Chromosomal Assignments of Novel Genes Expressed in HL60 Granulocytes

By collecting 3'-directed cDNA sequences called gene signatures(GSs) on a large scale, it is possible to make an expressionprofile of genes in a particular tissue, as well as discoveringa number of novel genes. A total of 305 novel GSs collectedfrom granulocytoid cells derived from HL60, a human promyelocyticleukemia cell line, by exposure to dimethyl sulfoxide were radiolabeledand used for Southern blot analyses to determine the copy numberof the corresponding genes. Of these, 198 GSs identified asrepresenting single-copy genes were then used as probes forhybridization analyses using a monochromosomal hybrid cell DNApanel. Sixty-nine of them were assigned to individual chromosomes.These results demonstrate that the chromosomal distributionof the GSs seems not to be proportional to the cytogenetic lengthof each chromosome.     

Identifying Novel Drug Targets by iDTPnd: A Case Study of Kinase Inhibitors

Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52% and a specificity of 55%. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein–small molecule interactions, when sufficient drug–target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.     

Detection of Genes with Atypical Nucleotide Sequence in Microbial Genomes

Along the gene, nucleotides in various codon positions tend to exert a slight but observable influence on the nucleotide choice at neighboring positions. Such context biases are different in different organisms and can be used as genomic signatures. In this paper, we will focus specifically on the dinucleotide composed of a third codon position nucleotide and its succeeding first position nucleotide. Using the 16 possible dinucleotide combinations, we calculate how well individual genes conform to the observed mean dinucleotide frequencies of an entire genome, forming a distance measure for each gene. It is found that genes from different genomes can be separated with a high degree of accuracy, according to these distance values. In particular, we address the problem of recent horizontal gene transfer, and how imported genes may be evaluated by their poor assimilation to the host's context biases. By concentrating on the third- and succeeding first position nucleotides, we eliminate most spurious contributions from codon usage and amino-acid requirements, focusing mainly on mutational effects. Since imported genes are expected to converge only gradually to genomic signatures, it is possible to question whether a gene present in only one of two closely related organisms has been imported into one organism or deleted in the other. Striking correlations between the proposed distance measure and poor homology are observed when Escherichia coli genes are compared to Salmonella typhi, indicating that sets of outlier genes in E. coli may contain a high number of genes that have been imported into E. coli, and not deleted in S. typhi. Received: 16 January 2001 / Accepted: 30 August 2001     

Prognostic and predictive role of a metabolic rate‐limiting enzyme signature in hepatocellular carcinoma

ObjectivesAbnormal expression of metabolic rate‐limiting enzymes drives the occurrence and progression of hepatocellular carcinoma (HCC). This study aimed to elucidate the comprehensive model of metabolic rate‐limiting enzymes associated with the prognosis of HCC.Materials and MethodsHCC animal model and TCGA project were used to screen out differentially expressed metabolic rate‐limiting enzyme. Cox regression, least absolute shrinkage and selection operation (LASSO) and experimentally verification were performed to identify metabolic rate‐limiting enzyme signature. The area under the receiver operating characteristic curve (AUC) and prognostic nomogram were used to assess the efficacy of the signature in the three HCC cohorts (TCGA training cohort, internal cohort and an independent validation cohort).ResultsA classifier based on three rate‐limiting enzymes (RRM1, UCK2 and G6PD) was conducted and serves as independent prognostic factor. This effect was further confirmed in an independent cohort, which indicated that the AUC at year 5 was 0.715 (95% CI: 0.653‐0.777) for clinical risk score, whereas it was significantly increased to 0.852 (95% CI: 0.798‐0.906) when combination of the clinical with signature risk score. Moreover, a comprehensive nomogram including the signature and clinicopathological aspects resulted in significantly predict the individual outcomes.ConclusionsOur results highlighted the prognostic value of rate‐limiting enzymes in HCC, which may be useful for accurate risk assessment in guiding clinical management and treatment decisions.     

Plant O-methyltransferases: molecular analysis,common signature and classification

Comparative analysis of the predicted amino acid sequences of a number of plant O-methyltransferase cDNA clones show that they share some 32–71% sequence identity, and can be grouped according to the different compounds they utilise as substrates. Five highly conserved regions are proposed as a signature for plant O-methyltransferases, two of which (regions I and IV) are believed to be involved in S-adenosyl-L-methionine and metal binding, respectively. The glycine-rich signature regions include a 36 amino acid domain which is located in the mid-terminal section of the carboxy terminus of most O-methyltransferase sequences. Cladistic analysis of the amino acid sequences suggests that plant O-methyltransferases may have arisen from common ancestral genes that were driven by different structural and/or functional requirements, and whose descendants segregated into different biochemical species. A comprehensive classification of plant O-methyltransferases is proposed following the guidelines of the Commission of Plant Gene Nomenclature.     

The unique interaction between the summer annual desert plant Salsola inermis Forssk and weevils residing on its roots: mutualism or parasitism?

1. Herbivores and parasites are likely to impose less damage on their host when their growth rate is slow and their dependency on the host is high. Accordingly, it was hypothesised that evolution would favour neutral or even beneficial interactions between a below-ground herbivore and a plant during the harsh season in a desert ecosystem. 2. This study characterised the relationship between the summer annual plant Salsola inermis Forssk (Chenopodiaceae) and weevils developing in a mud chamber attached to its roots in the Negev Desert of Israel. Plant seedlings were exposed to adult weevils (Conorhynchus palumbus Olivier or Menecleonus virgatus Schoenherr; Coleoptera: Curculionidae) in a controlled outside setting, to induce oviposition and larval establishment. The following were quantified: plant growth, above-ground biomass, fruit biomass, and fruit size, as well as relative C and N contents, and isotopic signatures (δ¹³C and δ¹⁵N) in plant tissues. 3. Exposure to weevils did not reduce plant survival but significantly and negatively affected plant growth and seed production. However, these effects were mainly due to above-ground herbivory by adults rather than root herbivory by larvae, and might have been overestimated. Interestingly, %N and δ¹⁵N were significantly higher, and the C:N ratio was significantly lower, in plants with larval establishment, suggesting that weevils affect the plant nitrogen budget. 4. The overall results do not support the notion of mutualistic interactions; yet, slow consumption, a low infestation level, and, possibly, N supplementation to the plant may enable the plant to tolerate herbivory under natural conditions.     

Lung mediated auditory contrast enhancement improves the Signal-to-noise ratio for communication in frogs

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