The SRA gene: the key to understanding the nature of Trypanosoma brucei rhodesiense.
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Animals↗
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Sequencing of Neisseria meningitidis penA gene: the key to success in defining penicillin G breakpoints.
Testing of susceptibility to penicillin G by E-test and sequencing of an internal fragment of the penA gene were done for 43 meningococcal strains. Those strains for which the MIC was >/=0.094 micro g/ml showed mosaic alleles, so 0.094 micro g/ml is suggested as the penicillin G intermediate breakpoint when E-test is used.
Alleles↗
Analysis of the nucleotide sequence of the Streptomyces glaucescens tcmI genes provides key information about the enzymology of polyketide antibiotic biosynthesis.
Key information about the biosynthesis of polyketide metabolites has been uncovered by sequence analysis of the tetracenomycin C polyketide synthase genes (tcml) from Streptomyces glaucescens GLA.0. The sequence data revealed the presence of three complete open reading frames (ORFs). ORF1 and ORF2 appear to be translationally coupled and would encode proteins containing 426 and 405 amino acids, respectively. The two deduced proteins are homologous to known beta-ketoacyl synthases. ORF3 begins 70 nucleotides after the stop codon of ORF2 and would code for an 83 amino acid protein with a strong resemblance to known bacterial, animal and plant acyl-carrier proteins (ACP). The presence of an ACP gene within the tcm gene cluster suggests that different ACPs are used in fatty acid and polyketide biosynthesis in Streptomyces. We conclude from these data and earlier information that polyketide biosynthesis in S. glaucescens, and most likely in other bacteria, involves a multienzyme complex consisting of at least five types of enzymes: acylCoA transferases that load the acyl and 2-carboxyacyl precursors onto the ACP; a beta-ketoacyl synthase that, along with the acylated ACP, forms the poly-beta-ketoacyl intermediates; a poly-beta-ketone cyclase that forms carbocyclic structures from the latter intermediates; a beta-ketoacyl oxidoreductase that forms beta-hydroxyacyl intermediates or reduces ketone groups in fully formed polyketides; and a thioesterase that releases the assembled polyketide from the enzyme.
Amino Acid Sequence↗
Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture.
A singular challenge in stem cell research today is the expansion and propagation of functional adult stem cells. Unlike embryonic stem cells, which are immortal in culture, adult stem cells are notorious for the difficulty encountered when attempts are made to expand them in culture. One overlooked reason for this difficulty may be the inherent asymmetric cell kinetics of stem cells in postnatal somatic tissues. Senescence is the expected fate of a culture whose growth depends on adult stem cells that divide with asymmetric cell kinetics. Therefore, the bioengineering of strategies to expand adult stem cells in culture requires knowledge of cellular mechanisms that control asymmetric cell kinetics. The properties of several genes recently implicated to function in a cellular pathway(s) that regulates asymmetric cell kinetics are discussed. Understanding the function of these genes in asymmetric cell kinetics mechanisms may be the key that unlocks the adult stem cell expansion problem.
Animals↗
The trfB region of broad host range plasmid RK2: the nucleotide sequence reveals incC and key regulatory gene trfB/korA/korD as overlapping genes.
We report the nucleotide sequence of the trfB region of broad host range plasmid RK2. This region encodes the following loci: trfB, identical to korA and korD, which encodes a key transcriptional repressor of certain RK2 operons; incC, which appears to be involved in plasmid maintenance, possibley through post-transcriptional regulation of trfA product levels; the start of korB, which encodes a second transcriptional repressor of operons involved in stable inheritance of RK2. These loci are expressed as part of the trfB operon. In combination with deletion analysis, transcriptional and translation fusions and 'maxicell' analysis of polypeptides, the DNA sequence allows a number of conclusions to be drawn. First, the korB ORF start codon overlaps the incC ORF stop codon, suggesting the possibility of translational coupling between these two genes. Second, the trfB ORF lies entirely within the first third of the incC ORF using a different phase. Third, the incC ORF appears to contain a second transcriptional start whose function appears to be coupled to translation of the trfB ORF. Analysis of codon usage in the region of overlap between incC and trfB suggests that the incC gene may have evolved before the trfB gene. Determination of the DNA sequence of a mutant in which the product of trfB is rendered defective for transcriptional repression reveals an amino acid alteration within a region of this polypeptide which exhibits homology to the alpha helix-turn-alpha helix motif characteristic of many DNA binding proteins, and which is probably responsible for recognition of the trfB operator by this protein.
Amino Acid Sequence↗
Bioinformatics analysis of ferroptosis in frozen shoulder.
OBJECTIVES: Frozen shoulder is a common shoulder disease that significantly affects the patient's life and work. Ferroptosis is a new type of programmed cell death, which is involved in many diseases. However, there have been no studies reporting the relationship between frozen shoulders and ferroptosis. This study identified potential molecular markers of ferroptosis in frozen shoulders to provide more effective strategies for the treatment of frozen shoulders. METHODS: GSE238053 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes to obtain differentially expressed genes (DEGs). The signaling pathways and biological functions of DEGs were performed by WebGestalt and Metascape. The interactions related to these DEGs and the key genes between frozen shoulders and ferroptosis was performed by STRING and Cytoscape. A frozen shoulders rat model was used to validate our predicted genes, Western Blot and qRT-PCR was used to assess the expression levels of our genes of interest. RESULTS: A total of 34 DEGs between GSE238053 and Ferroptosis Database were obtained, most of which were involved in the HIF-1 signaling pathway and inflammatory response. A protein-protein interaction network was obtained by Cytoscape and the key genes (IL-6, HMOX1 and TLR4) were screened by MCODE. Our results of Western Blot showed that the protein expression level of TLR4 and HMOX1 were elevated, and the protein level of IL-6 decreased in frozen shoulders rat model. The mRNA level after frozen shoulders showed that IL-6 was upregulated, whereas TLR4 and HMOX1were downregulated. CONCLUSIONS: The results demonstrated that ferroptosis may affect the pathological process of frozen shoulders through these signaling pathways and genes. The identification of IL-6, HMOX1 and TLR4 genes can provide new therapeutic targets for frozen shoulders.
Ferroptosis↗
The Enterococcus faecalis fsrB gene, a key component of the fsr quorum-sensing system, is associated with virulence in the rabbit endophthalmitis model.
We used a rabbit endophthalmitis model to explore the role of fsrB, a gene required for the function of the fsr quorum-sensing system of Enterococcus faecalis, in pathogenicity. A nonpolar deletion mutant of fsrB had significantly reduced virulence compared to wild type. Complementation of mutation restored virulence. These data corroborate the role of fsrB in E. faecalis pathogenesis and suggest that the rabbit endophthalmitis model can be used to study the in vivo role of quorum sensing.
Animals↗
Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture.
A singular challenge in stem cell research today is the expansion and propagation of functional adult stem cells. Unlike embryonic stem cells, which are immortal in culture, adult stem cells are notorious for the difficulty encountered when attempts are made to expand them in culture. One overlooked reason for this difficulty may be the inherent asymmetric cell kinetics of stem cells in postnatal somatic tissues. Senescence is the expected fate of a culture whose growth depends on adult stem cells that divide with asymmetric cell kinetics. Therefore, the bioengineering of strategies to expand adult stem cells in culture requires knowledge of cellular mechanisms that control asymmetric cell kinetics. The properties of several genes recently implicated to function in a cellular pathway(s) that regulates asymmetric cell kinetics are discussed. Understanding the function of these genes in asymmetric cell kinetics mechanisms may be the key that unlocks the adult stem cell expansion problem.
Adult↗
Fasting activates the gene expression of UCP3 independent of genes necessary for lipid transport and oxidation in skeletal muscle.
Fasting triggers a complex array of adaptive metabolic and hormonal responses including an augmentation in the capacity for mitochondrial fatty acid (FA) oxidation in skeletal muscle. This study hypothesized that this adaptive response is mediated by increased mRNA of key genes central to the regulation of fat oxidation in human skeletal muscle. Fasting dramatically increased UCP3 gene expression, by 5-fold at 15 h and 10-fold at 40 h. However the expression of key genes responsible for the uptake, transport, oxidation, and re-esterification of FA remained unchanged following 15 and 40 h of fasting. Likewise there was no change in the mRNA abundance of transcription factors. This suggests a unique role for UCP3 in the regulation of FA homeostasis during fasting as adaptation to 40 h of fasting does not require alterations in the expression of other genes necessary for lipid metabolism.
Adaptation, Physiological↗
Structure, function and evolution of sex-determining systems in Dipteran insects.
Nature has evolved an astonishing variety of genetic and epigenetic sex-determining systems which all achieve the same result, the generation of two sexes. Genetic and molecular analyses, mainly performed during the last 20 years, have gradually revealed the mechanisms that govern sexual differentiation in a few model organisms. In this review, we will introduce the sex-determining system of Drosophila and compare the fruitfly to the housefly Musca domestica and other Dipteran insects. Despite the ostensible variety, all these insects use the same basic strategy: a primary genetic signal that is different in males and females, a key gene that responds to the primary signal, and a double-switch gene that eventually selects between two alternative sexual programmes. These parallels, however, do not extend to the molecular level. Except for the double-switch gene doublesex at the end of the cascade, no functional homologies were found between more distantly related insects. In particular, Sex-lethal, the key gene that controls sexual differentiation in Drosophila, does not have a sex-determining function in any other genus studied so far. These results show that sex-determining cascades, in comparison to other regulatory pathways, evolve much more rapidly.
Alternative Splicing↗
[Cloning and analysis of cDNA encoding key enzyme gene (dxr) of the non-MVA pathway in Taxus chinensis cells].
Two distinct routes (classical mevalonate pathway and a novel mevalonate-independent pathway) are utilized by plants for the biosynthesis of isopentenyl diphosphate, the universal precursor of isoprenoids (Fig. 1). Present researches indicated that taxol was synthesized mainly via non-mevalonate pathway, but not genetic evidence was showed. The second step in non-mevalonate pathway involves an intramolecular rearrangement and subsequent reduction of deoxyxylulose phosphate to yield 2-C-methyl-D-erythritol-4-phosphate, and 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) with responsibility for this reaction was considered as a key enzyme. As a tool for the isolation of genes in terpenoid biosynthesis in plants, total RNA was prepared from Taxus chinensis suspension cells, a cell type highly specialized for diterpene (taxol). A reverse transcription-PCR strategy based on the design of degenerated oligonucleotides was developed for isolating the gene encoding a gymnosperm homolog of this enzyme from Taxus chinensis. Through sequence analysis by Blast P online, the resulting cDNA showed highly homologous to 1-deoxy-D-xylulose 5-phosphate reductoisomerases, with 95% identification compared with Arabidopsis thaliana (Q9XFS9), 94% with Mentha x piperita (Q9XESO), 80% with Synechococcus elongatus (Q8DK30), 78% with Synechocystis sp. PCC 6803 (Q55663) and Nostoc sp. PCC 7120 (Q8YP49), and 73% with Synechococcus leopoliensis (Q9RKT1). Deduced amino acid sequences were also analyzed by PROSITE, ClustalX (1.81) and Phylio (3.6 alpha), and data present evidence for the existence of this deoxyxyluose phosphate reductoisomerase in Taxus chinensis. This is the first report of the dxr gene cloned from gymnosperm.
Aldose-Ketose Isomerases↗
Genomic and evolutionary analysis reveals dynamic variations of MKK3 gene, a key regulator for seed dormancy in barley.
Barley (Hordeum vulgare L.) is an important crop in the world, and its seed dormancy is primarily controlled by a mitogen-activated protein kinase kinase 3 (MKK3) gene. Although kinase activity of MKK3 and its roles in barley post-domestication have been widely studied, the pre-domestication evolution of MKK3 and the spread of nondormant alleles among global barley varieties remain largely unexplored. In this study, we analyzed MKK3 sequences in barley and its wild progenitor (Hordeum spontaneum K. Koch) and identified two polymorphic miniature inverted-repeat transposable elements (MITEs). Comparative analyses indicated that the insertions/excision of the MITEs predated the current estimates of barley domestication. Examination of the barley pangenomes coupled with droplet digital polymerase chain reaction revealed extensive copy number variation of MKK3 and suggested that transposons likely contributed to tandem amplification of the MKK3 gene on chromosome 5H. Additionally, approximately 1-Kb MKK3 sequences were found on chromosomes 1H and 6H. Further analysis indicated that these short MKK3 sequences were captured by a CACTA transposon that also contained fragments from four other expressed genes. The acquisition of MKK3 was estimated to be between 1.9 and 2.5 million years ago. Together, these findings illuminate the dynamic pre-domestication evolution of the MKK3 gene and identify three divergent MKK3 haplotype groups including a unique lineage predominant in Ethiopian germplasm. This study highlights the contribution of transposons to structural diversification and evolutionary differentiation of the MKK3 locus and provides helpful information for understanding the complex history of MKK3 gene in barley and also for improving preharvest sprouting tolerant varieties under distinct natural conditions.
Hordeum↗
Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation.
UNLABELLED: A bioinformatics-based analysis of endochondral bone formation model detected several genes upregulated in this process. Among these genes the dickkopf homolog 3 (Dkk3) was upregulated and further studies showed that its expression affects in vitro and in vivo osteogenesis. This study indicates a possible role of Dkk3 in regulating bone formation. INTRODUCTION: Endochondral bone formation is a complex biological process involving numerous chondrogenic, osteogenic, and angiogenic proteins, only some of which have been well studied. Additional key genes may have important roles as well. We hypothesized that to identify key genes and signaling pathways crucial for bone formation, a comprehensive gene discovery strategy should be applied to an established in vivo model of osteogenesis. MATERIALS AND METHODS: We used in vivo implanted C3H10T1/2 cells that had been genetically engineered to express human bone morphogenetic protein-2 (BMP2) in a tetracycline-regulated system that controls osteogenic differentiation. Oligonucleotide microarray data from the implants (n = 4 repeats) was analyzed using coupled two-way clustering (CTWC) and statistical methods. For studying the effects of dickkopf homolog 3 (Dkk3) in chondrogenesis and osteogenesis, C3H10T1/2 mesenchymal progenitors were used. RESULTS: The CTWC revealed temporal expression of Dkk3 with other chondrogenesis-, osteogenesis-, and Wnt-related genes. Quantitative RT-PCR confirmed the expression of Dkk3 in the implants. C3H10T1/2 cells that expressed Dkk3 in the presence of BMP2 displayed lower levels of alkaline phosphatase and collagen I mRNA expression than control C3H10T1/2 cells that did not express Dkk3. Interestingly, the levels of collagen II mRNA expression, Alcian blue staining, and glucose aminoglycans (GAGs) production were not influenced by Dkk3 expression. In vivo microCT and bioluminescence imaging revealed that co-expression of Dkk3 and BMP2 by implanted C3H10T1/2 cells induced the formation of significantly lower quantities of bone than cells expressing only BMP2. CONCLUSIONS: A bioinformatics analysis enabled the identification of Dkk3 as a pivotal gene with a novel function in endochondral bone formation. Our results showed that Dkk3 might have inhibitory effects on osteogenesis, but no effect on chondrogenesis, indicating that Dkk3 plays a regulatory role in endochondral bone formation. Further mechanistic studies are required to reveal the mechanism of action of Dkk3 in endochondral bone formation.
Adaptor Proteins, Signal Transducing↗
Gene expression in the cell cycle of human T lymphocytes: I. Predicted gene and protein networks.
The key genes involved in the cell cycle of human T lymphocytes were identified by iterative searches of gene-related databases, as derived also from DNA microarray experimentation, revealing and predicting interactions between those genes, assigning scores to each of the genes according to numbers of interaction for each gene weighted by significance of each interaction, and finally applying several types of clustering algorithms to genes basing on the assigned scores. All clustering algorithms applied, both hierarchical and K-means, invariably selected the same six "leader" genes involved in controlling the cell cycle of human T lymphocytes. Relations of the six genes to experimental data describing switching between stages of cell cycle of human T lymphocytes are discussed.
Algorithms↗
Dissection of Tbx1 and Fgf interactions in mouse models of 22q11DS suggests functional redundancy.
The 22q11 deletion syndrome (22q11DS) is characterized by abnormal development of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1 as a key gene in the etiology of the syndrome, in part, via interaction with the fibroblast growth factor (Fgf) genes. Three murine Fgfs, Fgf3, Fgf8 and Fgf10 are coexpressed in different combinations with Tbx1. They are all strongly downregulated in Tbx1-/- embryos, implicating epistatic interactions. Supporting this, Tbx1 and Fgf8 have been shown to genetically interact in the development of the fourth pharyngeal arch artery (PAA) and Fgf10 was identified to be a direct downstream target of Tbx1. To dissect the epistatic relationships of these genes during embryonic development and the molecular pathogenesis of the Tbx1 mutant phenotype, we generated Fgf10+/-;Tbx1+/- and Fgf3-/-;Tbx1+/- mice. Despite strong hypotheses that Fgf10 is the key gene downstream of Tbx1 in the development of the anterior heart field, we do not find evidence for genetic interaction between Tbx1 and Fgf10. Also, the Fgf3-/-;Tbx1+/- mutant mice do not show an additive phenotype. Furthermore, more severe defects do not occur in Fgf8+/-;Tbx1+/- mutants by crossing in the Fgf3 null allele. There is a possible additive effect only in PAA remodeling in the Fgf10+/-;Tbx1+/-;Fgf8+/- embryos. Our findings underscore the importance of potential functional redundancy with additional Fgfs in the development of the pharyngeal apparatus and cardiovascular system via Tbx1. This redundancy should be considered when looking at individual FGF genes as modifiers of 22q11DS.
Animals↗
Involvement of the octadecanoid pathway and protein phosphorylation in fungal elicitor-induced expression of terpenoid indole alkaloid biosynthetic genes in catharanthus roseus
Two key genes in terpenoid indole alkaloid biosynthesis, Tdc and Str, encoding tryptophan decarboxylase and strictosidine synthase, respectively, are coordinately induced by fungal elicitors in suspension-cultured Catharanthus roseus cells. We have studied the roles of the jasmonate biosynthetic pathway and of protein phosphorylation in signal transduction initiated by a partially purified elicitor from yeast extract. In addition to activating Tdc and Str gene expression, the elicitor also induced the biosynthesis of jasmonic acid. The jasmonate precursor alpha-linolenic acid or methyl jasmonate (MeJA) itself induced Tdc and Str gene expression when added exogenously. Diethyldithiocarbamic acid, an inhibitor of jasmonate biosynthesis, blocked both the elicitor-induced formation of jasmonic acid and the activation of terpenoid indole alkaloid biosynthetic genes. The protein kinase inhibitor K-252a abolished both elicitor-induced jasmonate biosynthesis and MeJA-induced Tdc and Str gene expression. Analysis of the expression of Str promoter/gusA fusions in transgenic C. roseus cells showed that the elicitor and MeJA act at the transcriptional level. These results demonstrate that the jasmonate biosynthetic pathway is an integral part of the elicitor-triggered signal transduction pathway that results in the coordinate expression of the Tdc and Str genes and that protein kinases act both upstream and downstream of jasmonates.
Journal Article↗
DNA-binding activity of the A-factor receptor protein and its recognition DNA sequences.
The A-factor receptor protein (ArpA) containing an alpha-helix-turn-alpha-helix DNA-binding consensus sequence at its N-terminal portion plays a key role in the regulation of secondary metabolism and cell differentiation in Streptomyces griseus. A binding site forming a palindrome 24bp in length was initially recovered from a pool of random-sequence oligonucleotides by rounds of a binding/immunoprecipitation/amplification procedure with histidine-tagged ArpA and anti-ArpA antibody. By means of further binding/gel retardation/amplification experiments on the basis of the recovered sequence, a 22 bp palindromic binding site with the sequence 5'-GG(T/C)CGGT(A/T)(T/C)G(T/G)-3' as one half of the palindrome was deduced as a consensus sequence recognized and bound by ArpA. ArpA did not bind to the binding site in the presence of its ligand, A-factor. In addition, exogenous addition of A-factor to the ArpA-DNA complex induced immediate release of ArpA from the DNA. All of these data are consistent with the idea, obtained from previous genetic studies, that ArpA acts as a repressor-type regulator for secondary metabolism and cellular differentiation by preventing the expression of a certain key gene(s) during the early growth phase. A-factor, produced in a growth-dependent manner, releases ArpA from the DNA, thus switching on the expression of the key gene(s), leading to the onset of secondary metabolism and aerial mycelium formation.
Animals↗
Genetic abnormalities in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a very common endocrinopathy and is the major cause of anovulatory infertility. It is also associated with an increased risk of non insulin dependent diabetes (NIDDM) in later life. Despite the importance of PCOS to women's health, little is known about its aetiology. Because of the well-known familial clustering of cases of PCOS, recent studies in our department have focused on clinical and molecular genetic studies in an attempt to identify key genes which may be involved in its aetiology. We have found evidence that a polymorphism in the regulatory region of CYP11a (encoding P450 cholesterol side chain cleavage, also an important enzyme in the steroidogenic pathway) is associated with and linked to PCOS. In examination of the insulin gene (INS), we have shown, in three separate populations, that class III alleles in the INS-VNTR (the minisatellite in the regulatory region of the insulin gene) are associated with PCOS. Variation in this element has also been implicated in the aetiology of NIDDM. We propose that PCOS is an oligogenic disorder in which a small number of key genes interact with environmental factors (notably dietary), the balance of which factors determine, the typically heterogeneous, clinical and biochemical phenotype.
Cholesterol Side-Chain Cleavage Enzyme↗