bluuebunny/crossref_metadata_2025_split huggingface dataset:
GATA‐6 gene enhancer contains nested regulatory modules for primary myocardium and the embedded nascent atrioventricular conduction system
Authors: Adamo Richard F. , Guay Catherine L. , Edwards Angela V. , Wessels Andy , Burch John B.E. 
Published: September 2004

AbstractThe cGATA‐6 gene is flanked by an enhancer that selectively marks the atrioventricular conduction system (AVCS) in transgenic mice. This enhancer reads anterior/posterior and medial/lateral positional information very early in the cardiogenic program and remains active in progressively more restricted regions of primary myocardium leading up to the emergence of a histologically distinct AVCS. We undertook to parse this enhancer to resolve how the respective AVCS‐specific transcription program is regulated at the molecular level. We determined that this AVCS enhancer includes a 102 bp module that is sufficient to restrict expression to primary nonchamber myocardium. This offers a novel tool to analyze the early molecular delineation of primary and chamber myocardium, which subsequently give rise to components of the central and peripheral conduction system, respectively. Furthermore, we show that this 102 bp module in turn contains a nested 47 bp core module that has the potential to direct expression specifically to the AVCS domain of primary myocardium, albeit with low efficiency. Accordingly, we show that a GATA site and a GC‐rich site in the 102 bp region bolster the activity of the nested 47 bp AVCS core region even within the context of the parental 1,478 bp enhancer. These are the first functional elements to be reported for a cardiac conduction system‐specific control region. © 2004 Wiley‐Liss, Inc.
The muscular network of the sheep right atrium and frequency‐dependent breakdown of wave propagation
Authors: Berenfeld Omer , Zaitsev Alexey V. 
Published: September 2004

AbstractThe complex branching structure of the right atrium (RA) muscular network may provide the substrate for complex patterns of propagation during atrial fibrillation (AF). As AF results in some cases from stable sources in the left atrium (LA) with fibrillatory conduction toward the RA, we hypothesize that periodic input to the RA at an exceedingly high frequency results in disorganized wave propagation associated with the complex structure of the RA. Optical mapping was performed in isolated coronary‐perfused sheep RA. Rhythmic pacing of Bachmann's bundle allowed well‐controlled and realistic conditions for LA‐driven RA. Pacing at increasingly higher frequencies led to increasing delays in activation distal to major branching sites of the Crista terminalis and pectinate bundles, culminating in spatially distributed intermittent blockade at and above ∼ 6.5 Hz. At this breakdown frequency, the dominant frequencies of the RA response activity became spatially nonuniform. Such frequency‐dependent changes were independent of action potential duration. Rather, the spatial boundaries between proximal and distal frequencies correlated well with branch sites of the pectinate musculature. Thus, there exists a breakdown frequency in the sheep RA below which activity is periodic throughout the atrium and above which it is fibrillation‐like, consistent with the ideas that during AF, high‐frequency activation initiated in the LA undergoes fibrillatory conduction toward the RA, and that sink‐to‐source mismatch effect at branch points of the Crista terminalis and pectinate muscles is important in determining the complexity of the arrhythmia. © 2004 Wiley‐Liss, Inc.
Developmental transitions in electrical activation patterns in chick embryonic heart
Authors: Sedmera David , Reckova Maria , Bigelow Michael R. , Dealmeida Angela , Stanley Chiffvon P. , Mikawa Takashi , Gourdie Robert G. , Thompson Robert P. 
Published: September 2004

AbstractThe specialized conduction tissue network mediates coordinated propagation of electrical activity through the adult vertebrate heart. Following activation of the atria, the activation wave is slowed down in the atrioventricular canal or node, then spreads rapidly into the left and right ventricles via the His‐Purkinje system (HPS). This results in the ventricle being activated from the apex toward the base and is thought to represent HPS function. The development of mature HPS function in embryogenesis follows significant phases of cardiac morphogenesis. Initially, cardiac impulse propagates in a slow, linear, and isotropic fashion from the sinus venosus at the most caudal portion of the tubular heart. Although the speed of impulse propagation gradually increases, ventricular activation in the looped heart still follows the direction of blood flow. Eventually, the immature base‐to‐apex sequence of ventricular activation undergoes an apparent reversal, maturing to apex‐to‐base pattern. The embryonic chick heart has been studied intensively by both electrophysiological and morphological techniques, and the morphology of its conduction system (which is similar to mammals) is well characterized. One interesting but seldom studied feature is the anterior septal branch (ASB), which came sharply to focus (together with the rest of the ventricular conduction system) in our birthdating studies. Using an optical mapping approach, we show that ASB serves to activate ventricular surface between stages 16 and 25, predating the functionality of the His bundle/bundle branches. Heart morphogenesis and conduction system formation are thus linked, and studying the abnormal activation patterns could further our understanding of pathogenesis of congenital heart disease. © 2004 Wiley‐Liss, Inc.
Structure‐function relationship in the AV junction
Authors: Efimov Igor R. , Nikolski Vladimir P. , Rothenberg Florence , Greener Ian D. , Li Jue , Dobrzynski Halina , Boyett Mark 
Published: September 2004

AbstractIn the normal heart, the atrioventricular node (AVN) is part of the sole pathway between the atria and ventricles. Under normal physiological conditions, the AVN controls appropriate frequency‐dependent delay of contractions. The AVN also plays an important role in pathology: it protects ventricles during atrial tachyarrhythmia, and during sinoatrial node failure an AV junctional pacemaker can drive the heart. Finally, the AV junction provides an anatomical substrate for reentry. Using fluorescent imaging with voltage‐sensitive dyes and immunohistochemistry, we have investigated the structure‐function relationship of the AV junction during normal conduction, reentry, and junctional rhythm. We identified molecular and structural heterogeneity that provides a substrate for the dual‐pathway AVN conduction. We observed heterogeneity of expression of three isoforms of connexins: Cx43, Cx45, and Cx40. We identified the site of origin of junctional rhythm at the posterior extension of the AV node in 79% (n = 14) of the studied hearts. This structure was similar to the compact AV node as determined by morphologic and molecular investigations. In particular, both the posterior extension and the compact node express the pacemaking channel HCN4 (responsible for the IF current) and neurofilament 160. In the rabbit heart, AV junction conduction, reentrant arrhythmia, and spontaneous rhythm are governed by heterogeneity of expression of several isoforms of gap junctions and ion channels. Uniform neurofilament expression suggests that AV nodal posterior extensions are an integral part of the cardiac pacemaking and conduction system. On the other hand, differential expression of Cx isoforms in this region provides an explanation of longitudinal dissociation, dual‐pathway electrophysiology, and AV nodal reentrant arrhythmogenesis. © 2004 Wiley‐Liss, Inc.
Cytoarchitecture and intercalated disks of the working myocardium and the conduction system in the mammalian heart
Authors: Shimada Tatsuo , Kawazato Hiroaki , Yasuda Aiko , Ono Noriaki , Sueda Kana 
Published: September 2004

AbstractWorking and specialized cardiac myocytes and their intercalated disks (ID) in the mammalian heart were examined by transmission and scanning electron microscopy. The NaOH/ultrasonication treatment of cardiac tissues resulted in the digestion of collagen fibers and separation of intercellular junctions. Auricular and ventricular myocytes were cylindrical in shape, bifurcated, and connected end‐to‐end at the ID. The ID in the working myocardium showed a stair‐like profile, consisting of steps (plicate segments) and corresponding risers (interplicate segments). The ventricular myocytes had many steps and risers. The steps were filled with numerous finger‐like microprojections, including desmosomes, fasciae adherentes, and small gap junctions. The risers showed the smooth surface, including desmosomes and large gap junctions. The cell strands of the sinoatrial node were oriented linearly, while those of the atrioventricular node formed a reticular network. The ID in both nodal cells was underdeveloped, having few microprojections. Myocytes in the His bundle and its branches were arranged in parallel, and Purkinje cell strands formed reticular networks. The ID in the His‐Purkinje system was irregular in appearance, and the microprojections were larger in size and smaller in number than those of working myocytes. There were few microprojections in the sheep Purkinje cells. The gap junctions in the conduction system were few or small in size in the nodal tissue, but large in the His‐Purkinje system. 2004. © 2004 Wiley‐Liss, Inc.
Conduction abnormality in gap junction protein connexin45‐deficient embryonic stem cell‐derived cardiac myocytes
Authors: Egashira Katsuko , Nishii Kiyomasa , Nakamura Kei‐Ichiro , Kumai Madoka , Morimoto Sachio , Shibata Yosaburo 
Published: September 2004

AbstractIn early‐stage heart, the cardiac impulse does not propagate through the specialized conduction system but spreads from myocyte to myocyte. We hypothesized that the gap junction protein connexin45 (Cx45) regulates early‐stage contractions, because it is the only gap junction protein described in early hearts. Cx45‐deficient (Cx45−/−) mice die of heart failure, concomitantly displaying other complex defects in the cardiovascular system. In order to determine the specific cardiac muscular function of Cx45, we created Cx45−/− embryonic stem (ES) cells to be differentiated into cardiac muscle in vitro. Unlike the coordinated contractions of wild‐type cells, differentiated Cx45−/− cardiac myocytes showed high and irregular pulsation rates. Alterations of the electrophysiological properties of the Cx45−/− cardiac myocytes were indicated both by extracellular recording on planar multielectrode array probes and by intracellular Ca2+ recording of the fluorescent Ca2+ indicator fura‐2. The in vitro system minimizes an influence of hemodynamic factors that complicate the phenotypes of Cx45−/− mice. Our results indicate that Cx45 is an essential connexin for coordinated conduction through early cardiac myocytes. © 2004 Wiley‐Liss, Inc.
Towards a three‐α‐helix bundle protein that binds volatile general anesthetics
Authors: Manderson Gavin A. , Johansson Jonas S. 
Published: September 2004

AbstractThe general anesthetics halothane and chloroform are capable of binding to synthetic water‐soluble four‐α‐helix bundles, which model the putative in vivo receptors. In this study, we investigate the binding of these anesthetics to synthetic water‐soluble three‐α‐helix bundles. A series of variants containing up to four X‐to‐Ala and up to four X‐to‐Met substitutions was made; and the effect of these substitutions on structure, stability and anesthetic binding affinity was examined. Generally, the amount of α‐helix and the stability of the three‐α‐helix bundles decreased as the number of X‐to‐Ala substitutions increased. A concomitant red‐shift in tryptophan fluorescence λmax was seen, suggesting an increased flexibility of the native structure. Up to four X‐to‐Met substitutions had little effect on the amount of α‐helix, but an increase in tryptophan λmax was seen for the variants with three and four methionine substitutions. The exceptions were a) a variant with a clustering of alanine and methionine residues at one end of the three‐α‐helix bundle, suggesting a gate structure that can admit ligand molecules; and b) a variant with a single Leu35Ala substitution, suggesting that at select positions, the size of the side chain is important for defining anesthetic binding affinity. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Effect of chain length on coiled‐coil stability: Decreasing stability with increasing chain length
Authors: Kwok Stanley C. , Hodges Robert S. 
Published: September 2004

AbstractThe de novo design and biophysical characterization of three series of two‐stranded α‐helical coiled coils with different chain lengths are described. Our goal was to examine how increasing chain length would affect protein folding and stability when one or more heptad repeat(s) of K–A–E–A–L–E–G (gabcdef) was inserted into the central region of different coiled‐coil host proteins. This heptad was designed to maintain the continuous 3–4 hydrophobic repeat of the coiled‐coil host and introduce an Ala and Leu residue in the hydrophobic core at the a and d position, respectively, and a pair of stabilizing interchain ionic i to i′ + 5 (g to e′) interactions per heptad inserted. The secondary structures of the three series of disulfide‐bridged polypeptides were studied by CD spectroscopy and their stabilities determined by chemical and thermal denaturation. The results showed that successive insertions of this heptad systematically decreased the stability of all the coiled coils studied regardless of the overall initial stability of the host coiled coil. These observations are in contrast to the generally accepted implication that the folding and stability of coiled coils are enhanced with increasing chain length. Our results imply that, in these examples where an Ala and Leu hydrophobic residue were introduced into the coiled‐coil core per inserted heptad, there was still insufficient stability to overcome unfavorable entropy associated with chain length extension, even though the inserted heptad contained the most stabilizing hydrophobic residue (Leu) at position d and stabilizing ionic attractions. © 2004 Wiley Periodicals, Inc. Bioploymers (Pept Sci), 2004
Influence of conformational flexibility on biological activity in cyclic astin analogues
Authors: Saviano Gabriella , Benedetti Ettore , Cozzolino Rosanna , De Capua Antonia , Laccetti Paolo , Palladino Pasquale , Zanotti Giancarlo , Amodeo Pietro , Tancredi Teodorico , Rossi Filomena 
Published: September 2004

AbstractThe astins, a family of natural antitumor cyclopeptides, from the roots of Aster tataricus, consist of a 16‐membered ring system containing uncoded amino acid residues. The backbone conformation, with a cis‐3,4‐dichlorinated proline residue, plays an important role in antineoplastic activity. The acyclic astins, on the other hand, do not show antitumor activity, suggesting that the cyclic nature of astins may be a key role in their biological properties. Although the antineoplastic activity of natural astins has been screened in vitro and in vivo, the mechanism of action has never been investigated. With the aim at elucidating the influence of conformational flexibility on biological activity, we have designed and synthesized several astin analogues containing either Aib and the nonproteinogenic Abu and (S)β3hPhe residues, able to modify the peptide backbone structure, or the peptide bond surrogate SO2NH. Tested for their antitumor effect, our astin‐related cyclopeptides are able to inhibit the growth of tumor cell lines, while the acyclic astins are inefficacious. The present work reports on the structure–activity study of a selected synthetic cyclotetrapeptide corresponding to the sequence c[ThrAib(S)β3hPheΨ(CH2SO2NH)Abu], synthesized by classical methods and characterized conformationally by two‐dimensional NMR and molecular dynamics analyses. © 2004 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2004
Host–guest complexation of oxicam NSAIDs with β‐cyclodextrin
Authors: Banerjee Rona , Chakraborty Hirak , Sarkar Munna 
Published: September 2004

AbstractSpectroscopic and molecular modeling techniques have been employed to study the interaction of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs) with a polysaccharide such as β‐cyclodextrin (β‐cd). β‐cd is a good drug delivery system and is known to reduce harmful side effects of these drugs in the gastrointestinal tract and to increase their clinical efficacy. A detailed understanding of such host–guest interaction helps in designing a better drug delivery system coupled with increased therapeutic potential. However, there exists a controversy as to which prototropic form of piroxicam, a drug belonging to the oxicam group, becomes encapsulated in the host and also the stoichiometry of binding. In this study, we have revisited that controversy using steady state fluorescence, absorption, fluorescence anisotropy measurements, and molecular modeling techniques. In addition, we have for the first time studied the interactions of two other oxicam drugs, viz. tenoxicam and meloxicam, with β‐cd in aqueous solution. In all cases the neutral forms of these drugs were incorporated in the β‐cd cavity with a binding stoichiometry of 1:1 host : guest. The values of the binding constants for piroxicam, meloxicam, and tenoxicam with β‐cyclodextrin are 134 ± 21, 114 ± 15, and 115 ± 13 M−1, respectively. Molecular modeling studies show that the minimum energy configuration gives favorable interaction energy between the host and the guest in the complex with 1:1 stoichiometry when the conjugated rings of the drugs are inside the hydrophobic bucket‐like cavity of β‐cd and the third ring is exposed to the solvent. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Geometry drives the “deviated‐bending” of the bi‐tubular structures of the 9+2 axoneme in the flagellum
Authors: Cibert Christian , Heck Jean‐Vivien 
Published: September 2004

AbstractThe axoneme “9+2” is basically a system constituted of a cylinder of 9 microtubule doublets surrounding a central pair of microtubules. These bi‐tubular structures are considered as the support system of the active molecular complexes that generate and regulate the axonemal movement. Schoutens has calculated their moments of inertia [Schoutens, 1994: Journal of Theoretical Biology 171:163–177]. The results obtained allowed us to assume that these bi‐tubular systems are endowed with dynamic properties that could be involved in the regulation of the axonemal machinery. For the first time, using the finite elements methods and the resistance of material principles, we have now calculated that the curvature of the axoneme induces the deviated‐bending of the bi‐tubular structures of the axoneme, because of their geometry only; they behave as beams in a framework. This approach is similar to the one used to measure the deflection of a single microtubule [Kasas et al., 2004: Chem Phys Chem 5:252–257]. These behaviors induce internal movement or constraints of either couples or triplets of doublets within the axonemal cylinder that could be directly involved in a constrained or a spontaneous “convergence/divergence” equilibrium of the cylindrical generatrices that they draw along the axonemal cylinder, which could apparently regulate the activity of the axonemal motors (the dynein arms). These results are discussed here, taking into consideration the dynamic propagation of the wave train along the flagellar axoneme, and the regulated balance between the activities of the two opposite sides of the axoneme during the beat. This study raises a few questions about the architecture‐activity duo of the axonemal doublets. Cell Motil. Cytoskeleton 59:153–168, 2004. © 2004 Wiley‐Liss, Inc.
The clinical value of tumor burden at diagnosis in Hodgkin lymphoma
Authors: Gobbi Paolo G. , Broglia Chiara , Di Giulio Giuseppe , Mantelli Monica , Anselmo Paola , Merli Francesco , Zinzani Pier L. , Rossi Gabriele , Callea Vincenzo , Iannitto Emilio , Paulli Marco , Garioni Lorena , Ascari Edoardo 
Published: September 2004

AbstractBACKGROUNDThe authors investigated the clinical role of tumor burden (TB) in patients with Hodgkin lymphoma, relating this parameter to most of the current clinical and prognostic factors and to the best predictive multifactorial models.METHODSThe volume of TB at diagnosis was measured directly from the initial staging computed tomography scans in 351 patients who were treated on standard protocols. The mean patient age was 34.0 years ± 16.4 years. Forty‐six patients had clinical Stage I disease, 201 patients had Stage II disease, 64 patients had Stage III disease, and 40 patients had Stage IV disease. There were 146 symptomatic patients. Overall survival (OS), disease‐free survival (DFS), and time to treatment failure (TTF) were the time parameters evaluated in the multivariate analysis. Logistic regression was applied according to those who achieved or failed complete remission.RESULTSThe mean TB normalized to body surface area (rTB) was 137.8 cm3/m2± 124.7 cm3/m2(range, 1.9–694.5 cm3/m2). In multivariate analysis, rTB was the best predictor of TTF, DFS, and complete remission; the second best predictor of OS after patient age; and largely superior to all prognostic models analyzed. For the same stage and treatment, patients who were destined to clinical failure had an initial rTB 60–108% higher compared with the initial rTB in patients who achieved a cure, whereas differences in drug dose intensity were not significant.CONCLUSIONSIn the current study, it was found that the rTB, as a prognostic factor, was more effective than and was independent of hitherto used factors and scores. The rTB may be a tool for evaluating the curative potential of treatment combinations, allowing physicians and patients to make better therapeutic choices earlier. Cancer 2004. © 2004 American Cancer Society.
Late‐delayed cerebral involvement in systemic non‐Hodgkin lymphoma
Authors: Lossos Alexander , Ashhab Yaqoub , Sverdlin Elena , Amir Gail , Ben‐Yehuda Dina , Siegal Tali 
Published: September 2004

AbstractBACKGROUNDCentral nervous system involvement is a well recognized complication of systemic non‐Hodgkin lymphoma. Most central nervous system recurrences occur within the first 2 years after the initial diagnosis and are considered to represent clonally related recurrence of systemic disease. The authors attempted to investigate the clonal relation between the late‐delayed central nervous system involvement and the original systemic tumor.METHODSThe authors studied archival, formalin fixed, paraffin embedded tissue samples from 8 patients with isolated cerebral involvement diagnosed > 3 years after their initial presentation with aggressive, systemic, B‐cell non‐Hodgkin lymphoma. The rearranged immunoglobulin heavy‐chain variable region genes (VH) from both sites were amplified by polymerase chain reaction and were sequenced when necessary.RESULTSIn three of five patients who had interpretable results, a distinct, monoclonal, VH family‐specific band profile was obtained from the cerebral and systemic lymphoma. In the other two patients, a similar VH band pattern was observed and also was compared using direct sequencing, which demonstrated sequence differences between tumors from the two sites.CONCLUSIONSClonal variance between the cerebral and systemic lymphoma in these patients suggested the possibility that some instances of late‐delayed recurrence in the central nervous system represent a second, new B‐cell lymphoma rather than a true recurrence of the original systemic tumor, a finding that may have significant clinical and biologic implications. Cancer 2004. © 2004 American Cancer Society.