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PubMed2026

Elucidating shared genetic signals between type 2 diabetes and three neurodegenerative dementia phenotypes.

Type 2 diabetes (T2D) and dementia frequently co-occur, yet the biological mechanisms underlying this comorbidity remain incompletely understood. Here, we systematically investigate shared genetic signals between T2D and three forms of neurodegenerative dementia (Alzheimer disease, Lewy body dementia, and sporadic frontotemporal dementia) using large-scale genome-wide association studies of clinically diagnosed individuals. We identify five genomic regions harboring shared association signals between T2D and at least one dementia subtype. Among these, the APOE locus was common to all dementia subtypes, whereas the remaining four loci (GBA, CRY2/PEX16/MAPK8IP1, INO80E, and NSF) were each shared exclusively between T2D and one dementia subtype. Integrating multi-omics data across several disease-relevant tissues and orthogonal lines of functional evidence, we prioritize 26 candidate genes through which these shared genetic loci potentially mediate their effect. Pathway enrichment highlights lipid and lipoprotein regulatory biology as a central shared axis. Mendelian randomization analyses using genetically regulated gene expression in relevant tissues indicate pleiotropic mechanisms with divergent phenotypic consequences. Our findings identify shared genetic loci between T2D and neurodegenerative dementia, revealing systemic metabolic-neurodegenerative trade-offs and highlighting key genes that underpin the comorbidity, providing a framework for improved understanding of age-related multi-morbidity.

Alzheimer disease↗

PubMed2002

Individualized total cavopulmonary connection technique for patients with asplenia syndrome.

BACKGROUND: Outcomes after univentricular repair for patients with asplenia syndrome remain unsatisfactory, not only because of clinical difficulties in patient selection, but also secondary to technical difficulties in the separation of the systemic and pulmonary circulations, particularly with the rerouting technique for the inferior systemic veins. METHODS: Between February 1995 and May 2000, a total of 14 consecutive patients with asplenia syndrome underwent bidirectional cavopulmonary connection with obliteration of additional pulmonary blood flow, followed by a total cavopulmonary connection. The rerouting technique for inferior systemic venous blood flow was individualized to optimize laminar nonturbulent flow characteristics in the pathway, and to minimize prosthetic load and suture load on the atrial wall. The lateral tunnel or tube conduit technique was used in an extraatrial, intra-extraatrial, or intraatrial fashion. No fenestration was applied. RESULTS: No hospital mortality was observed. Systemic venous flow was evaluated using magnetic resonance angiography, revealing no signs of obstruction, turbulence, or stasis either in or near the reconstructed pathways, irrespective of the rerouting technique. Postoperative catheterization revealed favorable hemodynamics including an inferior vena cava pressure of 13 +/- 2 mm Hg and arterial oxygen saturation of 93.4% +/- 3.5% at room air. All patients have remained free of symptoms, although 1 patient died of acute septic complications 3.5 years after the procedure. CONCLUSIONS: The complexity of cardiac anomalies in asplenia syndrome warrants individualization of the total cavopulmonary connection technique used in reconstruction of the inferior systemic venous pathway. Optimizing flow characteristics in the pathway should be a priority. A staging approach allows suitable selection of candidates for univentricular repair.

Abnormalities, Multiple↗

PubMed2002

Bacterially expressed and refolded receptor binding domain of Plasmodium falciparum EBA-175 elicits invasion inhibitory antibodies.

Malaria parasites make specific receptor-ligand interactions to invade erythrocytes. A 175 kDa Plasmodium falciparum erythrocyte binding antigen (EBA-175) binds sialic acid residues on glycophorin A during invasion of human erythrocytes. The receptor-binding domain of EBA-175 lies in a conserved, amino-terminal, cysteine-rich region, region F2 of EBA-175 (PfF2), that is homologous to the binding domains of other erythrocyte binding proteins such as Plasmodium vivax Duffy binding protein. We have developed methods to produce recombinant PfF2 in its functional form. Recombinant PfF2 was expressed in Escherichia coli, purified from inclusion bodies, renatured by oxidative refolding and purified to homogeneity by ion-exchange and gel filtration chromatography. Refolded PfF2 has been characterized using biochemical and biophysical methods and shown to be pure, homogenous and functional in that it binds human erythrocytes with specificity. Immunization with refolded PfF2 yields high titre antibodies that efficiently inhibit P. falciparum invasion of erythrocytes in vitro. Importantly, antibodies raised against PfF2 block invasion by a P. falciparum field isolate that invades erythrocytes using multiple pathways. These observations support the development of recombinant PfF2 as a vaccine candidate for P. falciparum malaria.

Animals↗

PubMed1998

Arrest of Trypanosoma brucei rhodesiense and T. brucei brucei in the S-phase of the cell cycle by (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA).

African trypanosomes are incapable of purine de novo synthesis. They use salvage pathways to meet their purine requirements. Therefore, purine analogues appear as potential candidates to interfere in trypanosome metabolism. The acyclic adenosine analogue (S)-9-(-3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA) expressed antitrypanosomal activity in vitro and vivo. When exposed to 20 microM (S)-HPMPA, trypanosomes were arrested in the S-phase of the cell cycle and were unable to enter G2-phase. Thymidine uptake and incorporation was inhibited almost completely. Only nuclear DNA replication was inhibited, while mitochondrial DNA replication and kinetoplast division was not inhibited. The antitrypanosomal effect was reversible when cells were exposed for 12 h. As a control, aphidicolin arrested trypanosomes in the G1-phase of the cell cycle at a concentration of 30 microM. At 20 microM (S)-HPMPA, glycolysis was not effected, while leucine and adenine uptake were reduced with prolonged exposure.

Adenine↗

PubMed1997

Isolation and characterization of a mammalian homolog of the Drosophila white gene.

The Drosophila melanogaster white gene is a member of the ABC transporter superfamily of ATPase transmembrane proteins and is involved in the cellular uptake of guanine and tryptophan. We have cloned and sequenced human and mouse homologs of white which share 55-58% amino acid similarity with the Drosophila protein. Northern analysis reveals that the mammalian homolog is highly expressed in several tissues, including brain, spleen, lung and placenta. We have localized the gene to human chromosome 21q22.3 by means of fluorescence in situ hybridization and linkage analysis using a (CA)n polymorphism. The human homolog maps to the interval between D21S212 and D21S171, a region which includes loci for bipolar affective disorder and a recessive form of deafness. Since tryptophan is a precursor for the neurotransmitter serotonin and neurotoxic metabolites of the kynurenine pathway, we propose that the human homolog of white is a suitable candidate gene for these neurological disorders in humans.

ATP-Binding Cassette Transporters↗

PubMed2000

The DRD2 gene and the risk for alcohol dependence in bipolar patients.

The high co-morbidity between bipolar disorder and alcohol dependence may have different explanations, one of them being the existence of common genetic factors for the two disorders. Several candidate genes may be involved but the genes acting in the dopaminergic pathway may be more specifically involved. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder. One hundred and twenty-two French (for at least two generations) patients were recruited on the basis of hospital or outpatient files and were interviewed with the DIGS. The A1 allele frequencies were compared between four groups, namely, with bipolar patients and co-morbid alcohol dependence (N = 21), with bipolar patients without alcohol morbidity (N = 31), with alcohol dependence without mood disorder (N = 35) and unaffected controls (N = 35). The Hardy Weinberg equilibrium for the DRD2 Taq1 A1 genotypes was respected for the sample as a whole, and for each subsample. We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%), neither from patients with alcohol dependence (37.1%), patients with bipolar disorder (48.4%) nor patients with alcohol dependence and bipolar disorder (28.6%). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the presence of the A1 allele of the DRD2 gene. We thus found no evidence for a significant role of the A1 allele of the D2 dopamine receptor gene in the specific association between bipolar disorder and alcohol dependence in our sample.

Adult↗

PubMedDate not supplied

Exceptionally high protection of photocarcinogenesis by topical application of (--)-epigallocatechin-3-gallate in hydrophilic cream in SKH-1 hairless mouse model: relationship to inhibition of UVB-induced global DNA hypomethylation.

(--)-Epigallocatechin-3-gallate (EGCG) has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic cream as a vehicle for EGCG. Treatment with EGCG ( approximately 1 mg/cm(2) skin area) in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKH-1 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB)-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVB-induced global DNA hypomethylation pattern. Long-term application of EGCG did not show any apparent sign of toxicity in mice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.

5-Methylcytosine↗

PubMed2004

Catalytic mechanism of the cyclohydrolase activity of human aminoimidazole carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase.

The bifunctional enzyme aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) is responsible for catalysis of the last two steps in the de novo purine pathway. Using recently determined crystal structures of ATIC as a guide, four candidate residues, Lys66, Tyr104, Asp125, and Lys137, were identified for site-directed mutagenesis to study the cyclohydrolase activity of this bifunctional enzyme. Steady-state kinetic experiments on these mutants have shown that none of these residues are absolutely required for catalytic activity; however, they strongly influence the efficiency of the reaction. Since the FAICAR binding site is made up mostly of backbone interactions with highly conserved residues, we postulate that these conserved interactions orient FAICAR in the active site to favor the intramolecular ring closure reaction and that this reaction may be catalyzed by an orbital steering mechanism. Furthermore, it was shown that Lys137 is responsible for the increase in cyclohydrolase activity for dimeric ATIC, which was reported previously by our laboratory. From the experiments presented here, a catalytic mechanism for the cyclohydrolase activity is postulated.

Alanine↗

PubMed2005

Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation.

HIV-1 envelope glycoprotein-mediated fusion is driven by the concerted coalescence of the HIV-1 gp41 N- and C-helical regions, which results in the formation of 6-helix bundles. These two regions are considered prime targets for peptides and antibodies that inhibit HIV-1 entry. However, the parameters that govern this inhibition have yet to be elucidated. We address this issue by monitoring the temporal sequence of conformational states of HIV-1 gp41 during the course of HIV-1-mediated cell-cell fusion by quantitative video microscopy using reagents that bind to N- and C-helical regions, respectively. Env-expressing cells were primed by incubation with target cells at different times at 37 degrees C followed by washing. The reactivity of triggered gp41 to the NC-1 monoclonal antibody, which we demonstrate here to bind to N-helical gp41 trimers, increased rapidly to a maximal level in the primed state but decreased once stable fusion junctions had formed. In contrast, reactivity with 5-helix, which binds to the C-helical region of gp41, increased continuously as a function of time following the priming. The peptide N36(Mut(e,g)) reduced NC-1 monoclonal antibody binding and enhanced 5-helix binding, consistent with the notion that this molecule promotes dissociation of gp41 trimers. This inactivation pathway may be important for the design of entry inhibitors and vaccine candidates.

AIDS Vaccines↗

PubMed1997

Regulation of neuronal diversity in the Xenopus retina by Delta signalling.

To generate the variety of mature neurons and glia found in the developing retina, the competence of pluripotent progenitor cells to respond to extracellular signals must be controlled. Delta, a ligand of the Notch receptor, is a candidate for regulating progenitor competence on the grounds that activation of the pathway involving Notch and Delta can inhibit cellular differentiation. Here we test this possibility in the developing Xenopus retina by misexpression of Delta messenger RNA. We find that Delta-misexpressing cells with wild-type neighbours adopt earlier fates, primarily becoming ganglion cells and cone photoreceptors. Progenitors transfected with Delta later in development also produce rod photoreceptors, but not the latest-generated cell types, demonstrating the importance of timing in Delta function. We conclude that Delta signalling in the vertebrate retina is a basic regulatory mechanism that can be used to generate neuronal diversity.

Animals↗

PubMed2006

The downstream modulator of interferon-gamma, STAT1 is not genetically associated to the Dutch coeliac disease population.

Coeliac disease (CD) is a complex genetic disorder. Its etiology is owing to multiple genes and environmental factors, such as gluten. The first event in the pathogenesis of CD after the ingestion of gluten is the activation of a Th1 immune response that leads to villous atrophy. Although this immune response seems crucial to the disease's development, only the HLA-DQ2/DQ8 genes have been identified as causative immune genes related to CD. Recently, the activation of the transcription factor STAT1 and changes in its expression levels have confirmed the participation of the Janus kinase-signal transducer and activator of transcription pathway in CD. Furthermore, as the STAT-1 gene is a positional candidate located in the CELIAC3 locus on chromosome 2, we speculate that alterations in this gene could be primarily responsible for the aberrant immune response that characterizes CD. Based on this functional and genetic evidence, we investigated the primary contribution of STAT-1 to CD. We performed a comprehensive genetic association study using five tag SNPs fully covering the STAT-1 gene in a Dutch cohort of 355 independent CD cases and 360 healthy controls. Neither the alleles, nor the genotypes in the case-control genetic association studies, nor the haplotype analysis showed any association to the STAT-1 gene in the Dutch CD population. Our results do not point to a primary involvement of the STAT-1 gene in the Dutch CD population.

Case-Control Studies↗

PubMed2004

The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder.

The dopamine D4 receptor (D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD) based on genetic studies reporting that particular polymorphisms are present at a higher frequency in affected children. However, the direct participation of the D4R in the onset or progression of ADHD has not been tested. Here, we generated a mouse model with high face value to screen candidate genes for the clinical disorder by neonatal disruption of central dopaminergic pathways with 6-hydroxydopamine (6-OHDA). The lesioned mice exhibited hyperactivity that waned after puberty, paradoxical hypolocomotor responses to amphetamine and methylphenidate, poor behavioral inhibition in approach/avoidance conflict tests and deficits in continuously performed motor coordination tasks. To determine whether the D4R plays a role in these behavioral phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4(-/-)). Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain neurons were reduced to the same extent in both genotypes, Drd4(-/-) mice lesioned with 6-OHDA did not develop hyperactivity. Similarly, the D4R antagonist PNU-101387G prevented hyperactivity in wild-type 6-OHDA-lesioned mice. Furthermore, wild-type mice lesioned with 6-OHDA showed an absence of behavioral inhibition when tested in the open field or the elevated plus maze, while their Drd4(-/-) siblings exhibited normal avoidance for the unprotected areas of these mazes. Together, our results from a combination of genetic and pharmacological approaches demonstrate that D4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition, relevant features present in this ADHD-like mouse model.

Amphetamine↗

PubMed2001

Molecular epidemiology of preterm delivery: methodology and challenges.

Preterm delivery (PTD) appears to be a complex trait determined by both genetic and environmental factors. Few studies have examined genetic influence on PTD. The overall goal of our study is to examine major candidate genes of PTD and to test gene-environment interactions. Our study includes 500 preterm trios, including 500 preterm babies and their parents and 500 maternal age-matched term controls. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamionotic inflammation: interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacental vascular lesions: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We will also perform standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene-environment interactions. The major environmental, nutritional and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene-environment interactions. This study integrates epidemiological and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding of genetic influences on PTD and gene-environment interactions.

Adult↗

PubMed2006

[Targets of antithrombotic drugs].

New antithrombotic agents are being developed not only to improve efficacy, but also to increase safety in comparison with widely used conventional agents such as the oral anticoagulants. New anticoagulant, antiplatelet, and profibrinolytic compounds are currently under study in drug development programs, and most of those in phase II or III of development are derived from the observation of natural phenomena and merely mimic processes developed by mammalians, including humans, to avoid thrombosis, or by blood-sucking insects or animals to prevent coagulation of the blood their are feeding on. By contrast, drug candidates identified by means of rigorous research and designed to target new pathways and achieve direct and specific inhibition of factors that are presumed to play an important role in thrombogenesis have generally failed to show any benefit and sometimes even induce deleterious effects. The clinical development of new drugs, even those mimicking natural phenomena, improves our knowledge of the pathogenesis of thrombosis and sheds light, retrospectively, on previous conceptual errors. The improvement in our basic knowledge and the development of new types of drugs suggest that, in contrast to the current antithrombotic compounds that are used in a broad range of clinical settings, use of new drugs should be restricted to specific situations in which their mechanisms of action are predicted to deliver the highest medical benefit. A major obstacle resides in the fact that current drug development programs are still required to comply with long obsolete guidelines based on the characteristics of first-generation antithrombotic agents, and that do not take into account the specific mechanisms of action of new drugs. This situation should change, however, and new antithrombotic drugs should soon be able to benefit from adapted development programs that will make it possible to determine their optimal risk-benefit ratio.

Blood Coagulation↗

PubMed2001

The -590C/T and -34C/T interleukin-4 promoter polymorphisms are not associated with atopic eczema in childhood.

Susceptibility to the development of asthma and other atopic diseases is known to have a genetic component. To date, several studies have linked chromosome 5q31 to asthma and atopy in human beings. This region harbors a cluster of cytokine and growth factor genes, IL-4 presenting as a prime atopy candidate gene, inasmuch as it plays a pivotal role in the atopy pathway. Our approach was to identify polymorphisms within the promoter regions of IL-4 and test their association with atopic eczema. Polymorphisms were typed in a cohort of 76 small nuclear families and 25 triads with childhood atopic eczema. The genotypes were used to test for linkage in the presence of association with atopic eczema. A new polymorphism, -34C/T, was identified and studied with a known polymorphism, -590C/T. On its own, each polymorphism showed no association with atopic eczema. The 2 polymorphisms were used to generate haplotypes, and a significant result was found for the -590C/-34C haplotype. However, after Bonferroni correction for multiple testing, the association became nonsignificant. Neither polymorphism predisposes to early-onset atopic eczema by itself, but suggestive linkage was found for the -590C/-34C haplotype in this study.

Child↗

PubMed2004

Genetic control of branching in foxtail millet.

Reduction in vegetative branching is commonplace when crops are domesticated from their wild progenitors. We have identified genetic loci responsible for these changes in foxtail millet (Setaria italica), a crop closely related to maize but whose genetics are little known. Quantitative trait locus (QTL) analysis and comparative genomics reveal that basal branching (tillering) and axillary branching are partially controlled by separate loci, and that the orthologue of teosinte branched1, the major gene controlling branching phenotype in maize, has only a minor and variable effect. We identify other candidate genes for control of branching, including a number of hormone biosynthesis pathway genes. These results suggest that similar phenotypic effects may not be produced by orthologous loci, even in closely related species, and that results from well characterized model systems such as maize must be reviewed critically before being applied to other species.

Analysis of Variance↗

PubMed1999

O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase.

The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O2-responsive K+ channels. K+ channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K+ channels are not themselves "O2 sensors" but rather respond to the reduced redox state created by hypoxic inhibition of candidate O2 sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O2. Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K+ channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K+ current but lack the specificity to identify the O2-sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O2-sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages > airways and veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O2 species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K+ current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O2 sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O2 sensor in mice.

Animals↗

PubMed2000

Utilization of oriented peptide libraries to identify substrate motifs selected by ATM.

The ataxia telangiectasia mutated (ATM) gene encodes a serine/threonine protein kinase that plays a critical role in genomic surveillance and development. Here, we use a peptide library approach to define the in vitro substrate specificity of ATM kinase activity. The peptide library analysis identified an optimal sequence with a central core motif of LSQE that is preferentially phosphorylated by ATM. The contributions of the amino acids surrounding serine in the LSQE motif were assessed by utilizing specific peptide libraries or individual peptide substrates. All amino acids comprising the LSQE sequence were critical for maximum peptide substrate suitability for ATM. The DNA-dependent protein kinase (DNA-PK), a Ser/Thr kinase related to ATM and important in DNA repair, was compared with ATM in terms of peptide substrate selectivity. DNA-PK was found to be unique in its preference of neighboring amino acids to the phosphorylated serine. Peptide library analyses defined a preferred amino acid motif for ATM that permits clear distinctions between ATM and DNA-PK kinase activity. Data base searches using the library-derived ATM sequence identified previously characterized substrates of ATM, as well as novel candidate substrate targets that may function downstream in ATM-directed signaling pathways.

Amino Acid Motifs↗