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PubMed2002

Cardiac resynchronization therapy for heart failure: biventricular pacing and beyond.

In the early 1990s, attempts at treating patients with dilated cardiomyopathy and end-stage heart failure by using right-sided, dual-chamber pacing met with equivocal results. Although initially discouraging, this work did provide further insight into the electromechanical consequences of advanced heart failure and suggested that atrial-synchronized biventricular pacing, or cardiac resynchronization therapy, might provide better and more consistent symptomatic and hemodynamic improvement. Several studies have recently validated the safety and efficacy of cardiac resynchronization therapy in advanced heart failure. Data from these studies have shown statistically significant improvements in left ventricular ejection fraction, New York Heart Association class, exercise tolerance, and quality of life. Observed reductions in morbidity and mortality await confirmation from ongoing large-scale outcomes studies. This article reviews the evolution of pacing in heart failure and discusses the underlying mechanisms that are potentially responsible for the improvement seen in patients receiving cardiac resynchronization therapy. In addition, the results of recently completed clinical trials, as well as the status of ongoing clinical trials, are reviewed.

Arrhythmias, Cardiac↗
PubMed2006

Poly(vinyl pyrrolidone): a dual functional reductant and stabilizer for the facile synthesis of noble metal nanoplates in aqueous solutions.

Poly(vinyl pyrrolidone) (PVP) has been extensively used in the solution-phase synthesis of many types of colloidal particles, where it is mainly considered as a steric stabilizer or capping agent with a major role to protect the product from agglomeration. In a recent study, we discovered that the hydroxyl end groups of PVP could also serve as a very mild reductant for kinetically controlled synthesis of Ag nanoplates with yields as high as 75%. Here we further demonstrate that hydroxyl-terminated PVP is also a well-suited reductant for the aqueous synthesis of circular, triangular, and hexagonal nanoplates made of other noble metals including Pd, Au, and Pt. The reduction kinetics of a metal salt by the hydroxyl end groups of PVP can be maneuvered in at least two different ways to facilitate the evolution of plate morphology: (i) by adjusting the molar ratio of PVP to the salt precursor and (ii) by altering the molecular weight of PVP. Unlike previously reported studies of Ag and Au thin plates, light was found to have a negligible role in the present synthesis.

Journal Article↗
PubMed1997

Relational mapping of MYCN and DDXI in band 2p24 and analysis of amplicon arrays in double minute chromosomes and homogeneously staining regions by use of free chromatin FISH.

MYCN amplification has been observed in diverse neuronal tumors including neuroblastoma, retinoblastoma, and small cell carcinoma of the lung, and has been correlated with a poor prognosis in advanced-stage neuroblastomas. Recent studies have shown a co-amplification of DDXI, a DEAD box gene, and MYCN in retinoblastoma and neuroblastoma. DDXI has been mapped to within a megabase of the MYCN gene in band 2p24. In the present study, the relational map of DDXI and MYCN by fluorescence in situ hybridization (FISH) mapping to metaphase cells and extended free chromatin fibers indicated that DDXI is telomeric to MYCN. Dual-color FISH analysis of amplicons within arrays of extended chromatin fibers was performed to examine the physical relationship of MYCN and DDXI within double minute chromosomes (dmins) and homogeneously staining regions (hsrs). No regular reiterated amplicon repeat unit was present in the hsrs, but detailed analysis of the configurations of DDXI and MYCN within each array indicated that multiple rearrangements generated a complex hsr amplicon structure. Similarly, analysis of a cell line bearing dmins showed that a composite amplicon structure involving deletions and/or duplications of MYCN and DDXI is a feature of dmin formation. These data are consistent with a molecular mechanism involving many rearrangements during the evolution of gene amplification, resulting in complex amplicon structures with distinct changes in relative gene copy number and considerable variation in intragenic distances between coamplified genes.

Blotting, Southern↗
PubMed1998

Clonality Studies in the Analysis of Adrenal Medullary Proliferations: Application Principles and Limitations.

Clonality remains as the hallmark of neoplasms. A dual genetic approach using markers nonrelated (e.g., X-chromosome inactivation assays) and related to the malignant transformation (such as loss of heterozygosity analyses of tumor-suppressor genes) would provide useful clonality information from early and advanced tumor stages, respectively. Tumor progression and clonal selection would result in genetic instability and heterogeneous expression of those molecular markers related to the malignant pathway. Therefore, only the coexistence of multiple genetic abnormalities would support the clonal nature as an expression of convergent cell selection. Considering those facts, the currently available evidence on tumorigenesis and clonality in the adrenal medulla can be summarized as follows: 1. Multistep tumorigenesis defines the evolution of pheochromocytomas, as evidenced by the presence of several genetic alterations. 2. Both the significant association of nonrandom genetic alterations (specially 1p and 22q interstitial deletions) and the topographic accumulation of genetic deletions at the peripheral tumor compartment support a convergent clone selection for these neoplasms. 3. Although many genetic loci show nonrandom abnormalities, the most frequently involved locates on chromosome 1p regardless of genetic tumor background (sporadic or inherited predisposition). 4. Most pheochromocytomas should begin as monoclonal proliferations that do not always correlate with histopathologic features, particularly in inherited tumor syndromes. 5. Early histopathologic stages, described as adrenal medullary hyperplasias, are defined by hyperproliferative features in animal models and monoclonal patterns in the adrenal nodules from patients with MEN-2a.

Journal Article↗
PubMed2025

A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens.

Genetic mutations are closely linked to human diseases, yet the relationship between many mutations and their corresponding phenotypes remains poorly understood. Furthermore, tools to study the connection between nucleotide variations and phenotypes are limited. To address this issue, we developed ACGBEmax by fusing the dual-functional deaminase, engineered N-methylpurine DNA glycosylase, and evolved SOS response associated peptidase domain with nCas9(D10A). ACGBEmax enables the precise conversion of A, C, and G to other bases in mammalian cells, thereby generating an extensive range of base mutations types. We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed in situ mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.

Animals↗
PubMed2005

Dual-domain, dual-targeting organellar protein presequences in Arabidopsis can use non-AUG start codons.

The processes accompanying endosymbiosis have led to a complex network of interorganellar protein traffic that originates from nuclear genes encoding mitochondrial and plastid proteins. A significant proportion of nucleus-encoded organellar proteins are dual targeted, and the process by which a protein acquires the capacity for both mitochondrial and plastid targeting may involve intergenic DNA exchange coupled with the incorporation of sequences residing upstream of the gene. We evaluated targeting and sequence alignment features of two organellar DNA polymerase genes from Arabidopsis thaliana. Within one of these two loci, protein targeting appeared to be plastidic when the 5' untranslated leader region (UTR) was deleted and translation could only initiate at the annotated ATG start codon but dual targeted when the 5' UTR was included. Introduction of stop codons at various sites within the putative UTR demonstrated that this region is translated and influences protein targeting capacity. However, no ATG start codon was found within this upstream, translated region, suggesting that translation initiates at a non-ATG start. We identified a CTG codon that likely accounts for much of this initiation. Investigation of the 5' region of other nucleus-encoded organellar genes suggests that several genes may incorporate upstream sequences to influence targeting capacity. We postulate that a combination of intergenic recombination and some relaxation of constraints on translation initiation has acted in the evolution of protein targeting specificity for those proteins capable of functioning in both plastids and mitochondria.

5' Untranslated Regions↗
PubMed1998

Dual effect of interleukin 4 on HIV-1 expression: implications for viral phenotypic switch and disease progression.

We report that interleukin 4 (IL-4) inhibits the propagation of non-syncytia-inducing and increases the propagation of syncytia-inducing HIV-1 isolates by two mechanisms. It differentially regulates the two major HIV-1 coreceptors, CCR5 and CXCR4, in human peripheral blood mononuclear cells, increasing CXCR4 and decreasing CCR5 expression in primary CD4(+) T-lymphocytes. In addition, IL-4 stimulates the expression of all HIV-1 isolates via a transcriptional activation mechanism. The combination of these effects results in increased propagation of CXCR4-using and inhibition of CCR5-using HIV-1 strains. IL-4 also activates HIV-1 expression in primary monocytes/macrophages but does not affect CCR5 expression. These results identify IL-4 as an important regulator of HIV-1 and suggest a critical role for this cytokine in the control of viral evolution and in the phenotypic switch from non-syncytia-inducing to syncytia-inducing, which leads to accelerated disease progression.

CD4-Positive T-Lymphocytes↗
PubMedDate not supplied

The dual role of wild phages for horizontal gene transfer among Salmonella strains.

Salmonella bacteriophages seem to mediate horizontal transfer of virulence functions among Salmonella strains in two different ways: by general transduction and also by lysogenic conversion. The majority of wild phages isolated from Salmonella strains belong to the P22 like phages and were able to transduce. Our data show that the lysogenic conversion is generally accompanied by changes in the susceptibility to the typing phages used for epidemiological purposes. Similar phage type conversions to S. Typhimurium DT104 could be detected upon lysogenization with two other S. Typhimurium strains. For some S. Typhimurium strains the typical phage pattern is actually associated with alterations of virulence characteristics. For example, all tested wild type isolates of phage types DT49 and DT204 were found to be SopE phi-lysogens. The Anderson typing phages interfere with the prophages and/or cryptic phages and so the complex genetic short-term evolution can be demonstrated in the lab. This is one reason for the successful application of phage typing in Salmonella epidemiology since the 50s.

Bacteriophage Typing↗
PubMed1998

The cox2 locus of the primitive angiosperm plant Acorus calamus: molecular structure, transcript processing and RNA editing.

Acorus calamus, or sweet flag, is a semiaquatic plant of uncertain taxonomic position. Molecular phylogenetic analysis using plastid rbcL sequences have suggested that Acorus calamus might be the most ancient surviving representative of the ancestral monocotyledonous plants. In order to provide molecular and phylogenetic data for the mitochondrial genetic system of Acorus, we have determined the structure of a mitochondrial locus, the cytochrome oxidase subunit II gene cox2. The Acorus cox2 gene harbors an unusually small group II intron, the smallest plant mitochondrial intron known to date. The transcript undergoes C-to-U RNA editing at eight sites. One of these sites is likely to play a dual functional role in both intron splicing and protein function. The 3' end of the mature transcript folds into a characteristic stem-loop structure that is presumably required for mitochondrial mRNA stability. Phylogenetic analysis of the cox2 sequence data, as well as the unusual intron structure, all support an evolutionarily isolated position for Acorus calamus.

Base Sequence↗
PubMed2002

Secretory lysosomes.

Regulated secretion of stored secretory products is important in many cell types. In contrast to professional secretory cells, which store their secretory products in specialized secretory granules, some secretory cells store their secretory proteins in a dual-function organelle, called a secretory lysosome. Functionally, secretory lysosomes are unusual in that they serve both as a degradative and as a secretory compartment. Recent work shows that cells with secretory lysosomes use new sorting and secretory pathways. The importance of these organelles is highlighted by several genetic diseases, in which immune function and pigmentation--two processes that normally involve secretory lysosomes--are impaired.

Animals↗
PubMed1995

CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells.

We have analysed the molecular basis for the function of the C/EBP alpha transactivation domain. We have previously found that the three C/EBP alpha transactivation elements (TEs) synergistically activate transcription in mammalian cells. We now report that two of these elements, TE-I and -II, co-operatively mediate in vitro binding of C/EBP alpha to TBP and TFIIB, two essential components of the RNA polymerase II basal transcriptional apparatus. The TBP and TFIIB binding elements of C/EBP alpha coincide, and require amino acid motifs conserved between the activating members of the C/EBP family. These same motifs are necessary for the transcription activation function of TE-I and -II in both yeast and mammalian cells. Our data demonstrate a biochemical basis for the modular buildup of transactivation domains, and indicate that this modularity is conserved in eukaryote evolution. We also show that the same amino acid motifs in a cellular activator can co-operate to mediate contacts between the activator and two distinct basal transcription factors. These results suggest that domains of TBP and TFIIB that interact with activating surfaces are functionally similar and may be structurally related, and support the idea that the same amino acid motifs in an activator carry out multiple functions during the initiation process.

Amino Acid Sequence↗
PubMed2003

Effects of BM-573, a novel thromboxane A2 inhibitor, on pulmonary hemodynamics in endotoxic shock.

Thromboxane A2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The effects of a novel dual TXA2 synthase inhibitor and TXA2 receptor antagonist (BM-573) on pulmonary hemodynamics were investigated in endotoxic shock. 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 +/- 1.8 (T0) to 42 +/- 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 +/- 1.6 (T0) to 25 +/- 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO2 decreased from 131 +/- 21 (T0) to 74 +/- 12 mmHg (T300) (p < 0.05), while in Anta group, PaO2 was 241 +/- 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA2 plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA2 synthesis and of TXA2 receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation.

Animals↗
PubMed2000

[Obstructive myocardiopathic hypertrophy and sequential atrioventricular stimulation. Immediate results and long term follow-up. Seven years experience].

BACKGROUND: Sequential pacing as a primary treatment for patients with severe hypertrophic obstructive cardiomyopathy is still under controversy. In this study we sought to evaluate the effects of pacing on left ventricular systolic and diastolic function, its repercussion on pathophysiology and the possible changes in clinical evolution and functional class in patients who didn't respond to medical therapy. PATIENTS AND METHODS: Thirty-four patients with severe hypertrophic obstructive cardiomyopathy in functional class III-IV underwent evaluation. The mean age was 64 +/- 11 years. Sixty-two per cent were over 65. The study protocol included Holter monitoring, baseline echo-Doppler, during pacing, at 6 months and at the end of follow-up, and a complete catheterization and coronary angiography. Mean follow-up time was 36 +/- 20 month (range 6-74). In four patients sequential pacing was ineffective and the protocol had to be discontinued. Thirty patients received a permanent dual-chamber pacemaker and systolic and diastolic function were evaluated by hemodynamic, angiographic and eco-Doppler studies. RESULTS: Long-term stimulation reduced the subaortic gradient from 95 +/- 38 to 39 +/- 28 mmHg (p < 0.001), left ventricular systolic pressure from 207 +/- 38 to 164 +/- 30 mmHg (p < 0.001) and left ventricular end-diastolic pressure from 23 +/- 7 to 14 +/- 5 mmHg (p < 0.001), pulmonary capillary wedge pressure from 19 +/- 7 to 14 +/- 5 mmHg (p < 0.001), ejection fraction from 79 +/- 6 to 71 +/- 6% (p < 0.001) and mitral insufficiency. Diastolic function improved with an increase in early filling from 39 +/- 11 to 52 +/- 10% (p < 0.001) and E/A relation from 0.93 +/- 0.4 to 1.6 +/- 0.8 (p < 0.001), and a reduction in late filling from the left ventricle from 36 +/- 10% to 24 +/- 10% (p < 0.001). The speed of the E wave increased from 0.83 +/- 0.3 to 0.92 +/- 0.3 (p < 0.001) and we observed a reduction of the A wave from 93 +/- 0.3 to 0.66 +/- 0.2 (p < 0.001), pressure-half time from 95 +/- 34 to 66 +/- 19 ms (p < 0.001) and we observed deceleration time from 320 +/- 90 to 221 +/- 57 (p < 0.01). All patients have improved their functional class, allowing a reduction in pharmacological therapy. Two exitus of cardiological origin occurred. CONCLUSIONS: Sequential AV pacing in selected patients with severe hypertrophic obstructive cardiomyopathy can reduce subaortic gradient, pulmonary capillary wedge, left ventricular filling pressures and the severity of mitral regurgitation, and improve the markedly altered diastolic function. The significant symptomatic improvement allows a reduction in medical treatment. Thus, it represents a viable alternative to open-heart surgery, particularly in elderly patients, with lower morbidity and mortality rates.

Adult↗
PubMed2001

A dual-color FISH gene map of the proximal region of rat Chromosome 4 and comparative analysis in human and mouse.

The development and refinement of the rat genome map is a prerequisite for a continued qualified and fruitful use of this model system for the study of complex traits. In two distinct rat cancer models, recurrent amplification affecting the proximal region of rat Chr 4 was detected. To further characterize this region, we turned to the evolutionarily conserved chromosome segments in human Chr 7 and mouse Chrs 5 and 6 to identify functional and positional candidate genes. By means of single- and dual-color FISH on metaphase, prometaphase, and interphase chromatin, 15 genes in rat Chr 4q11-q23 (Cdk5, Hgf, Dmtf1, Abcb1, Cyp51, Cdk6, Tac1, Asns, Cav1, Met, Wnt2, Cftr, Smoh, Braf, Arhgef5) were mapped and aligned. In the course of this work, six cancer-related rat genes were isolated de novo and partly sequenced. Ten loci were also mapped by FISH in the mouse. The map provides the framework for a more detailed genetic characterization of individual tumor amplicons, but may also be valuable for the analysis of this region in other rat models of human complex disease. In addition, our data facilitate the analysis of events in mammalian chromosomal evolution affecting the region. In a comparison with human sequence data, we found that there is considerable conservation in this region both in gene order and in distances between genes. There is a single evolutionary breakpoint between rat and mouse and two between rat and human. Since our analysis shows that the three breaks all occurred in different positions, they must be independent of one another. The data tend to support the notion that the genomic configuration in rat Chr 4 is ancestral compared with that in humans and mice.

Animals↗
PubMed2006

Application of in-situ attenuated total reflection-Fourier transform infrared spectroscopy for the understanding of complex reaction mechanism and kinetics: formic acid oxidation on a Pt film electrode at elevated temperatures.

The potential of in-situ Fourier transform infrared (FTIR) spectroscopy measurements in an attenuated total reflection configuration (ATR-FTIRS) for the evaluation of reaction pathways, elementary reaction steps, and their kinetics is demonstrated for formic acid electrooxidation on a Pt film electrode. Quantitative kinetic information on two elementary steps, formic acid dehydration and CO(ad) oxidation, and on the contributions of the related pathways in the dual path reaction mechanism are derived from IR spectroscopic signals in simultaneous electrochemical and ATR-FTIRS measurements over a wide temperature range (25-80 degrees C). Linearly and multiply bonded CO(ad) and bridge-bonded formate are the only formic acid related stable reaction intermediates detected. With increasing temperature, the steady-state IR signal of CO(ad) increases, while that of formate decreases. Reaction rates for CO(ad) formation via formic acid dehydration and for CO(ad) oxidation as well as the activation energies of these processes were determined at different temperatures, potentials, and surface conditions (with and without preadsorbed CO from formic acid dehydration) from the temporal evolution of the IR intensities of CO(ad) during adsorption/reaction transients, using an IR intensity-CO(ad) coverage calibration. At potentials up to 0.75 V and temperatures from 25 to 80 degrees C, the "indirect" CO pathway contributes less than 5% (at potentials < or =0.6 V significantly below 1%) to the total Faradaic reaction current, making the "direct" pathway by far the dominant one under the present reaction conditions. Much higher activation energies for CO(ad) formation and CO(ad) oxidation compared with the effective activation energy of the total reaction, derived from the Faradaic currents, support this conclusion.

Journal Article↗
PubMed1997

Recombination creates novel L1 (LINE-1) elements in Rattus norvegicus.

Mammalian L1 (long interspersed repeated DNA. LINE-1) retrotransposons consist of a 5' untranslated region (UTR) with regulatory properties, two protein encoding regions (ORF I, ORF II, which encodes a reverse transcriptase) and a 3' UTR. L1 elements have been evolving in mammals for > 100 million years and this process continues to generate novel L1 subfamilies in modern species. Here we characterized the youngest known subfamily in Rattus norvegicus, L1mlvi2, and unexpectedly found that this element has a dual ancestry. While its 3' UTR shares the same lineage as its nearest chronologically antecedent subfamilies, L13 and L14, its ORF I sequence does not. The L1mlvi2 ORF I was derived from an ancestral ORF I sequence that was the evolutionary precursor of the L13 and L14 ORF I. We suggest that an ancestral ORF I sequence was recruited into the modern L1mlvi2 subfamily by recombination that possibly could have resulted from template strand switching by the reverse transcriptase during L1 replication. This mechanism could also account for some of the structural features of rodent L1 5' UTR and ORF I sequences including one of the more dramatic features of L1 evolution in mammals, namely the repeated acquisition of novel 5' UTRs.

Animals↗
PubMedDate not supplied

Proposal of a dimensional model of personality disorders.

During recent years there has been a growing interest on several aspects regarding psychopathology in general and particularly with personality disorders, such as dual psychopathology, comorbidity and dimensional models. Going from the Eysenck's three-factor model to the Fiske's five-factor one, from the Cloninger's psychobiological model to the Millon's biosocial one, a wide variety of personality analysis models, as well as dimensions to which the different personality disorders should be anchored, have been proposed. Here, we propose a dimensional model for personality disorders based on DSM-IV criteria, which are cognitive style (field dependence-independence), prevalent emotion (anger-fear), interpersonal style (submissiveness-dominance), and impulse control (impulsiveness-compulsiveness). We consider that these dimensions are related to different levels of cerebral complexity, assuming that evolution operates under the redundancy principle. Based on these dimensions, a bimodal model in which antisocial personality (high field dependence, anger, dominance, and impulsiveness) and schizotypal personality (low field dependence, fear, submissiveness, and compulsiveness) would be anchored in each extreme is proposed. Between these two extremes, the rest of personality disorders, such as borderline, paranoid, narcissist, histrionic, dependent, passive-aggressive, avoidant, obsessive-compulsive, paranoid, and schizoid, would be anchored.

Humans↗
PubMed1998

Role of tumor necrosis factor-alpha in regulating fibrotic lung repair.

To study the role of tumor necrosis factor-alpha (TNF-alpha) in fibrotic lung repair, we evaluated changes in lung TNF-alpha content and binding during the evolution of the fibrotic response. We concomitantly examined the effect of TNF-alpha on lung fibroproliferative responses. Lung TNF-alpha increased early after injury, at a time when lung tissue and lung fibroblasts exhibited increased binding to the cytokine. Fibroblasts isolated during this phase, which have increased spontaneous proliferative activity, had significant reduction in DNA synthesis when exposed to TNF-alpha. In contrast, DNA synthesis in normal and repair phase fibroblasts was inhibited by TNF-alpha. We also examined mechanisms of transduction of the TNF-alpha fibroproliferative signal, and observed that phosphorylating enzymes and G-proteins were involved. We conclude that TNF-alpha has a dual role in fibrotic repair. During injury, when uncontrolled fibroblast proliferation occurs, TNF-alpha production is increased to slow down the fibroproliferative response. During repair, when fibroblasts participate in structural restitution, TNF-alpha plays a salutary role by stimulating cellular proliferation. These effects of TNF-alpha on cellular proliferation are mediated by activation of two separate signal transduction pathways, phosphorylating enzymes and G-proteins. The observed variability in the effect of TNF-alpha may be related to changes in the phenotypic and genotypic characteristics of repairing lung fibroblasts which alter their responsiveness to exogenous stimuli.

Animals↗