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PubMed1997

Telomeric fusions in cultured human fibroblasts as a source of genomic instability.

In a human fibroblast clone we studied the evolution, during culture propagation, of a dicentric chromosome consisting of the end-to-end association of the short arm of chromosome 5 and the long arm of chromosome 16. Dual-color fluorescence in situ hybridization (FISH) with painting probes allowed us to define the structure of a variety of derivative chromosomes and to identify the mechanisms by which they originated. Asymmetric interchanges involving the intercentromeric region of the dicentric, bridge-breakage-fusion events, or breaks followed by sister chromatid fusion, originate unstable hetero- or homodicentric chromosomes with deletion or duplication; breakages not followed by reunion, or intradicentric recombination, presumably originate stable rearranged monocentric chromosomes. The variety of the derivatives is extremely large because the observed events may involve any site of the intercentromeric region, although the majority of them occurs after a break in 16qh. The results of this investigation document the evolution through successive steps of a telomeric fusion, a chromosome anomaly frequently observed in tumor and senescent cells. They also demonstrate that in cultured cells of normal origin, starting with this anomaly, various chromosomal mechanisms may produce translocations, duplications, and deletions. The karyotype instability produced by a telomeric fusion can be relevant for carcinogenesis because it may generate genetic changes critical in the multistep process of transformation.

Cells, Cultured↗
PubMed2006

Molecular organization of 5S rDNAs in Rajidae (Chondrichthyes): Structural features and evolution of piscine 5S rRNA genes and nontranscribed intergenic spacers.

The genomic and gene organisation of 5S rDNA clusters have been extensively characterized in bony fish and eukaryotes, providing general issues for understanding the molecular evolution of this multigene DNA family. By contrast, the 5S rDNA features have been rarely investigated in cartilaginous fish (only three species). Here, we provide evidence for a dual 5S rDNA gene system in the Rajidae by sequence analysis of the coding region (5S) and adjacent nontranscribed spacer (NTS) in five Mediterranean species of rays (Rajidae), and in a large number of piscine taxa including lampreys and bony fish. As documented in several bony fish, two functional 5S rDNA types were found here also in the rajid genome: a short one (I) and a long one (II), distinguished by distinct 5S and NTS sequences. That the ancestral piscine genome had these two 5S rDNA loci might be argued from the occurrence of homologous dual gene systems that exist in several fish taxa and from 5S phylogenetic relationships. An extensive analysis of NTS-II sequences of Rajidae and Dasyatidae revealed the occurrence of large simple sequence repeat (SSR) regions that are formed by microsatellite arrays. The localization and organization of SSR within the NTS-II are conserved in Rajiformes since the Upper Cretaceous. The direct correlation between the SSRs extension and the NTS length indicated that they might play a role in the maintenance of the larger 5S rDNA clusters in rays. The phylogenetic analysis indicated that NTS-II is a valuable systematic tool limited to distantly related taxa of Rajiformes.

Animals↗
PubMed2004

Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate.

Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.

Animals↗
PubMed2006

Discovery and evaluation of dual CDK1 and CDK2 inhibitors.

In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line-specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis.

Animals↗
PubMed2003

Genotype, obesity and cardiovascular disease--has technical and social advancement outstripped evolution?

Teleologically, our ancestors were highly adapted hunter-gatherers. In recent history, the environment in which Homo sapiens exists has altered drastically and humans are exposed to environments for which the hunter-gatherer genotype is ill-suited. The adoption of a sedentary Western lifestyle, and the case of obtaining food of a high calorific content imposed upon a thrifty genotype, have resulted in the current global epidemic of obesity, Type 2 diabetes and the Metabolic Syndrome. The ramification of this epidemic is that cardiovascular disease is becoming a global healthcare problem, which will have its greatest impact on the developing nations. A global strategy is required to reduce the impact of the Western lifestyle on the health of developing nations and prevent obesity and Type 2 diabetes. Such an approach needs to be culturally sensitive, integrated, and multidisciplinary and involve a range of interventions that work at the individual and community levels. If lifestyle measures fail, then pharmacological intervention may be necessary. For this, novel agents such as dual PPARalpha/gamma agonists may be the therapy of the future.

Adaptation, Physiological↗
PubMed1997

Benign myoclonic epilepsy: long-term follow-up of 11 new cases.

The authors report a long-term follow-up of 11 new subjects with benign myoclonic epilepsy. There were some unusual clinical features such as the need for dual therapy in 45.5% of subjects, and the presence of non-epileptic myoclonus in 54.5%, neither of which influenced the prognosis. Neuropsychological and behavioral evolution was less favorable in 45.5% of patients (mental retardation, school learning problems, attention deficit disorder, hyperkinesia, aggressiveness, irritability, negativism). The less favorable neuropsychological outcome might be related to additional interacting factors such as personal antecedents, seizure onset and antiepileptic treatment.

Adolescent↗
PubMed2006

Frequency of HIV type 1 dual infection and HIV diversity: analysis of low- and high-risk populations in Mbeya Region, Tanzania.

HIV-1 diversity, frequency of recombinants, and dual infection were determined in two populations with different HIV risk behavior. A high-risk cohort of 600 female bar workers and a normal-risk population of 1,108 antenatal clinic attendees and blood donors were recruited. Behavioral data were assessed and blood for HIV- 1 diagnosis and genotyping was sampled. HIV-1 subtypes were defined through the multiregion hybridization assay (MHA(acd)). HIV-1 prevalence differed significantly among the two populations. The prevalence was 67.8% in the population of bar workers and 17% in the normal-risk population (antenatal care attendees and blood donors). Within the normal-risk population the HIV-1 prevalence was lowest in the group of volunteer blood donors. The frequency of HIV-1 infection in women was 1.7 times higher than in men. The overall subtype distribution was A (8.5%), C (40.8%), D (3.8%), AC (25.4%), AD (5.4%), CD (8.8%), and ACD (7.3%). In the high-risk population there was a higher percentage of HIV-1 recombinant strains (54% vs. 40%, p < 0.05) and a higher frequency of dual infections (19% vs. 9%, p < 0.02) compared to the normal-risk population. High-risk populations may play an important role in the evolution of HIV, as they can provide an opportunity for the virus to coinfect, recombine, and adapt to the host-specific genetic background.

Adolescent↗
PubMed2005

Reticulated platelets: a reliable measure to reduce prophylactic platelet transfusions after intensive chemotherapy.

BACKGROUND: Reticulated platelets (RPs) are the youngest circulating platelets (PLTs). The aim of our study was to predict PLT recovery with RP percentage (RP%) and therefore to identify PLT transfusions that could be avoided after autologous peripheral blood progenitor cell (PBPC) transplantation. STUDY DESIGN AND METHODS: With a whole-blood dual-labeling flow cytometric method, RP% was prospectively assessed in 47 patients who received myeloablative chemotherapy followed by autologous PBPC transplantation. Retrospective analysis of RP evolution identified three time points: nadir of the RP% (NRP), imminent PLT recovery (IPR) corresponding to an RP% of greater than 7 percent, and PLT transfusion autonomy (PTA). RESULTS: Median occurrences of NRP, IPR, and PTA were on Days +5, +8, and +12 after transplantation, respectively. The RP% value at NRP (4%) was significantly lower compared to the IPR (15%) and PTA (14%). Thirty patients (64%) achieved PTA within 4 days after IPR. On Day +8, if RP% was greater than 7 percent, positive and negative predictive values for PTA within 4 days, specificity, and sensitivity were 79, 63, 66, and 76 percent, respectively. Fever between IPR and PTA was the only factor found to negatively influence PLT recovery (p = 0.02). All patients required at least one PLT transfusion. Among patients with rapid PLT recovery (IPR-PTA interval < 4 days; n = 30), half of them received one PLT transfusion after RP increase, which could be avoided. CONCLUSION: These encouraging results may allow us to reduce the prophylactic PLT transfusion according to patients RP% increase.

Adult↗
PubMed2005

Accurate polarization measurements with a dual photoelastic modulator.

Measurements of the polarization effects in multimirror experiments by using a dual photoelastic modulator are described. The effect of single and multiple mirrors in polarization measurements in two and three dimensions is discussed, and experimental results show how symmetrical placement of mirrors in three-dimensional geometry can eliminate changes in the polarization. Calibration procedures for a dual photoelastic modulator and potential error sources such as misalignment of analyzer, signal dc offset, and neglect of aperture size are presented. Mirror-surface evolution and how it can disturb the polarization measurement are also addressed.

Journal Article↗
PubMed1999

Intracellular gene transfer in action: dual transcription and multiple silencings of nuclear and mitochondrial cox2 genes in legumes.

The respiratory gene cox2, normally present in the mitochondrion, was previously shown to have been functionally transferred to the nucleus during flowering plant evolution, possibly during the diversification of legumes. To search for novel intermediate stages in the process of intracellular gene transfer and to assess the evolutionary timing and frequency of cox2 transfer, activation, and inactivation, we examined nuclear and mitochondrial (mt) cox2 presence and expression in over 25 legume genera and mt cox2 presence in 392 genera. Transfer and activation of cox2 appear to have occurred during recent legume evolution, more recently than previously inferred. Many intermediate stages of the gene transfer process are represented by cox2 genes in the studied legumes. Nine legumes contain intact copies of both nuclear and mt cox2, although transcripts could not be detected for some of these genes. Both cox2 genes are transcribed in seven legumes that are phylogenetically interspersed with species displaying only nuclear or mt cox2 expression. Inactivation of cox2 in each genome has taken place multiple times and in a variety of ways, including loss of detectable transcripts or transcript editing and partial to complete gene loss. Phylogenetic evidence shows about the same number (3-5) of separate inactivations of nuclear and mt cox2, suggesting that there is no selective advantage for a mt vs. nuclear location of cox2 in plants. The current distribution of cox2 presence and expression between the nucleus and mitochondrion in the studied legumes is probably the result of chance mutations silencing either cox2 gene.

Cell Nucleus↗
PubMed1983

Acquisitive evolution of ribitol dehydrogenase in Klebsiella pneumoniae.

Selection in continuous culture of Klebsiella pneumoniae mutants that have gained the ability to utilize xylitol while also retaining regulatory control over ribitol utilization was achieved with a dual-substrate regime. Initial steady-state cultures of wild-type organisms were maintained with 0.005% (0.329 mM) ribitol. Mutants of various types proliferated when the composition of the limiting medium was changed to 0.005% ribitol plus 0.250% (16.43 mM) xylitol.

Culture Media↗
PubMed1998

Spike-wave complexes and fast components of cortically generated seizures. III. Synchronizing mechanisms.

The intracortical and thalamocortical synchronization of spontaneously occurring or bicuculline-induced seizures, consisting of spike-wave (SW) or polyspike-wave (PSW) complexes at 2-3 Hz and fast runs at 10-15 Hz, was investigated in cats under ketamine-xylazine anesthesia. We used single and dual simultaneous intracellular recordings from cortical areas 5 and 7, and extracellular recordings of unit firing and field potentials from neocortical areas 5, 7, 17, 18, as well as related thalamic nuclei. The evolution of time delays between paroxysmal depolarizing events in single neurons or neuronal pools recorded from adjacent and distant sites was analyzed by using 1) sequential cross-correlations between field potentials, 2) averaged activities triggered by the spiky component of cortical SW/PSW complexes, and 3) time histograms between neuronal discharges. In all instances, the paroxysmal activities recorded from the dorsal thalamus lagged the onset of seizures in neocortex. The time lags between simultaneously impaled cortical neurons were significantly smaller during SW complexes than during the prior epochs of slow oscillation. During seizures, as during the slow oscillation, the intracortical synchrony was reduced with increased distance between different cortical sites. Dual intracellular recordings showed that, during the same seizure, time lags were not constant and, instead, reflected alternating precession of the recorded foci. After transection between areas 5 and 7, the intracortical synchrony was lost, but corticothalamocortical volleys could partially restore seizure synchrony. These data show that the neocortex leads the thalamus during SW/PSW seizures, that time lags between cortical foci are not static, and that thalamus may assist synchronization of SW/PSW seizures after disconnection of intracortical synaptic linkages.

Anesthesia↗
PubMed2006

Crab scars reveal survival advantage of left-handed snails.

Biological asymmetries are important elements of the structure and function of many living organisms. Using the Plio-Pleistocene fossil record of crab predation on morphologically similar pairs of right- and left-handed snail species, we show here for the first time, contrary to traditional wisdom, that rare left-handed coiling promotes survival from attacks by right-handed crabs. This frequency-dependent result influences the balance of selection processes that maintain left-handedness at the species level and parallels some social interactions in human cultures, such as sports that involve dual contests between opponents of opposite handedness.

Adaptation, Physiological↗
PubMed2005

A genome-wide study of dual coding regions in human alternatively spliced genes.

Alternative splicing is a major mechanism for gene product regulation in many multicellular organisms. By using different exon combinations, some coding regions can encode amino acids in multiple reading frames in different transcripts. Here we performed a systematic search through a set of high-quality human transcripts and show that approximately 7% of alternatively spliced genes contain dual (multiple) coding regions. By using a conservative criterion, we found that in these regions most secondary reading frames evolved recently in mammals, and a significant proportion of them may be specific to primates. Based on the presence of in-frame stop codons in orthologous sequences in other animals, we further classified ancestral and derived reading frames in these regions. Our results indicated that ancestral reading frames are usually under stronger selection than are derived reading frames. Ancestral reading frames mainly influence the coding properties of these dual coding regions. Compared with coding regions of the whole genome, ancestral reading frames largely maintain similar nucleotide composition at each codon position and amino acid usage, while derived reading frames are significantly different. Our results also indicated that prior to acquisition of a new reading frame, the suppression of in-frame stop codons in the ancestral state is mainly achieved by one-step transition substitutions at the first or second codon position. Finally, the selective forces imposed on these dual coding regions will also be discussed.

Alternative Splicing↗
PubMed2005

Bifunctional isocitrate-homoisocitrate dehydrogenase: a missing link in the evolution of beta-decarboxylating dehydrogenase.

Beta-decarboxylating dehydrogenases comprise 3-isopropylmalate dehydrogenase, isocitrate dehydrogenase, and homoisocitrate dehydrogenase. They share a high degree of amino acid sequence identity and occupy equivalent positions in the amino acid biosynthetic pathways for leucine, glutamate, and lysine, respectively. Therefore, not only the enzymes but also the whole pathways should have evolved from a common ancestral pathway. In Pyrococcus horikoshii, only one pathway of the three has been identified in the genomic sequence, and PH1722 is the sole beta-decarboxylating dehydrogenase gene. The organism does not require leucine, glutamate, or lysine for growth; the single pathway might play multiple (i.e., ancestral) roles in amino acid biosynthesis. The PH1722 gene was cloned and expressed in Escherichia coli and the substrate specificity of the recombinant enzyme was investigated. It exhibited activities on isocitrate and homoisocitrate at near equal efficiency, but not on 3-isopropylmalate. PH1722 is thus a novel, bifunctional beta-decarboxylating dehydrogenase, which likely plays a dual role in glutamate and lysine biosynthesis in vivo.

Alcohol Oxidoreductases↗
PubMed2026

RND-mediated efflux couples antimicrobial resistance and hypervirulence in contemporary Vibrio cholerae.

The prevailing view in bacterial pathogenesis is that antimicrobial resistance and virulence are constrained by evolutionary trade-offs, with resistance mechanisms imposing fitness costs that attenuate pathogenic potential. Herein we document that contemporary Vibrio cholerae clinical isolates from the ongoing seventh pandemic have circumvented this paradigm by coupling multidrug resistance with hypervirulence. We examined five geographically diverse Wave 3 isolates collected between 2017 and 2019 and compared them to early pandemic strains. These contemporary isolates exhibited both broad-spectrum antimicrobial resistance and markedly enhanced colonization capacity in the infant mouse model. Phylogenetic analysis of 67 O1 El Tor genomes spanning 1960-2019 confirmed that the isolates cluster within a representative Wave 3 sublineage. We identified the VexB RND efflux pump as a mediator of this coupled phenotype. Elevated vexB expression in the contemporary isolates conferred resistance to multiple antibiotic classes, while vexB inactivation simultaneously impaired resistance and colonization. This dual function was not observed in early pandemic strains, consistent with a recent evolutionary adaptation. VexB-mediated hypervirulence occurred through multiple pathways independent of cholera toxin and toxin-coregulated pilus production levels. VexB deletion impaired bacterial adherence to intestinal epithelial cells, impaired motility, and increased susceptibility to membrane-active antimicrobials. In contrast, laboratory evolution under antibiotic pressure alone generated resistant but avirulent strains, demonstrating that complex selective forces in nature enabled the co-optimization of resistance and virulence. These findings establish VexB as a molecular link between antimicrobial resistance and hypervirulence in pandemic V. cholerae, highlighting efflux pumps as dual-function therapeutic targets whose inhibition could both restore antibiotic activity and attenuate disease.

Animals↗
PubMed2002

Impact of antiretroviral protocols on dynamics of AIDS progression markers.

AIMS: To assess the "real life" effectiveness of different antiretroviral therapies (ART). METHODS: A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study A), and in 61 HIV-1 infected children on the evolution of the most relevant markers of progression (study B). All children were categorised into four groups: untreated (NT); on monotherapy (MT); on combination therapy (dual-ART); and on potent ART (HAART). RESULTS: No child in the HAART group progressed to AIDS, whereas 14 children in the NT and seven in the MT groups progressed to AIDS, respectively, the differences being statistically significant. There was a mean increase of 8 units of %CD4+ per year; this was greater in the HAART group than in the other groups. The mean decrease in viral load was 0.65 log(10) copies/ml per year; this was greater in the HAART group than in the NT and MT groups. The HAART group had the lowest probability of returning to baseline %CD4+ and viral load. CONCLUSION: Potent ART had the greatest protective effect against progression to AIDS in this observational study.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Evolution of the primary and secondary structures of the E1a mRNAs of the adenovirus.

In this paper we investigate and compare (evolutionary) patterns in the primary and secondary structure of four homologous E1a mRNAs of the adenovirus. Our main results are as follows: (1) The similarity of the coding regions of the mRNA sequences reflects both similarity in function (i.e., oncogenicity) and evolutionary divergence. (2) The similarity of the leader and the trailer regions reflects host specificity (i.e., human or simian) and must therefore arise from convergence. (3) Minimal energy foldings of the mRNAs show similar secondary structures (in particular around the splice sites). The conservation of pre-mRNA secondary structure shows that mRNAs are subject to selection constraints in addition to those associated with proteins. (4) The conserved secondary (helical) structures consist of nonhomologous subsequences, i.e., shifts have occurred. The observed shifts near the splice sites seem to be the simplest way of dealing with the dual constraints.

Adenoviridae↗