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PubMedDate not supplied

Ligands for the vitamin D endocrine system: different shapes function as agonists and antagonists for genomic and rapid response receptors or as a ligand for the plasma vitamin D binding protein.

The integrated operation of the vitamin D endocrine system which produces the steroid hormone 1alpha,25(OH)(2)-vitamin D(3) (1alpha,25(OH)(2)D(3)) is dependent on four classes of proteins each of which have inherent in their secondary and tertiary structure a ligand binding domain (LBD) that allows the stereospecific binding of 1alpha,25(OH)(2)D(3) or related analogs as a substrate or ligand. These LBDs include: (a) the cytochrome P450 enzymes in the liver, kidney, and other tissues which metabolize vitamin D(3) into biologically active metabolites; (b) the plasma vitamin D binding protein (DBP) which selectively transports these hydrophobic molecules to the various target organs of the vitamin D endocrine system; (c) the nuclear receptor VDR(nuc) that is involved in regulation of gene transcription in over 30 cell types which possess this receptor; and (d) a plasma membrane receptor, VDR(mem), that is involved in initiation of signal transduction pathways which generate rapid biological responses. This article reviews the evidence that supports the conclusions that the LBD of the DBP, VDR(mem) and VDR(nuc) each select as their preferred ligand a unique shape of the conformationally flexible 1alpha,25(OH)(2)D(3). Two critical aspects of the conformationally flexible 1alpha,25(OH)(2)D(3) molecule which defines the optimum ligand shape are (a) the orientation and relative rigidity of the flexible 8 carbon side chain and (b) the position of the A ring in relation to the C/D rings as determined by the extent of rotation around the 6,7 single carbon bond of the seco B ring. These conclusions are based on consideration of structure-function studies of over 300 analogs of 1alpha,25(OH)(2)D(3), of these, 22 analogs are highlighted in this presentation.

Animals↗
PubMedDate not supplied

Different shapes of the steroid hormone 1alpha,25(OH)(2)-vitamin D(3) act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses.

Vitamin D(3) produces biologic responses as a consequence of its metabolism into 1alpha,25(OH)(2)-vitamin D(3) [1alpha,25(OH)(2)D(3)] and 24R,25(OH)(2)-vitamin D(3). The metabolic production of these two seco steroids and their generation of the plethora of biologic actions that are attributable to the parent vitamin D(3) are orchestrated via the integrated operation of the vitamin D endocrine system. This system is very similar in its organization to that of classic endocrine systems and is characterized by an endocrine gland (the kidney, the source of the two steroid hormones), target cells which possess receptors for the steroid hormones, and a feed-back loop involving changes in serum Ca(2+) that alter the secretion of parathyroid hormone (a stimulator of the renal 1-hydroxylase) which modulates the output by the kidney of the steroid hormones. There are, however, at least two unique aspects to the vitamin D endocrine system. (a) The chemical structures of vitamin D and its steroid hormones dictate that these be highly conformationally flexible molecules present a wide variety of shapes to their biologic environments. (b) It is now believed that 1alpha,25(OH)(2)D(3) produces biologic responses through two distinct receptors which recognize totally different shapes of the conformationally flexible 1alpha,25(OH)(2)D(3). Thus, the classic actions of 1alpha,25(OH)(2)D(3) to regulate gene transcription occur as a consequence of the stereospecific interaction of a modified 6-s-trans bowl-shape of 1alpha,25(OH)(2)D(3) with its nuclear receptor (VDR(nuc)). The ability of 1alpha,25(OH)(2)D(3) to generate a variety of rapid (seconds to minutes) biologic responses (opening of chloride channels, activation of PKC and MAP kinases) requires a planar 6-s-cis ligand shape which is recognized by a putative plasma membrane receptor (VDR(mem)) to initiate appropriate signal transduction pathways. This report summarizes the evidence for the specificity of different ligand shapes and the operation of the two receptor families for 1alpha,25(OH)(2)D(3).

Animals↗
PubMed2005

NMD microarray analysis for rapid genome-wide screen of mutated genes in cancer.

Gene mutations play a critical role in cancer development and progression, and their identification offers possibilities for accurate diagnostics and therapeutic targeting. Finding genes undergoing mutations is challenging and slow, even in the post-genomic era. A new approach was recently developed by Noensie and Dietz to prioritize and focus the search, making use of nonsense-mediated mRNA decay (NMD) inhibition and microarray analysis (NMD microarrays) in the identification of transcripts containing nonsense mutations. We combined NMD microarrays with array-based CGH (comparative genomic hybridization) in order to identify inactivation of tumor suppressor genes in cancer. Such a "mutatomics" screening of prostate cancer cell lines led to the identification of inactivating mutations in the EPHB2 gene. Up to 8% of metastatic uncultured prostate cancers also showed mutations of this gene whose loss of function may confer loss of tissue architecture. NMD microarray analysis could turn out to be a powerful research method to identify novel mutated genes in cancer cell lines, providing targets that could then be further investigated for their clinical relevance and therapeutic potential.

Animals↗
PubMed2004

Significance of the genetic relationships deduced from partial nucleotide sequencing of infectious bursal disease virus genome segments A or B.

The rapid genomic characterization of infectious bursal disease virus (IBDV) requires determining which partial nucleotide (nt) sequences derived from IBDV segments A or B would produce phylogenetic information as significant as sequencing the whole corresponding segments. Long nt coding sequences of 27 IBDV segments A (aa 20-991) and 21 segments B (aa 7-stop codon) were retrieved from databanks and used to compute reference phylogenetic trees using Neighbor Joining (NJ) and Parsimony (P): clusters appearing in the NJ and P reference trees with a bootstrap value greater than 80% were considered as significant (Whole Segment Clusters, WSC). The sequences were then cut into overlapping regions. These were used to compute phylogenetic trees which were compared with reference ones. Of the partial sequences, the VP2 gene best represented IBDV segment A (10 out of 13 WSC were conserved), and the 5' two thirds of segment B best represented segment B (5 to 6 conserved WSC out of 6). Implementation of the Plato programme finally demonstrated that the region encoding VP2 variable domain (vVP2, segment A) is the only region of IBDV genome with a significantly different evolution rate, which result is consistent with vVP2 being subjected to a high selection pressure.

Databases, Genetic↗
PubMed1992

Aldosterone-specific membrane receptors and rapid non-genomic actions of mineralocorticoids.

Functional studies in extrarenal, non-epithelial cells such as smooth muscle cells and more recently circulating human lymphocytes have provided increasing evidence that aldosterone produces not only classical genomic effects, but also rapid, non-genomic effects on transmembrane electrolyte movements. These involve activation of the sodium/proton exchanger of the cell membrane at very low, physiological concentrations of aldosterone with an acute onset within 1-2 min. A second messenger cascade involved is the inositol 1,4,5-trisphosphate/calcium pathway which responds over the same rapid time course. Such changes clearly cannot be explained by genomic mechanisms, which are responsible for later effects than the membrane related rapid responses. The mechanisms underlying these rapid effects of aldosterone on electrolytes have been extensively studied in human lymphocytes, which thus may represent valuable tools in the delineation of the receptor-effector mechanisms involved. The unique characteristics of this new pathway for steroid action include its rapid time course, 10,000-fold selectivity for aldosterone over cortisol and the ineffectiveness of spironolactones, classical mineralocorticoid antagonists, as antagonists of the response.

Aldosterone↗
PubMed2005

Allopolyploidy--a shaping force in the evolution of wheat genomes.

Recent studies have shown that allopolyploidy accelerates genome evolution in wheat in two ways: (1) allopolyploidization triggers rapid genome changes (revolutionary changes) through the instantaneous generation of a variety of cardinal genetic and epigenetic alterations, and (2) the allopolyploid condition facilitates sporadic genomic changes during the life of the species (evolutionary changes) that are not attainable at the diploid level. The revolutionary changes comprise (1) non-random elimination of coding and non-coding DNA sequences, (2) epigenetic changes such as DNA methylation of coding and non-coding DNA leading, among others, to gene silencing, (3) activation of genes and retroelements which in turn alters the expression of adjacent genes. These highly reproducible changes occur in the F1 hybrids or in the first generation(s) of the nascent allopolyploids and were similar to those that occurred twice in nature: first in the formation of allotetraploid wheat (approximately 0.5 million years ago) and second in the formation of hexaploid wheat (approximately 10,000 years ago). Elimination of non-coding sequences from one of the two homoeologous pairs in tetraploids and from two homoeologous pairs in hexaploids, augments the differentiation of homoeologous chromosomes at the polyploid level, thus providing the physical basis for the diploid-like meiotic behavior of allopolyploid wheat. Regulation of gene expression may lead to improved inter-genomic interactions. Gene inactivation brings about rapid diploidization while activation of genes through demethylation or through transcriptional activation of retroelements altering the expression of adjacent genes, leads to novel expression patterns. The evolutionary changes comprise (1) horizontal inter-genomic transfer of chromosome segments between the constituent genomes, (2) production of recombinant genomes through hybridization and introgression between different allopolyploid species or, more seldom, between allopolyploids and diploids, and (3) mutations. These phenomena, emphasizing the plasticity of the genome with regards to both structure and function, might improve the adaptability of the newly formed allopolyploids and facilitate their rapid and successful establishment in nature.

Chromosomes, Plant↗
PubMed2006

[Development of rapid and simple genomic diagnostic method].

To develop the rapid and simple genomic diagnostic method, we analyzed the partial dnaA sequence of 27 mycobacterial species. The partial dnaA sequence could distinguish M. kansasii and M. gastri. Based on this region and RLEP sequence of M. leprae, we established the loop-mediated isothermal amplification method (LAMP) to detect each species. The LAMP method for M. kansasii and M. gastri, could detect 500 copies. Five copies of M. leprae genomic DNA could be detect in 30min. To simplify the sample processing, the LAMP assay was performed with FTA filter paper. M. leprae bacilli were applied on filter paper that lyses bacilli and bound DNA, eliminating sample centrifugation and extraction procedures. Assays of number standards showed reproducible detection rate 50 bacilli of M. leprae. Thus, The LAMP assay combined with FTA card has the advantages of rapid and simple detection and provides a practical, economical, and specific method for the diagnosis of M. leprae and NTM infection.

Bacterial Proteins↗
PubMed2005

Polyploidy and genome evolution in plants.

Genome doubling (polyploidy) has been and continues to be a pervasive force in plant evolution. Modern plant genomes harbor evidence of multiple rounds of past polyploidization events, often followed by massive silencing and elimination of duplicated genes. Recent studies have refined our inferences of the number and timing of polyploidy events and the impact of these events on genome structure. Many polyploids experience extensive and rapid genomic alterations, some arising with the onset of polyploidy. Survivorship of duplicated genes are differential across gene classes, with some duplicate genes more prone to retention than others. Recent theory is now supported by evidence showing that genes that are retained in duplicate typically diversify in function or undergo subfunctionalization. Polyploidy has extensive effects on gene expression, with gene silencing accompanying polyploid formation and continuing over evolutionary time.

Evolution, Molecular↗
PubMed2001

Protein structure prediction in genomics.

As the number of completely sequenced genomes rapidly increases, including now the complete Human Genome sequence, the post-genomic problems of genome-scale protein structure determination and the issue of gene function identification become ever more pressing. In fact, these problems can be seen as interrelated in that experimentally determining or predicting or the structure of proteins encoded by genes of interest is one possible means to glean subtle hints as to the functions of these genes. The applicability of this approach to gene characterisation is reviewed, along with a brief survey of the reliability of large-scale protein structure prediction methods and the prospects for the development of new prediction methods.

Animals↗
PubMed2026

Genomic Sequencing in Neonatal Encephalopathy and Suspected Hypoxic-Ischaemic Encephalopathy: A Systematic Review.

BACKGROUND: Neonatal encephalopathy (NE) is a major cause of neonatal mortality and long-term neurological disability. Although hypoxic-ischaemic encephalopathy (HIE) is the most common cause, several genetic disorders may mimic or coexist with hypoxic-ischaemic injury. Next-generation sequencing has emerged as a promising diagnostic tool in this setting. This systematic review evaluated the current evidence on genomic sequencing in NE. MATERIAL AND METHODS: A systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in PROSPERO. PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included neonates (≤28 days) with NE, suspected or confirmed HIE, HIE mimics, or unexplained NE who underwent genomic sequencing. Whole-exome sequencing (WES), whole-genome sequencing (WGS), clinical exome sequencing (CES), rapid genomic sequencing, and targeted next-generation sequencing panels were considered. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Seven studies met the inclusion criteria. Considerable heterogeneity was observed regarding patient selection, sequencing strategies, and reported outcomes. Among diagnostic sequencing studies, diagnostic yield ranged from 23.5% to 53.1%. Pathogenic and likely pathogenic variants were identified in genes associated with developmental and epileptic encephalopathies, metabolic disorders, mitochondrial diseases, and neurodevelopmental syndromes, including SCN2A, KCNQ2, CACNA1A, STXBP1, PTPN11, BCOR, MMUT, COQ2, and GBE1. Genomic sequencing frequently refined or changed the initial diagnosis, improved prognostic assessment and genetic counselling, and, in selected cases, guided disease-specific treatment. One study investigated genetic susceptibility to hypoxic-ischaemic injury rather than diagnostic sequencing. CONCLUSIONS: Genomic sequencing provides clinically meaningful diagnoses in a substantial proportion of neonates with unexplained NE or atypical HIE presentations. Current evidence supports integrating genomic sequencing into the diagnostic evaluation of selected infants, although larger prospective studies are needed to define its optimal timing, clinical utility, and cost-effectiveness.

Humans↗
PubMed2006

Genome Annotation Transfer Utility (GATU): rapid annotation of viral genomes using a closely related reference genome.

BACKGROUND: Since DNA sequencing has become easier and cheaper, an increasing number of closely related viral genomes have been sequenced. However, many of these have been deposited in GenBank without annotations, severely limiting their value to researchers. While maintaining comprehensive genomic databases for a set of virus families at the Viral Bioinformatics Resource Center http://www.biovirus.org and Viral Bioinformatics - Canada http://www.virology.ca, we found that researchers were unnecessarily spending time annotating viral genomes that were close relatives of already annotated viruses. We have therefore designed and implemented a novel tool, Genome Annotation Transfer Utility (GATU), to transfer annotations from a previously annotated reference genome to a new target genome, thereby greatly reducing this laborious task. RESULTS: GATU transfers annotations from a reference genome to a closely related target genome, while still giving the user final control over which annotations should be included. GATU also detects open reading frames present in the target but not the reference genome and provides the user with a variety of bioinformatics tools to quickly determine if these ORFs should also be included in the annotation. After this process is complete, GATU saves the newly annotated genome as a GenBank, EMBL or XML-format file. The software is coded in Java and runs on a variety of computer platforms. Its user-friendly Graphical User Interface is specifically designed for users trained in the biological sciences. CONCLUSION: GATU greatly simplifies the initial stages of genome annotation by using a closely related genome as a reference. It is not intended to be a gene prediction tool or a "complete" annotation system, but we have found that it significantly reduces the time required for annotation of genes and mature peptides as well as helping to standardize gene names between related organisms by transferring reference genome annotations to the target genome. The program is freely available under the General Public License and can be accessed along with documentation and tutorial from http://www.virology.ca/gatu.

Amino Acid Sequence↗
PubMed1993

Genomic scanning for expressed sequences in Xp21 identifies the glycerol kinase gene.

Rapid genomic scanning methods are required to identify expressed sequences and we report an efficient, sensitive and specific approach which relies upon hybridization of an amplified, labeled cDNA library to digested cosmid DNA. We identified expressed sequences within a cosmid in the glycerol kinase (GK) "critical region" of Xp21 that had impressive similarity to prokaryotic GKs. We used this genomic sequence information to clone the human hepatic GK cDNA. Independent confirmation of the identity of this gene was obtained by functional complementation of GK deficient E. coli mutants with a construct containing the complete human X-linked GK coding sequence.

Amino Acid Sequence↗
PubMed2003

A rapid method of genomic array analysis of scaffold/matrix attachment regions (S/MARs) identifies a 2.5-Mb region of enhanced scaffold/matrix attachment at a human neocentromere.

Human neocentromeres are fully functional centromeres that arise at previously noncentromeric regions of the genome. We have tested a rapid procedure of genomic array analysis of chromosome scaffold/matrix attachment regions (S/MARs), involving the isolation of S/MAR DNA and hybridization of this DNA to a genomic BAC/PAC array. Using this procedure, we have defined a 2.5-Mb domain of S/MAR-enriched chromatin that fully encompasses a previously mapped centromere protein-A (CENP-A)-associated domain at a human neocentromere. We have independently verified this procedure using a previously established fluorescence in situ hybridization method on salt-treated metaphase chromosomes. In silico sequence analysis of the S/MAR-enriched and surrounding regions has revealed no outstanding sequence-related predisposition. This study defines the S/MAR-enriched domain of a higher eukaryotic centromere and provides a method that has broad application for the mapping of S/MAR attachment sites over large genomic regions or throughout a genome.

Cell Line, Transformed↗
PubMed2005

Shared molecular characteristics of successfully transformed mitochondrial genomes in Chlamydomonas reinhardtii.

Three types of respiratory deficient mitochondrial strains have been reported in Chlamydomonas reinhardtii: a deficiency due to (i) two base substitutions causing an amino acid change in the apocytochrome b (COB) gene (i.e., strain named dum-15), (ii) one base deletion in the COXI gene (dum-19), or (iii) a large deletion extending from the left terminus of the genome to somewhere in the COB gene (dum-1, -14, and -16). We found that these respiratory deficient strains of C. reinhardtii can be divided into two groups: strains that are constantly transformable and those could not be transformed in our experiments. All transformable mitochondrial strains were limited to the type that has a large deletion in the left arm of the genome. For these mitochondria, transformation was successful not only with purified intact mitochondrial genomes but also with DNA-constructs containing the compensating regions. In comparison, mitochondria of all the non-transformable strains have both of their genome termini intact, leading us to speculate that mitochondria lacking their left genome terminus have unstable genomes and might have a higher potential for recombination. Analysis of mitochondrial gene organization in the resulting respiratory active transformants was performed by DNA sequencing and restriction enzyme digestion. Such analysis showed that homologous recombination occurred at various regions between the mitochondrial genome and the artificial DNA-constructs. Further analysis by Southern hybridization showed that the wild-type genome rapidly replaces the respiratory deficient monomer and dimer mitochondrial genomes, while the E. coli vector region of the artificial DNA-construct likely does not remain in the mitochondria.

Animals↗
PubMed2006

Direct and rapid modification of a porcine xenoantigen gene (GGTA1).

The ability to modify animal genomes rapidly at a specific locus would be valuable both for research purposes and in the development of animals suitable for xenotransplantation. In a proof-of-concept study, we used a unique, homology-dependent strand transferase protein called drosophila recombination-associated protein (DRAP) and DNA oligonucleotides to modify the porcine gene encoding alpha 1,3 galactosyl transferase (GGTA1). This gene is responsible for generating xenotransplantation antigens resulting in hyperacute rejection. Pronuclear injection of DRAP and mutant oligonucleotides yielded piglets with heritable, modified alleles of GGTA1 in a direct, rapid and efficient manner. Cells derived from these piglets had markedly reduced alpha 1,3 galactosyl sugar epitopes. The simplicity of this method should permit rapid sequential or simultaneous modification of the various genes encoding or producing antigens that impose limits on xenotransplantation as they are discovered.

Amino Acid Sequence↗
PubMed2000

Baculovirus infection blocks the progression of fat body degradation during metamorphosis in Bombyx mori.

The effect of baculovirus infection into silkworm pupa particularly on programmed fat body degradation during metamorphosis was investigated. Pupal fat body degradation did not occur following infection with Bombyx mori nucleopolyhedrovirus (BmNPV). There were no histolytic differences between the fat body tissues of mock and BmNPV infected papae until 48 h postinfection (p.i.). Between 48 and 72 h p.i., significant differences were observed. In order to determine whether the histolysis of fat body was due to apoptosis, genomic DNAs were purified at various p.i. times and analyzed. Rapid genomic DNA fragmentation was observed at 24 and 48 h after pupation in both mock and BmNPV infected pupae. However, BmNPV infection clearly inhibited DNA fragmentation and ladder formation at 72 h and later times p.i. Furthermore, pulse-labeling analysis showed that BmNPV infection restored protein synthesis in fat body cells. These results suggested that fat body degradation during pupal-adult development was due to apoptosis, and that BmNPV was able to evoke a cellular response in these cells.

Animals↗
PubMed2004

In silico comparative analysis reveals a mosaic conservation of genes within a novel colinear region in wheat chromosome 1AS and rice chromosome 5S.

Comparative RFLP mapping has revealed extensive conservation of marker order in different grass genomes. However, microcolinearity studies at the sequence level have shown rapid genome evolution and many exceptions to colinearity. Most of these studies have focused on a limited size of genomic fragment and the extent of microcolinearity over large distances or across entire genomes remains poorly characterized in grasses. Here, we have investigated the microcolinearity between the rice genome and a total of 1,500 kb from physical BAC contigs on wheat chromosome 1AS. Using ESTs mapped in wheat chromosome bins as an additional source of physical data, we have identified 27 conserved orthologous sequences between wheat chromosome 1AS and a region of 1,210 kb located on rice chromosome 5S. Our results extend the orthology described earlier between wheat chromosome group 1S and rice chromosome 5S. Microcolinearity was found to be frequently disrupted by rearrangements which must have occurred after the divergence of wheat and rice. At the Lr10 orthologous loci, microrearrangements were due to the insertion of mobile elements, but also originated from gene movement, amplification, deletion and inversion. These mechanisms of genome evolution are at the origin of the mosaic conservation observed between the orthologous regions. Finally, in silico mapping of wheat genes identified an intragenomic colinearity between fragments from rice chromosome 1L and 5S, suggesting an ancestral segmental duplication in rice.

Chromosome Aberrations↗
PubMed2003

Formation of stable epialleles and their paramutation-like interaction in tetraploid Arabidopsis thaliana.

Polyploidization is found frequently in plants, and species previously considered to be diploid may show remnants of earlier polyploidization events on closer inspection of their genomes. The success of polyploids may lie in increased genetic redundancy supporting subsequent genetic diversification. Although doubling the genome does not generate diversity per se, recent studies show that rapid genomic rearrangements and changes in DNA modification and gene expression patterns are associated with polyploid formation. But recessive modifications will not become phenotypically apparent in early polyploid generations. Here we show that epialleles in tetraploid plants (but not in diploids) interact in trans and lead to heritable gene silencing persisting after segregation from the inactivating allele. This mechanism, resembling paramutation, leads to the establishment of functional epigenetic homozygosity and, thus, to conversion of new recessive alleles into traits expressed in early polyploid generations. Such interactions probably contribute to rapid adaptation and evolution of polyploid plant species.

Alleles↗