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PubMed2005

Bayesian decomposition analysis of bacterial phylogenomic profiles.

BACKGROUND: The past two decades have seen the appearance of new infectious diseases and the reemergence of old diseases previously thought to be under control. At the same time, the effectiveness of the existing antibacterials is rapidly decreasing due to the spread of multidrug-resistant pathogens. AIM: The aim of this study was to the identify candidate molecular targets (e.g. enzymes) within essential metabolic pathways specific to a significant subset of bacterial pathogens as the first step in the rational design of new antibacterial drugs. METHODS: We constructed a dataset of phylogenomic profiles (vectors that encode the similarity, measured by BLAST scores, of a gene across many species) for a series of 31 pathogenic bacteria of interest with 1073 genes taken from the reference organisms Escherichia coli and Mycobacterium tuberculosis. We applied Bayesian Decomposition, a matrix decomposition algorithm, to identify functional metabolic units comprising overlapping sets of genes in this dataset. RESULTS: Although no information on phylogeny was provided to the system, Bayesian Decomposition retrieved the known bacteria phylogenic relationships on the basis of the proteins necessary for survival. In addition, a set of genes required by all bacteria was identified, as well as components and enzymes specific to subsets of bacteria. CONCLUSION: The use of phylogenomic profiles and Bayesian Decomposition provide important insights for the design of new antibacterial therapeutics.

Algorithms↗

PubMed2002

Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms.

In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. Our results stress the need for combined genotype analysis when candidate genes are functionally involved in the same pathway.

Adolescent↗

PubMed2026

Integrated multi-omics analysis of metabolomics and proteomics uncovers dysregulated amino acid metabolism in HCC metastasis.

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics. METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients. RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log2 fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis. CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

Humans↗

PubMed1999

[Analysis of susceptibility genes to rheumatic diseases].

Recent evidence suggests that most of the rheumatic diseases are complex or multifactorial diseases with contributions from HLA and multiple non-HLA genes. Studies using candidate gene approach suggested that early components of the complement pathway, Fc receptor IIa, IIIa, mannose-binding lectin, IL-10 and TNFR2 might be potential non-HLA susceptibility genes to systemic lupus erythematosus, although substantial difference among populations are reported. Linkage analyses using affected sib pairs indicated several candidate regions on chromosome 1. A recently completed genome-wide linkage analysis of rheumatoid arthritis revealed a number of possible candidate regions in addition to HLA. Identification of the susceptibility genes will be accelerated along with technological advances and the accomplishment of human genome project, and will deepen our understanding of rheumatic diseases.

Genetic Predisposition to Disease↗

PubMed1999

Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein.

During somatic hypermutation of Ig V genes, mismatched nucleotide substitutions become candidates for removal by the DNA mismatch repair pathway. Previous studies have shown that V genes from mice deficient for the MSH2 and PMS2 mismatch repair proteins have frequencies of mutation that are comparable with those from wild-type (wt) mice; however, the pattern of mutation is altered. Because the absence of MSH2 and PMS2 produced different mutational spectra, we examined the role of another protein involved in mismatch repair, MLH1, on the frequency and pattern of hypermutation. MLH1-deficient mice were immunized with oxazolone Ag, and splenic B cells were analyzed for mutations in their V kappa Ox1 light chain genes. Although the frequency of mutation in MLH1-deficient mice was twofold lower than in wt mice, the pattern of mutation in Mlh1-/- clones was similar to wt clones. These findings suggest that the MLH1 protein has no direct effect on the mutational spectrum.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Prevalence of a 23bp insertion in exon 3 of the endothelial cell protein C receptor gene in venous thrombophilia.

BACKGROUND: The endothelial cell protein C receptor (EPCR) enhances protein C activation by the thrombin-thrombomodulin complex. As evidence is accumulating that EPCR is an important component of the protein C anticoagulant pathway, polymorphisms in the EPCR gene might be candidate risk factors predisposing to venous thromboembolism (VTE). Recently, a 23bp insertion in exon 3 of the EPCR gene has been identified, which duplicates the preceding 23 bases and results in a STOP codon downstream from the insertion point. However, the clinical significance of this mutation in VTE remains to be clarified. METHODS AND RESULTS: In this study we evaluated the EPCR 23bp insertion in 889 patients with documented VTE and in 500 healthy controls. The prevalence of the EPCR insertion among patients was 0.1%, which was not significantly different compared to controls (0.6%, p = 0.1). CONCLUSIONS: Our findings showed that the EPCR 23bp insertion is very rare in both patients with VTE and the general population and failed to support an association between the EPCR 23bp insertion and an increased risk of VTE.

Adult↗

PubMed2001

Molecular-pathogenetic classification of genetic disorders of the skeleton.

Genetic disorders of the skeleton (skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the "Nosology and Classification of the Osteochondrodysplasias," based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on genes and proteins cannot be easily merged into the clinical-radiographic classification. We present here, as a complement to the existing Nosology, a classification of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular-pathogenetic classification should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting research in this field.

Bone Diseases, Developmental↗

PubMed2002

Human limb malformations; an approach to the molecular basis of development.

Analysis of human inherited limb malformations and of mouse mutants copying individual human mutations team up to promote the understanding of vertebrate limb development as a model for molecular regulatory interactions in animals. The strength of the human genetic contribution lies in the increasingly complete information on the human genome, transcriptome and proteome, as well as in the wealth of individual mutations interfering with limb development available for study. Based on the strong fundament of the human genome project, mapping and identification of novel genes associated with limb defects extends considerably the range of candidates beyond the repertoire of developmental genes and pathways known from animals. Attempts to correlate genotype and phenotype uncover a very broad range of genetic heterogeneity, i.e. different genes underlying the same phenotype, or allelic heterogeneity between families, i.e. clinically distinct phenotypes associated with mutations affecting the same gene. Mechanisms other than simple Mendelian inheritance have to be taken into consideration. Phenotypic variability within families might be explained by different modifying genes or environmental influence, whereas asymmetry of limb defects within one patient may be caused by epigenetic factors, such as somatic mosaicism or X-inactivation, or by non-genetic factors. The intimate knowledge of the genes and events governing limb pattern formation in humans and animals will elucidate the regulatory interactions underlying normal and pathological development, homeostasis, and repair, and thus propose targets for preventive measures and novel approaches to therapeutic intervention in the new era of molecular medicine.

Bardet-Biedl Syndrome↗

PubMed2003

In-depth mutation and SNP discovery using DHPLC gene scanning.

Denaturing high-performance liquid chromatography (DHPLC) is a new technology used in the discovery of genetic variations (mutations), such as single-base substitutions (or single nucleotide polymorphisms) and small deletions or insertions. These genetic variations can be routinely detected by DHPLC gene scanning at the germ-line and somatic levels. Epigenetic alterations, such as changes in DNA methylation status at defined loci, can also be assessed using DHPLC-based methodologies. The biological impact of these genetic variations depends on the location and identity of the DNA sequence alteration. The discovery of functionally relevant genetic variations can be exploited throughout the drug discovery and development processes. Examples of the application of DHPLC for sequence variant detection will be presented and discussed, with emphasis on target validation by candidate gene scanning and mutation detection in disease pathway genes, as well as the discovery of therapeutically significant mutations associated with drug metabolism and resistance.

Animals↗

PubMed2003

A tyrosine hydroxylase microsatellite and hemodynamic response to stress in a multi-ethnic sample of youth.

OBJECTIVE: Behavioral stress is believed to have an impact on cardiovascular health. As the rate-limiting enzyme in the pathway for catecholamine synthesis, tyrosine hydroxylase is a candidate gene for variability in cardiovascular function. The aim of this study was to determine whether a relationship exists between a tyrosine hydroxylase microsatellite and resting hemodynamic function, and/or hemodynamic responsivity to laboratory stress. DESIGN: Subjects underwent 2 laboratory stressors: a video game challenge and a social competence interview. SETTING: The stressors were administered in a laboratory setting. PARTICIPANTS: Subjects were 292 10- to 20-year-old normotensive African-American and European-American twin pairs. MAIN OUTCOME MEASURES: Blood pressure (BP) and heart rate (HR) were measured at rest and in response to the stressors. RESULTS: Chi-square analyses using re-sampling to account for the twin design indicated that allele and genotype frequencies were significantly different between European Americans and African Americans (P < or = .0001). Analyses of variance indicated that the 184 and 199 bp alleles were associated with an attenuation of the hemodynamic response to stress with increasing age (P < or = .003, P < or = .002, respectively), while the 188 bp allele was associated with a higher resting systolic blood pressure (SBP) (P < or = .02), and greater hemodynamic response to stress with increasing BMI (P < or = .02). CONCLUSIONS: This study showed that in a multi-ethnic sample of normotensive adolescents, specific alleles of this tyrosine hydroxylase microsatellite were associated with protective or deleterious cardiovascular effects with subjects at rest and responding to stress.

Adolescent↗

PubMed2003

Polo-like kinases and the microtubule organization center: targets for cancer therapies.

Studies from eukaryotic model systems, ranging from yeast to human, indicate that Polo and Polo-like kinases (Plks) are essential for the activity of the microtubule organization center. Polo/Plks localize to centrosomes or spindle pole bodies and undergo dramatic subcellular relocation during the cell cycle. Deregulated activities of Plks often result in abnormalities in centrosome duplication, maturation, and/or microtubule dynamics. Genetic and biochemical approaches have identified several candidate genes that either lie in the same pathway as POLO/PLKs or whose products are direct targets of Polo/Plks during the centrosome cycle. Recent studies have demonstrated that mammalian Plks also regulate the function of the Golgi complex, a cellular organelle closely associated with the centrosome and also having microtubule organization activity. Furthermore, deregulated expression of human PLK1 and PLK3 is strongly correlated with the development of many types of malignancies, and ectopic expression of kinase-active Plk3 or Plk1 dominant negative protein leads to rapid cell death. Given that several effective anti-tumor drugs directly interfere with microtubule dynamics, mammalian Plks are excellent targets for the development of anticancer drugs.

Animals↗

PubMed2004

Expression of IL-18 in patients with head and neck squamous cell carcinoma.

Interleukin-18 (IL-18), a recently described cytokine secreted mainly by macrophages, stimulates interferon-gamma (IFN-gamma) production by natural killer cells and T cells. The purpose of this study was to determine tissue expression and serum levels of IL-18 in head and neck squamous cell carcinoma (HNSCC) and to evaluate ethanol and endotoxin-driven cytokine secretion. In 24 patients with primary HNSCC and 28 healthy controls, PBMC were isolated and incubated with 50 mM ethanol, LPS (doses 25 ng/ml, 250 ng/ml, 2500 ng/ml) and both agents for 24 h. Levels of IL-18 in serum, and cell supernatants were analysed by capture ELISA, IL-18 tissue level by immunoblotting. Serum levels of IL-8, IL-10 and IL-12, IFN-gamma, and endotoxin plasma levels were also determined. Statistical analysis involved Welch t-test and Page's test for trend. The majority of patients with HNSCC had high concentrations of serum IL-18. The level of IL-18 in the sera of these patients had a mean level of 271.7 pg/ml, while the mean IL-18 serum level in healthy controls was 174,0 pg/ml (p<0.001). Levels of IL-10 and IL-12, IFN-gamma were not increased in patients. Endotoxin was not detectable in either group. LPS stimulated dose-dependently IL-18 secretion from PBMC of patients and controls in vitro (p<0.05). Incubation with ethanol alone did not affect basal IL-18 secretion, but ethanol reduced LPS-stimulated IL-18 secretion compared to LPS stimulation alone. The mRNA expression of IL-18 in unstimulated PBMC and the response of PBMC to ethanol and LPS was similar in patients and controls. Our data on elevated serum levels of IL-18 in the majority of HNSCC cancer patients, irrespective of its biological activity, suggest that serum IL-18 might be a candidate for a new marker for HNSCC. The pathways for IL-18 production and its mechanisms of action in patients with HNSCC remain to be determined. Understanding of the immunological pathways might offer new therapeutic options in head and neck cancer in the future.

Carcinoma, Squamous Cell↗

PubMed2004

Shuttle craft: a candidate quantitative trait gene for Drosophila lifespan.

Variation in longevity in natural populations is attributable to the segregation of multiple interacting loci, whose effects are sensitive to the environment. Although there has been considerable recent progress towards understanding the environmental factors and genetic pathways that regulate lifespan, little is known about the genes causing naturally occurring variation in longevity. Previously, we used deficiency complementation mapping to map two closely linked quantitative trait loci (QTL) causing female-specific variation in longevity between the Oregon (Ore) and 2b strains of Drosophila melanogaster to 35B9-C3 and 35C3 on the second chromosome. The 35B9-C3 QTL encompasses a 50-kb region including four genes, for one of which, shuttle craft (stc), mutations have been generated. The 35C3 QTL localizes to a 200-kb interval with 15 genes, including three genes for which mutations exist (reduced (rd), guftagu (gft) and ms(2)35Ci). Here, we report quantitative complementation tests to mutations at these four positional candidate genes, and show that ms(2)35Ci and stc are novel candidate quantitative trait genes affecting variation in Drosophila longevity. Complementation tests with stc alleles reveal sex- and allele-specific failure to complement, and complementation effects are dependent on the genetic background, indicating considerable epistasis for lifespan. In addition, a homozygous viable stc allele has a sex-specific effect on lifespan. stc encodes an RNA polymerase II transcription factor, and is an attractive candidate gene for the regulation of longevity and variation in longevity, because it is required for motoneuron development and is expressed throughout development. Quantitative genetic analysis of naturally occurring variants with subtle effects on lifespan can identify novel candidate genes and pathways important in the regulation of longevity.

Aging↗

PubMed1991

New directions in cancer therapy based on aberrant expression of glycosphingolipids: anti-adhesion and ortho-signaling therapy.

Essentially all tumors express aberrantly glycosylated glycosphingolipids and glycoproteins, more commonly known as "tumor-associated carbohydrate antigens." In this article I propose two new forms of cancer therapy, anti-adhesion therapy and ortho-signaling therapy, which exploit these tumor-associated carbohydrates in distinct ways. The aim of anti-adhesion therapy is to disrupt the requisite carbohydrate-initiated interactions that occur between tumor cells and other cell types (e.g., endothelial cells, platelets) as tumors progress and metastasize. Candidate anti-adhesion agents include purified carbohydrates or glycosphingolipids representing H, Ley, sialosyl-Lex (or -Lea) GM3, or LacCer antigens, and monoclonal antibodies directed to these structures. The aim of ortho-signaling therapy is to disrupt mitogenic signaling pathways in tumor cells that are regulated by glycosphingolipids and/or their derivatives, including pathways involving receptor protein-kinases and protein kinase C. Candidate ortho-signaling agents are the glycosphingolipid regulator PDMP (1-phenyl-2-[decanoylamino]-3-morpholino-1-propanol) and the protein kinase C inhibitor DMS (N,N-dimethylsphingosine), both of which show antitumor activity in vitro and in animal studies.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed2004

Arabidopsis DNA double-strand break repair pathways.

DSBs (double-strand breaks) are one of the most serious forms of DNA damage that can occur in a cell's genome. DNA replication in cells containing DSBs, or following incorrect repair, may result in the loss of large amounts of genetic material, aneuploid daughter cells and cell death. There are two major pathways for DSB repair: HR (homologous recombination) uses an intact copy of the damaged region as a template for repair, whereas NHEJ (non-homologous end-joining) rejoins DNA ends independently of DNA sequence. In most plants, NHEJ is the predominant DSB repair pathway. Previously, the Arabidopsis NHEJ mutant atku80 was isolated and found to display hypersensitivity to bleomycin, a drug that causes DSBs in DNA. In the present study, the transcript profiles of wild-type and atku80 mutant plants grown in the presence and absence of bleomycin are determined by microarray analysis. Several genes displayed very strong transcriptional induction specifically in response to DNA damage, including the characterized DSB repair genes AtRAD51 and AtBRCA1. These results identify novel candidate genes that encode components of the DSB repair pathways active in NHEJ mutant plants.

Arabidopsis↗

PubMed2003

Genetic animal models of anxiety.

The focus of this review is on progress achieved in identifying specific genes conferring risk for anxiety disorders through the use of genetic animal models. We discuss gene-finding studies as well as those manipulating a candidate gene. Both human and animal studies thus far support the genetic complexity of anxiety. Clinical manifestations of these diseases are likely related to multiple genes. While different anxiety disorders and anxiety-related traits all appear to be genetically influenced, it has been difficult to ascertain genetic influences in common. Mouse studies have provisionally mapped several loci harboring genes that affect anxiety-related behavior. The growing array of mutant mice is providing valuable information about how genes and environment interact to affect anxious behavior via multiple neuropharmacological pathways. Classical genetic methods such as artificial selection of rodents for high or low anxiety are being employed. Expression array technologies have as yet not been employed, but can be expected to implicate novel candidates and neurobiological pathways.

Animals↗

PubMed2002

Psychiatric genetics: the case of single gene disorders.

Quantitative and molecular genetics have made important developments in the last three decades. There is increasing evidence of the role of heredity in the field of neuropsychiatric disorders in children. So far, only a few pathways between genes and behaviour have been unravelled. Quantitative genetics puts polygenic inheritance models forward. Molecular genetic research based on these models seems promising, but until now has provided only a limited explanation for the variance in the studied neuropsychiatric disorders. In these models the complexity of the expression of a single gene grows exponentially with the number of genes involved. Consequently, research on the gene-phenotype relationships and phenotypical variability in such models is extremely complex.The candidate gene approach, in which the gene-phenotype pathway of a single gene is studied, is more manageable, and in our opinion essential in understanding multiple gene models. We discuss recent findings in the field and their relevance for neuropsychiatric phenotypes. Single gene defects will only explain a part of the range of neuropsychiatric disorders in children, but the evidence that this approach can generate may help to clarify neuropsychiatric phenotypes. The discovery of single gene disorders in subgroups of subjects with a neuropsychiatric phenotype may result in new perspectives for their treatment.

Autistic Disorder↗

PubMed2004

Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma.

BACKGROUND: Overexpression of the hypoxia inducible factor 1 (HIF-1) and HIF-2 transcription factors and the consequent upregulation of hypoxia inducible mRNAs is a feature of many human cancers and may be unrelated to tissue hypoxia. Thus, the VHL (von Hippel-Lindau) tumour suppressor gene (TSG) regulates HIF-1 and HIF-2 expression in normoxia by targeting the alpha subunits for ubiquitination and proteolysis. Inactivation of the VHL TSG in VHL tumours and in sporadic clear cell renal cell carcinoma (RCC) results in overexpression of HIF-1 and HIF-2. However, RCC without VHL inactivation may demonstrate HIF upregulation, suggesting that VHL independent pathways for HIF activation also exist. In RCC, three candidate HIF activating genes exist-FIH-1 (factor inhibiting HIF), SDHB, and FH-which may be dependent or independent of VHL inactivation. AIMS: To investigate FIH-1, SDHB, and FH for somatic mutations in sporadic RCC. METHODS: Gene mutation was analysed in primary RCCs (clear cell RCCs, papillary RCCs, and oncocytomas) and RCC cell lines. SDHB mutation analysis was performed by denaturing high performance liquid chromatography followed by direct sequencing of aberrant PCR products. FH and FIH-1 mutation analysis were performed by single stranded conformational polymorphism and direct sequencing of PCR products. RESULTS: No mutations were identified in the three genes investigated. CONCLUSIONS: There was no evidence to suggest that somatic mutations occur in the FH, FIH-1, or SDHB TSGs in sporadic RCCs.

Base Sequence↗