gene is located at human chromosome 5q11.2.

Adult↗
PubMed2006

[Clinicopathological study of incidental cancer prostate in patients undergoing surgery for symptomatic diagnosis of BPH].

UNLABELLED: OBJECTIVES-INTRODUCTION: Retrospective study of a series of patients with prostate surgery (suprapubic prostate adenomectomy -APS-, and prostate transurethral resection -RTU-P-) for presumed BPH symptomatic non-respondent to the conservative medical treatment. Analysis of prevalence, incidence, clinical-pathological, treatment, tumor progression and evolution of the patients with incidental prostate cancer (CPI) detected. MATERIAL AND METHODS: 1593 patients with prostate surgery (APS and RTU-P) during 6 years (1996-2001) were revised. APS 35%, RTU-P 65%. Revision of all pathological anatomy of surgical specimens and the evolutions of the patients with CPI. RESULTS: 78 CPI; Prevalence 4,89%; Incidence 13 cases/year. Mean age 73.6 years. Digital rectal examination was normal in 100%, mean PSA 6 ng/ml (0.5-30). Group APS: 25 CPI (32%); prevalence 4.55%; incidence 4 cases/year; mean PSA 7.7 ng/ml (2.8-30); mean weight resection 65 gs. Group RTU-P: 53 CPI (68%); prevalence 5,07%; incidence 9 cases/year; mean PSA 5.2 ng/ml (0,5-29); mean weight resection 20 gs. 22% biopsy previously by high PSA, mean PSA 14 ng/ml (4,8-30). Gleason average 5 (mean 4.8), rank 3-8. pTla 66%, pTlb 33%. TREATMENT: 57% follow-up watched without treatment (wait and see); 18% hormonal treatment; 3% finasteride; 9% Radical Prostatectomy; 9% radiotherapy. Follow Lost 4%. Mean follow-up 47.19 months (12-96). Tumor progression 13.3% (10 patients). Specific CPI mortality 2.6% (2 patients). CONCLUSIONS: We didn't observe significant differences between the prevalence of CPI in both groups (APS and RTU-P). The detected tumours were mainly well differentiated and in stage pTla. In more than half of the cases an expectant attitude without treatment was decided. 13,3% of tumor progression after 47.19 months of follow mean and specific CPI mortality 2.6%.

Aged↗