bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Electrophysiologic Abnormalities in the CREBA133 Transgenic Mouse Model of Idiopathic Dilated Cardiomyopathy
Authors: ZHU WEI , LEPORE JOHN J. , SABA SAMIR , JOSEPH SAJU , LINK MARK S. , HOMOUD MUNTHER K. , ESTES N.A. MARK , WANG PAUL J. , LEIDEN JEFFREY M.
Published: September 2003

Introduction: We hypothesized that the transgenic mice expressing a dominant‐negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte‐specific α‐MHC promoter and displaying dilated cardiomyopathy would exhibit electrophysiologic abnormalities similar to those observed in human cardiomyopathy.

Methods and Results: Invasive electrophysiologic studies were performed on two age groups of mice: 11‐week‐old mice (n = 20, 9 transgenic mice and 11 wild‐type controls) and 17‐week‐old mice (n = 16, 7 transgenic mice and 9 wild‐type controls). Five additional transgenic mice underwent ambulatory ECG monitoring to determine the cause of death. The 11‐week‐old CREBA133 transgenic mice had longer PR and AH intervals than 11‐week‐old wild‐type controls (P < 0.001), whereas at 17 weeks of age the transgenic mice also demonstrated increased HV intervals and widened QRS duration (P < 0.05). At both 11 weeks and 17 weeks of age, AV Wenckebach cycle length, 2:1 AV cycle length, and AV nodal functional and effective refractory periods were significantly longer in transgenic mice than in controls (P < 0.05). Although no ventricular arrhythmias were inducible at 11 weeks of age, at 17 weeks of age, ventricular tachycardia was induced in 4 of the 7 CREBA133 transgenic mice but in none of the 9 wild‐type controls. All 5 CREBA133 transgenic mice that underwent ambulatory ECG monitoring revealed high‐grade AV block, but not ventricular arrhythmia, at the time of death.

Conclusion: These data suggest that CREBA133 transgenic mice manifest abnormalities of AV nodal and infra‐Hisian conduction and inducibility of ventricular arrhythmia, which are characteristics of human dilated cardiomyopathy. (J Cardiovasc Electrophysiol, Vol. 14, pp. 982‐989, September 2003)
Complete Occlusion of the Left Circumflex Coronary Artery After Radiofrequency Catheter Ablation in an Infant
Authors: PAUL THOMAS , KAKAVAND BAHRAM , BLAUFOX ANDREW D. , SAUL J. PHILIP
Published: September 2003

Radiofrequency catheter ablation of a left lateral accessory atrioventricular pathway was performed in a 5‐week‐old infant with drug‐refractory supraventricular tachycardia. Energy application via a 5‐French mapping and ablation catheter in the temperature‐controlled mode (60°C, 30 W) at the atrial aspect of the mitral valve annulus repeatedly resulted in termination of the tachycardia by conduction block within the pathway. Tachycardia remained inducible subsequently. After a safety energy application during sinus rhythm, significant ST‐segment elevation in the inferior, mid precordial, and left lateral leads was noted. Selective left coronary angiography revealed complete occlusion of the circumflex coronary artery. Moderate‐to‐severe mitral valve regurgitation developed, finally requiring mitral valve replacement. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1004‐1006, September 2003)
Combined Head‐Up Tilt and Lower Body Negative Pressure as an Experimental Model of Orthostatic Syncope
Authors: LELORIER PAUL , KLEIN GEORGE J. , KRAHN ANDREW , YEE RAYMOND , SKANES ALLAN , SHOEMAKER J. KEVIN
Published: September 2003

Introduction: The combination of head‐up tilt and incremental lower body negative pressure has shown promise in the diagnosis of orthostatic hypotension and neurocardiogenic syncope, although prior methodologies limited conclusions as to the reproducibility of the test. The aim of this study was to assess the efficacy and reproducibility of a protocol combining tilt and stages of incremental lower body negative pressure.

Methods and Results: Ten volunteers (6 men and 4 women; mean age 21 ± 1 years) participated in the study, which was composed of three sessions, 1 month apart, each consisting of 60° tilt followed by lower body suction in incremental levels of −10 mmHg for 5 minutes at each level. The primary outcome variable was the time to presyncope. Secondary variables were the levels of heart rate, blood pressure, cerebral blood flow, and end‐tidal CO2 at each level of the test. Presyncope could be achieved in all subjects. The mean times to presyncope were 24.6 ± 1.4 minutes, 26.2 ± 1.8 minutes, and 31.8 ± 1.6 minutes and were not different across tests (P = 0.3). Intrasubject variability was assessed by determining the mean average deviation from the mean, which was 3.2 ± 2.0 minutes. Changes in heart rate, blood pressure, end‐tidal CO2, and cerebral blood flow were consistent with repeat testing.

Conclusion: Lower body negative pressure combined with head‐up tilt in a staged protocol can safely and reliably induce presyncope in all normal subjects tested. The test is a potent and reproducible investigational tool for inducing hypotension and transient cerebral hypoperfusion. (J Cardiovasc Electrophysiol, Vol. 14, pp. 920‐924, September 2003)
Ventricular Flutter Induced During Electrophysiologic Studies in Patients with Old Myocardial Infarction:
Authors: VISKIN SAMI , ISH‐SHALOM MAYA , KOIFMAN EDWARD , ROZOVSKI URI , ZELTSER DAVID , GLICK AHARON , FINKELSTEIN ARIEL , HALKIN AMIR , FISH ROMAN , BELHASSEN BERNARD
Published: September 2003

Introduction: Induction of ventricular flutter during electrophysiologic (EP) studies (similar to that of ventricular fibrillation [VF]) often is viewed as a nonspecific response with limited prognostic significance. However, data supporting this dogma originate from patients without previously documented ventricular tachyarrhythmias. We examined the significance of ventricular flutter in patients with and without spontaneous ventricular arrhythmias.

Methods and Results: We conducted a cohort study of all patients with myocardial infarction (MI) undergoing EP studies at our institution. Of 344 consecutive patients, 181 had previously documented spontaneous sustained ventricular arrhythmias, 61 had suspected ventricular arrhythmias, and 102 had neither. Ventricular flutter was induced in 65 (19%) of the patients. Left ventricular ejection fraction was highest among patients with inducible VF (35 ± 13), lowest for patients with inducible sustained monomorphic ventricular tachycardia (SMVT; 27 ± 9), and intermediate for patients with inducible ventricular flutter (30 ± 10). Similarly, the coupling intervals needed to induce the arrhythmia were shortest for VF (200 ± 28 msec), intermediate for ventricular flutter (209 ± 27 msec), and longest for SMVT (230 ± 35 msec). During 5 ± 8 years of follow‐up, the risk for ventricular tachycardia/VF was high for patients with SMVT and ventricular flutter and low for patients with inducible VF and noninducible patients (46%, 34%, 17%, and 14%, P < 0.005).

Conclusion: Patients with inducible ventricular flutter appear to be “intermediate” between patients with inducible VF and patients with SMVT in terms of clinical and electrophysiologic correlates. However, the prognostic value of inducible ventricular flutter is comparable to that of SMVT. (J Cardiovasc Electrophysiol, Vol. 14, pp. 913‐919, September 2003)
Computational Model of the Ventricular Action Potential in Adult Spontaneously Hypertensive Rats
Authors: PADMALA SRIKANTH , DEMIR SEMAHAT S.
Published: September 2003

Introduction: Cardiac hypertrophy has substantial clinical significance because many hypertrophic cells have markedly prolonged repolarization behavior, which may lead to increased risk for cardiac arrhythmias. Spontaneously hypertensive rat (SHR) is one model of hypertension that is studied extensively and is considered to be the best laboratory model of human hypertension. We extended our previously published model of the rat ventricular myocyte to simulate the effects of hypertrophy in SHR.

Methods and Results: In SHR it has been shown that the membrane capacitance is increased, the density of transient outward K+ current is decreased, the sarcoplasmic reticulum Ca2+ ATPase activity is reduced, and the cell volumes are increased compared to those of the normal rat. We introduced these changes into our previous model of the rat ventricular myocyte and simulated the ventricular action potential of SHR. Our results demonstrated increased action potential duration (APD) and increased peak systolic value of the intracellular calcium transient in SHR. Simulations with reduced extracellular K+ concentration ([K+]o) have shown that there is increased APD shortening in SHR compared to that of the normal rat.

Conclusions: Our computational model qualitatively simulated the electrophysiologic changes observed in SHR and provided the plausible mechanistic linkage between the prolonged APD and increased inotropy. Our model results also demonstrated the electrophysiologic changes observed with reduced [K+]o in SHR, a finding that is clinically significant in hypertensive patients with left ventricular hypertrophy undergoing diuretic treatment. (J Cardiovasc Electrophysiol, Vol. 14, pp. 990‐995, September 2003)
Reentrant Tachycardia in Pulmonary Veins of Patients with Paroxysmal Atrial Fibrillation
Authors: TAKAHASHI YOSHIHIDE , IESAKA YOSHITO , TAKAHASHI ATSUSHI , GOYA MASAHIKO , KOBAYASHI KENZABUROU , FUJIWARA HIDEOMI , HIRAOKA MASAYASU
Published: September 2003

Introduction: Although slow automatic pulmonary vein (PV) activity dissociated from the atrium after achievement of PV isolation in patients with atrial fibrillation (AF) has been reported, little is known about dissociated PV tachycardia. The aim of this study was to investigate the inducibility and the mechanism of sustained PV tachycardia (SPVT).

Methods and Results: One hundred thirty‐two patients with drug‐refractory paroxysmal AF underwent PV isolation by radiofrequency catheter ablation. Programmed stimulation was performed in 269 PVs of 110 of these patients after achievement of PV isolation. In 7 PVs (2.6%; left superior PV: n = 2, right superior PV: n = 4, right inferior PV: n = 1) of 7 (6.4%) of 110 patients, 18 SPVTs were induced. Fifteen regular SPVTs (mean cycle length 152 ± 34 msec) were induced in 6 of 7 PVs, and 3 irregular SPVTs (cycle length range: 94–276 msec) were induced in 3 of 7 PVs. In 2 PVs, both regular and irregular SPVTs were induced. SPVT was terminated by burst pacing in 4 PVs, and entrainment was observed during regular SPVT in 5 PVs. Slow PV automatic activity dissociated from the atrium and decremental conduction properties were shown in all 7 PVs. The shortest pacing cycle length with 1:1 capture was ≤150 msec in 6 of 7 PVs.

Conclusion: Reentrant tachycardia can occur in some isolated PVs with both decremental conduction properties and short refractory periods, which suggests that reentry may be one of the mechanisms of PV arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 14, pp. 927‐932, September 2003)
Sleep Quality Among Patients Treated with Implantable Atrial Defibrillation Therapy:
Authors: SERBER, M.A. EVA R. , SEARS SAMUEL F. , SOTILE REBECCA O. , BURNS JASON L. , SCHWARTZMAN DAVID S. , HOYT ROBERT H. , ALVAREZ LUIS G. , UJHELYI MICHAEL R.
Published: September 2003

Introduction: The Medtronic ICD‐AT has atrial/ventricular therapies, which can be programmed to deliver atrial defibrillation during sleep, intended to potentially decrease shock anxiety/pain and lifestyle disruption. However, these shocks may diminish sleep quality. This study examined atrial shock characteristics (i.e., mode, frequency), AF symptoms, and psychological factors as determinants of sleep quality.

Methods and Results: The 96 ICD‐AT patients were mostly men (72%; M age 65 ± 12 years) and implanted for 1.6 years (SD = 0.8 years). Patients were divided into shock groups based on the proportion of mode (≥90%) of total atrial shocks received. Patients were grouped into either automatic‐nocturnal shock group (8 P.M.–8 A.M.; n = 35) or manual‐awake shock group (n = 42). Psychological measures included Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiology Studies‐Depression Scale, State‐Trait Anxiety Inventory, and Illness Intrusiveness Rating Scale. Atrial fibrillation disease burden was assessed via atrial symptom score and atrial shock use. PSQI global scores were similar between manual (7.67 ± 2.53) and automatic shock (8.20 ± 2.93) groups. A multiple hierarchical regression analysis indicated that no atrial shock variables were predictive of sleep quality; yet, both AF symptom (B = 0.226, P = 0.040) and depression (B = 0.392, P = 0.034) scores predicted diminished sleep quality, accounting for 42% of the variance in global sleep quality (P < 0.001).

Conclusion: These results suggest that atrial defibrillation therapy does not have a deleterious impact on sleep. However, the significance of AF symptoms and depression indicate that comprehensive care of both physical and psychological symptomatology may improve sleep quality in ICD‐AT patients. (J Cardiovasc Electrophysiol, Vol. 14, pp. 960‐964, September 2003)
New Method of Determining the Atrial Fibrillation Cycle Length During Human Atrial Fibrillation
Authors: SHIMIZU AKIHIKO , YOSHIGA YASUHIRO , YAMAGATA TOSHIHIKO , ESATO MASAHIRO , DOI MASAHIRO , KAKUGAWA HIROYUKI , KAMETANI RYOUSUKE , INOUE NORIKO , KANEMOTO MASASHI , MATSUZAKI MASUNORI
Published: September 2003

Introduction: The aim of this study was to investigate the usefulness of the autocorrelation function (reversed fast Fourier transform analysis) in determining the atrial fibrillation cycle length (AFCL) during human atrial fibrillation (AF).

Methods and Results: From 30 episodes of atrial electrograms recorded for 30 seconds from the high right atrium during type I AF in 16 patients, the mean, 5th percentile (p5), and 95th percentile (p95) of the AFCLs were measured by using a computer‐picked activation time. The peak, minimum, and maximum AFCLs also were measured by using the autocorrelation function. The mean AFCL was retrieved at the point of the maximum peak of the coefficient of the first positive autocorrelogram. The minimum AFCL (min AFCL) was chosen as the point where the first positive autocorrelogram crossed the baseline from negative to positive, and the maximum AFCL (max AFCL) was chosen as the point where the first positive autocorrelogram crossed the baseline from positive to negative. There was a significantly strong correlation between the mean and peak AFCLs (r = 0.995, P < 0.0001), p5 and min AFCLs (r = 0.953, P < 0.0001), and p95 and max AFCLs (r = 0.98, P < 0.0001).

Conclusion: The autocorrelation function was useful in determining the AFCLs, at least during type I AF. The min AFCL may be used as an index of the refractory period during AF when the p5 AFCL approximates the refractory period. (J Cardiovasc Electrophysiol, Vol. 14, pp. 965‐970, September 2003)
Transcardiac Pericardiocentesis:
Authors: HSU LI‐FERN , SCAVÉE CHRISTOPHE , JAÏS PIERRE , HOCINI MÉLÈZE , HAÏSSAGUERRE MICHEL
Published: September 2003

Life‐threatening cardiac tamponade is one of the most serious complications of catheter‐based cardiac procedures. Although most cases can be effectively treated by percutaneous pericardiocentesis, urgent surgical drainage is required in unsuccessful cases. Rarely, in collapsed patients, the delay for surgery, however minimal, may be fatal. We describe a technique whereby life‐saving pericardial drainage was rapidly achieved via a novel transcardiac approach, using the transseptal puncture kit, after failure of conventional pericardiocentesis in a patient with procedure‐related acute tamponade who rapidly deteriorated and developed cardiorespiratory arrest within a few minutes. Although surgical repair for the perforation had to be performed subsequently, the patient survived without sequelae. This transcardiac approach may be an important and potentially life‐saving adjunctive technique after failure of conventional pericardiocentesis in rapidly deteriorating or extremely unstable patients. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1001‐1003, September 2003)
Quantifying Intracardiac Organization of Atrial Arrhythmias Using Temporospatial Phase of the Electrocardiogram
Authors: NARAYAN SANJIV M. , FELD GREGORY K. , HASSANKHANI ALBORZ , BHARGAVA VALMIK
Published: September 2003

Introduction: Separating nonisthmus‐dependent atrial flutter (AFL) from “organized” atrial fibrillation (AF), or isthmus‐dependent AFL, may be difficult using ECG characteristics alone. We hypothesized that temporal and spatial phase analysis of ECG atrial waveforms could effectively separate these rhythms by quantifying subtle variations in ECG atrial activation during supraventricular tachycardias (SVT).

Methods and Results: We studied 52 patients at electrophysiologic study (EPS) who demonstrated isthmus‐dependent (n = 15) and nonisthmus‐dependent (n = 9) AFL, atrial tachycardia (n = 6), AV nodal reentry (n = 9), orthodromic reciprocating tachycardia (n = 6), and AF (n = 7). Atrial activity was represented as a series of correlations of an atrial template to successive time samples of the arrhythmia ECG. Spatial phase was analyzed as a reproducible relationship of this atrial activity between leads over time; temporal regularity was measured from power spectra. Spatial phase was maintained (coherent) in lead planes V5/aVF (XY), V5/V1 (XZ), and aVF/V1 (YZ) in 15 of 15 cases of isthmus‐dependent AFL, but in only 1 of 9 cases of nonisthmus‐dependent AFL (P < 0.01; χ2). Temporally, all cases of AFL showed one dominant peak on correlation spectra (magnitude >6 dB), suggesting one activation wavefront, although this was smeared in nonisthmus‐dependent cases. In contrast, AF showed inconsistent spatial phase in all planes and broad band spectra, consistent with multiple and/or variable activation paths. All other SVTs showed spatial coherence and one dominant spectral peak.

Conclusion: Coherence of temporal and spatial phase is a powerful approach to measure the spatial organization of intracardiac activation from the ECG that reveals a spectrum from SVT to isthmus‐dependent and nonisthmus‐dependent AFL, to AF. (J Cardiovasc Electrophysiol, Vol. 14, pp. 971‐981, September 2003)
On McMullin's Appreciation of Realism Concerning the Sciences
Authors: van Fraassen Bas C.
Published: September 2003

Constructive empiricism is indeed set squarely within a common sense realism that was foreign to much of the empiricist tradition. But I do not see this common sense realism, which I take myself to share with many scientific realists, as harboring or leading to scientific realism. That is in part because of the way I separate the opposition between empiricist and realist understanding of science from other issues that divide us in epistemology. This discussion brought to light our quite different conceptions of what is at issue between empiricists and realists in this area. After a response to McMullin's critique, however, I will be especially concerned to respond to his challenging proposal for a shift in the debate over realism concerning the sciences.
Pluralism, Entwinement, and the Levels of Selection
Authors: Wilson Robert A.
Published: September 2003

This paper distinguishes and critiques several forms of pluralism about the levels of selection, and introduces a novel way of thinking about the biological properties and processes typically conceptualized in terms of distinct levels. In particular, “levels” should be thought of as beingentwinedorfused.Since the pluralism discussed is held by divergent theorists, the argument has implications for many positions in the debate over the units of selection. And since the key points on which the paper turns apply beyond this specific issue, the paper may prove of general interest in thinking about the metaphysics of science
Leibniz on Force and Absolute Motion
Authors: Roberts John T.
Published: September 2003

I elaborate and defend an interpretation of Leibniz on which he is committed to a stronger space-time structure than so-called Leibnizian space-time, with absolute speeds grounded in his concept of force rather than in substantival space and time. I argue that this interpretation is well-motivated by Leibniz's mature writings, that it renders his views on space, time, motion, and force consistent with his metaphysics, and that it makes better sense of his replies to Clarke than does the standard interpretation. Further, it illuminates the way in which Leibniz took his physics to be grounded in his metaphysics.
Spontaneous Symmetry Breaking and Chance in a Classical World
Authors: Liu Chuang
Published: September 2003

This essay explores the nature of spontaneous symmetry breaking (SSB) in connection with a cluster of interrelated concepts such as Curie's symmetry principle, ergodicity, and chance and stability in classical systems. First, a clarification of the two existing senses of SSB is provided and an argument developed for a proposal for SSB, in which not only the possibilities but also the actual breakings are referred to. Second, a detailed analysis is given of classical SSB that answers the questions: (i) how we are justified in regarding it as a matter of chance, and (ii) why the breakings in it are equally probable. The answer provides some support to the applicability of ergodicity in special systems (such as ours).
Van Fraassen's Unappreciated Realism
Authors: McMullin Ernan
Published: September 2003

What is not often noted about Bas van Fraassen's distinctive approach to the scientific realism issue is that constructive empiricism, as he defines it, seems to involve a distinctively realist stance in regard to large parts of natural science. This apparent defection from the ranks of his more uncompromisingly anti-realist colleagues raises many questions. Is hereallyleaning to realism here? If he is, why is this not more widely noted? And, more important, if he is, is he entitled to this shyly realist concession? Does his many-pronged attack on what he sees as the main arguments in support of realism leave him with the wherewithal?
The Theory-Dependence of the Use of Instruments in Science
Authors: Chalmers Alan
Published: September 2003

The idea that the use of instruments in science is theory-dependent seems to threaten the extent to which the output of those instruments can act as an independent arbiter of theory. This issue is explored by studying an early use of the electron microscope to observe dislocations in crystals. It is shown that this usage did indeed involve the theory of the electron microscope but that, nevertheless, it was possible to argue strongly for the experimental results, the theory of dislocations being tested, and the theory of the instrument, all at the same time.
The Conserved Quantity Theory of Causation and Closed Systems
Authors: Choi Sungho
Published: September 2003

Advocates of the conserved quantity (CQ) theory of causation have their own peculiar problem with conservation laws. Since they analyze causal process and interaction in terms of conserved quantities that are in turn defined as physical quantities governed by conservation laws, they must formulate conservation laws in a way that does not invoke causation, or else circularity threatens. In this paper I will propose an adequate formulation of a conservation law that serves CQ theorists’ purpose.
The Coincidences of Time Travel
Authors: Dowe Phil
Published: September 2003

In this paper I consider two objections raised by Nick Smith (1997) to an argument against the probability of time travel given by Paul Horwich (1995, 1987). Horwich argues that time travel leads to inexplicable and improbable coincidences. I argue that one of Smith's objections fails, but that another is correct. I also consider an instructive way to defend Horwich's argument against the second of Smith's objections, but show that it too fails. I conclude that unless there is something faulty in the conception of explanation implicit in Horwich's argument, time travel presents us with nothing that is inexplicable.
Horizontal Models: From Bakers to Cats
Authors: Bokulich Alisa
Published: September 2003

At the center of quantum chaos research is a particular family of models known as quantum maps. These maps illustrate an important “horizontal” dimension to model construction that has been overlooked in the literature on models. Three ways in which quantum maps are being used to clarify the relationship between classical and quantum mechanics are examined. This study suggests that horizontal models may provide a new and fruitful framework for exploring intertheoretic relations.
Sophisticates or Dupes? Attitudes toward Food Consumers in Edwardian Britain
Authors: French Michael , Phillips Jim
Published: September 2003

In this article, we explore how reformers, manufacturers, and traders perceived British food consumers and the significance of those perceptions in debates about food quality and regulation. By considering basic commodities, our analysis extends a literature on consumption that is otherwise derived primarily from the study of luxury commodities, and it identifies conflicting images of the interests, competence, and concerns of early twentieth-century consumers. We find that discussions of appropriate policy involved competing interpretations of modernity and its implications for food consumers, and these discussions anticipated later twentieth-century debates.
Americans in Paris: The J. Walter Thompson Company in France, 1927–1968
Authors: Hultquist Clark Eric
Published: September 2003

J. Walter Thompson (JWT), the leading American advertising agency until the 1970s, established a branch office in Paris in 1927. While many of JWT's worldwide branches became the leading agencies in their respective countries, notably Great Britain and Germany, JWT-Paris foundered from the late 1920s through the early 1960s. This article focuses on the reasons why: cultural clashes between the French and Americans, a regulated and protected French market, anti-Americanism among French businesses, and American condescension and insensitivity. It concludes with an analysis of and the reasons for JWT-Paris's achievement of limited success by the late 1960s.
Regionalism in Stanford's Contribution to the Rise of Silicon Valley
Authors: Adams Stephen B.
Published: September 2003

In this article I explore the powerful sense of regional solidarity that accompanied the rise of Silicon Valley. From the early years of Stanford University, the university's leaders saw its mission as service to the West and shaped the school accordingly. At the same time, the perceived exploitation of the West at the hands of eastern interests fueled booster-like attempts to build self-sufficient indigenous local industry. Thus, regionalism helped align Stanford's interests with those of the area's high-tech firms for the first fifty years of Silicon Valley's development. The distinctive regional ethos of the West during the first half of the twentieth century is an ingredient of Silicon Valley's already prepared environment, an ingredient that would-be replicators ignore at their peril.
Identification of Putative Noncoding RNAs Among the RIKEN Mouse Full-Length cDNA Collection
Authors: Numata Koji , Kanai Akio , Saito Rintaro , Kondo Shinji , Adachi Jun , Wilming Laurens G. , Hume David A. ,   RIKEN GER Group,   GSL Members, Hayashizaki Yoshihide , Tomita Masaru
Published: September 2003

With the sequencing and annotation of genomes and transcriptomes of several eukaryotes, the importance of noncoding RNA (ncRNA)—RNA molecules that are not translated to protein products—has become more evident. A subclass of ncRNA transcripts are encoded by highly regulated, multi-exon, transcriptional units, are processed like typical protein-coding mRNAs and are increasingly implicated in regulation of many cellular functions in eukaryotes. This study describes the identification of candidate functional ncRNAs from among the RIKEN mouse full-length cDNA collection, which contains 60,770 sequences, by using a systematic computational filtering approach. We initially searched for previously reported ncRNAs and found nine murine ncRNAs and homologs of several previously described nonmouse ncRNAs. Through our computational approach to filter artifact-free clones that lack protein coding potential, we extracted 4280 transcripts as the largest-candidate set. Many clones in the set had EST hits, potential CpG islands surrounding the transcription start sites, and homologies with the human genome. This implies that many candidates are indeed transcribed in a regulated manner. Our results demonstrate that ncRNAs are a major functional subclass of processed transcripts in mammals.
Identification and Analysis of Chromodomain-Containing Proteins Encoded in the Mouse Transcriptome
Authors: Tajul-Arifin Khairina , Teasdale Rohan , Ravasi Timothy , Hume David A. ,   RIKEN GER Group,   GSL Members, Mattick John S.
Published: September 2003

The chromodomain is 40–50 amino acids in length and is conserved in a wide range of chromatic and regulatory proteins involved in chromatin remodeling. Chromodomain-containing proteins can be classified into families based on their broader characteristics, in particular the presence of other types of domains, and which correlate with different subclasses of the chromodomains themselves. Hidden Markov model (HMM)-generated profiles of different subclasses of chromodomains were used here to identify sequences encoding chromodomain-containing proteins in the mouse transcriptome and genome. A total of 36 different loci encoding proteins containing chromodomains, including 17 novel loci, were identified. Six of these loci (including three apparent pseudogenes, a novel HP1 ortholog, and two novel Msl-3 transcription factor-like proteins) are not present in the human genome, whereas the human genome contains four loci (two CDY orthologs and two apparent CDY pseudogenes) that are not present in mouse. A number of these loci exhibit alternative splicing to produce different isoforms, including 43 novel variants, some of which lack the chromodomain. The likely functions of these proteins are discussed in relation to the known functions of other chromodomain-containing proteins within the same family.
Cytokine-Related Genes Identified From the RIKEN Full-Length Mouse cDNA Data Set
Authors: Brusic Vladimir , Pillai Rekha S. , Silva Diego G. , Petrovsky Nikolai ,   RIKEN GER Group,   GSL Members, Schönbach Christian
Published: September 2003

To identify novel cytokine-related genes, we searched the set of 60,770 annotated RIKEN mouse cDNA clones (FANTOM2 clones), using keywords such as cytokine itself or cytokine names (such as interferon, interleukin, epidermal growth factor, fibroblast growth factor, and transforming growth factor). This search produced 108 known cytokines and cytokine-related products such as cytokine receptors, cytokine-associated genes, or their products (enhancers, accessory proteins, cytokine-induced genes). We found 15 clusters of FANTOM2 clones that are candidates for novel cytokine-related genes. These encoded products with strong sequence similarity to guanylate-binding protein (GBP-5), interleukin-1 receptor-associated kinase 2 (IRAK-2), interleukin 20 receptor α isoform 3, a member of the interferon-inducible proteins of the Ifi 200 cluster, four members of the membrane-associated family 1-8 of interferon-inducible proteins, one p27-like protein, and a hypothetical protein containing a Toll/Interleukin receptor domain. All four clones representing novel candidates of gene products from the family contain a novel highly conserved cross-species domain. Clones similar to growth factor-related products included transforming growth factor β-inducible early growth response protein 2 (TIEG-2), TGFβ-induced factor 2, integrin β-like 1, latent TGF-binding protein 4S, and FGF receptor 4B. We performed a detailed sequence analysis of the candidate novel genes to elucidate their likely functional properties.
Impact of Alternative Initiation, Splicing, and Termination on the Diversity of the mRNA Transcripts Encoded by the Mouse Transcriptome
Authors: Zavolan Mihaela , Kondo Shinji , Schönbach Christian , Adachi Jun , Hume David A. ,   RIKEN GER Group,   GSL Members, Hayashizaki Yoshihide , Gaasterland Terry
Published: September 2003

We analyzed the FANTOM2 clone set of 60,770 RIKEN full-length mouse cDNA sequences and 44,122 public mRNA sequences. We developed a new computational procedure to identify and classify the forms of splice variation evident in this data set and organized the results into a publicly accessible database that can be used for future expression array construction, structural genomics, and analyses of the mechanism and regulation of alternative splicing. Statistical analysis shows that at least 41% and possibly as much as 60% of multiexon genes in mouse have multiple splice forms. Of the transcription units with multiple splice forms, 49% contain transcripts in which the apparent use of an alternative transcription start (stop) is accompanied by alternative splicing of the initial (terminal) exon. This implies that alternative transcription may frequently induce alternative splicing. The fact that 73% of all exons with splice variation fall within the annotated coding region indicates that most splice variation is likely to affect the protein form. Finally, we compared the set of constitutive (present in all transcripts) exons with the set of cryptic (present only in some transcripts) exons and found statistically significant differences in their length distributions, the nucleotide distributions around their splice junctions, and the frequencies of occurrence of several short sequence motifs.
Inferring Higher Functional Information for RIKEN Mouse Full-Length cDNA Clones With FACTS
Authors: Nagashima Takeshi , Silva Diego G. , Petrovsky Nikolai , Socha Luis A. , Suzuki Harukazu , Saito Rintaro , Kasukawa Takeya , Kurochkin Igor V. , Konagaya Akihiko , Schönbach Christian
Published: September 2003

FACTS (Functional Association/Annotation of cDNA Clones from Text/Sequence Sources) is a semiautomated knowledge discovery and annotation system that integrates molecular function information derived from sequence analysis results (sequence inferred) with functional information extracted from text. Text-inferred information was extracted from keyword-based retrievals of MEDLINE abstracts and by matching of gene or protein names to OMIM, BIND, and DIP database entries. Using FACTS, we found that 47.5% of the 60,770 RIKEN mouse cDNA FANTOM2 clone annotations were informative for text searches. MEDLINE queries yielded molecular interaction-containing sentences for 23.1% of the clones. When disease MeSH and GO terms were matched with retrieved abstracts, 22.7% of clones were associated with potential diseases, and 32.5% with GO identifiers. A significant number (23.5%) of disease MeSH-associated clones were also found to have a hereditary disease association (OMIM Morbidmap). Inferred neoplastic and nervous system disease represented 49.6% and 36.0% of disease MeSH-associated clones, respectively. A comparison of sequence-based GO assignments with informative text-based GO assignments revealed that for 78.2% of clones, identical GO assignments were provided for that clone by either method, whereas for 21.8% of clones, the assignments differed. In contrast, for OMIM assignments, only 28.5% of clones had identical sequence-based and text-based OMIM assignments. Sequence, sentence, and term-based functional associations are included in the FACTS database (http://facts.gsc.riken.go.jp/), which permits results to be annotated and explored through web-accessible keyword and sequence search interfaces. The FACTS database will be a critical tool for investigating the functional complexity of the mouse transcriptome, cDNA-inferred interactome (molecular interactions), and pathome (pathologies).
Discovery of Imprinted Transcripts in the Mouse Transcriptome Using Large-Scale Expression Profiling
Authors: Nikaido Itoshi , Saito Chika , Mizuno Yosuke , Meguro Makiko , Bono Hidemasa , Kadomura Moritoshi , Kono Tomohiro , Morris Gerard A. , Lyons Paul A. , Oshimura Mitsuo ,   RIKEN GER Group,   GSL Members, Hayashizaki Yoshihide , Okazaki Yasushi
Published: September 2003

Candidate imprinted transcriptional units in the mouse genome were identified systematically from 27,663 FANTOM2 full-length mouse cDNA clones by expression profiling. Large-scale cDNA microarrays were used to detect differential expression dependent upon chromosomal parent of origin by comparing the mRNA levels in the total tissue of 9.5 dpc parthenogenote and androgenote mouse embryos. Of the FANTOM2 transcripts, 2114 were identified as candidates on the basis of the array data. Of these, 39 mapped to known imprinted regions of the mouse genome, 56 were considered as nonprotein-coding RNAs, and 159 were natural antisense transcripts. The imprinted expression of two transcripts located in the mouse chromosomal region syntenic to the human Prader-Willi syndrome region was confirmed experimentally. We further mapped all candidate imprinted transcripts to the mouse and human genome and were shown in correlation with the imprinting disease loci. These data provide a major resource for understanding the role of imprinting in mammalian inherited traits.
Continued Discovery of Transcriptional Units Expressed in Cells of the Mouse Mononuclear Phagocyte Lineage
Authors: Wells Christine A. , Ravasi Timothy , Sultana Razvan , Yagi Ken , Carninci Piero , Bono Hidemasa , Faulkner Geoffrey , Okazaki Yasushi , Quackenbush John , Hume David A. ,   RIKEN GER Group,   GSL Members, Lyons Paul A.
Published: September 2003

The current RIKEN transcript set represents a significant proportion of the mouse transcriptome but transcripts expressed in the innate and acquired immune systems are poorly represented. In the present study we have assessed the complexity of the transcriptome expressed in mouse macrophages before and after treatment with lipopolysaccharide, a global regulator of macrophage gene expression, using existing RIKEN 19K arrays. By comparison to array profiles of other cells and tissues, we identify a large set of macrophage-enriched genes, many of which have obvious functions in endocytosis and phagocytosis. In addition, a significant number of LPS-inducible genes were identified. The data suggest that macrophages are a complex source of mRNA for transcriptome studies. To assess complexity and identify additional macrophage expressed genes, cDNA libraries were created from purified populations of macrophage and dendritic cells, a functionally related cell type. Sequence analysis revealed a high incidence of novel mRNAs within these cDNA libraries. These studies provide insights into the depths of transcriptional complexity still untapped amongst products of inducible genes, and identify macrophage and dendritic cell populations as a starting point for sampling the inducible mammalian transcriptome.
CDS Annotation in Full-Length cDNA Sequence
Authors: Furuno Masaaki , Kasukawa Takeya , Saito Rintaro , Adachi Jun , Suzuki Harukazu , Baldarelli Richard , Hayashizaki Yoshihide , Okazaki Yasushi
Published: September 2003

The identification of coding sequences (CDS) is an important step in the functional annotation of genes. CDS prediction for mammalian genes from genomic sequence is complicated by the vast abundance of intergenic sequence in the genome, and provides little information about how different parts of potential CDS regions are expressed. In contrast, mammalian gene CDS prediction from cDNA sequence offers obvious advantages, yet encounters a different set of complexities when performed on high-throughput cDNA (HTC) sequences, such as the set of 60,770 cDNAs isolated from full-length enriched libraries of the FANTOM2 project. We developed a CDS annotation strategy that uses a variety of different CDS prediction programs to annotate the CDS regions of FANTOM2 cDNAs. These include rsCDS, which uses sequence similarity to known proteins; ProCrest; Longest-ORF and Truncated-ORF, which are ab initio based predictors; and finally, DECODER and NCBI CDS predictor, which use a combination of both principles. Aided by graphical displays of these CDS prediction results in the context of other sequence similarity results for each cDNA, FANTOM2 CDS inspection by curators and follow-up quality control procedures resulted in high quality CDS predictions for a total of 14,345 FANTOM2 clones.
Systematic Expression Profiling of the Mouse Transcriptome Using RIKEN cDNA Microarrays
Authors: Bono Hidemasa , Yagi Ken , Kasukawa Takeya , Nikaido Itoshi , Tominaga Naoko , Miki Rika , Mizuno Yosuke , Tomaru Yasuhiro , Goto Hitoshi , Nitanda Hiroyuki , Shimizu Daisuke , Makino Hirochika , Morita Tomoyuki , Fujiyama Junshin , Sakai Takehito , Shimoji Takashi , Hume David A. ,   RIKEN GER Group,   GSL Members, Hayashizaki Yoshihide , Okazaki Yasushi
Published: September 2003

The number of known mRNA transcripts in the mouse has been greatly expanded by the RIKEN Mouse Gene Encyclopedia project. Validation of their reproducible expression in a tissue is an important contribution to the study of functional genomics. In this report, we determine the expression profile of 57,931 clones on 20 mouse tissues using cDNA microarrays. Of these 57,931 clones, 22,928 clones correspond to the FANTOM2 clone set. The set represents 20,234 transcriptional units (TUs) out of 33,409 TUs in the FANTOM2 set. We identified 7206 separate clones that satisfied stringent criteria for tissue-specific expression. Gene Ontology terms were assigned for these 7206 clones, and the proportion of `molecular function' ontology for each tissue-specific clone was examined. These data will provide insights into the function of each tissue. Tissue-specific gene expression profiles obtained using our cDNA microarrays were also compared with the data extracted from the GNF Expression Atlas based on Affymetrix microarrays. One major outcome of the RIKEN transcriptome analysis is the identification of numerous nonprotein-coding mRNAs. The expression profile was also used to obtain evidence of expression for putative noncoding RNAs. In addition, 1926 clones (70%) of 2768 clones that were categorized as “unknown EST,” and 1969 (58%) clones of 3388 clones that were categorized as “unclassifiable” were also shown to be reproducibly expressed.
G Protein-Coupled Receptor Genes in the FANTOM2 Database
Authors: Kawasawa Yuka , McKenzie Louise M. , Hill David P. , Bono Hidemasa ,   RIKEN GER Group,   GSL Members, Yanagisawa Masashi
Published: September 2003

G protein-coupled receptors (GPCRs) comprise the largest family of receptor proteins in mammals and play important roles in many physiological and pathological processes. Gene expression of GPCRs is temporally and spatially regulated, and many splicing variants are also described. In many instances, different expression profiles of GPCR gene are accountable for the changes of its biological function. Therefore, it is intriguing to assess the complexity of the transcriptome of GPCRs in various mammalian organs. In this study, we took advantage of the FANTOM2 (Functional Annotation Meeting of Mouse cDNA 2) project, which aimed to collect full-length cDNAs inclusively from mouse tissues, and found 410 candidate GPCR cDNAs. Clustering of these clones into transcriptional units (TUs) reduced this number to 213. Out of these, 165 genes were represented within the known 308 GPCRs in the Mouse Genome Informatics (MGI) resource. The remaining 48 genes were new to mouse, and 14 of them had no clear mammalian ortholog. To dissect the detailed characteristics of each transcript, tissue distribution pattern and alternative splicing were also ascertained. We found many splicing variants of GPCRs that may have a relevance to disease occurrence. In addition, the difficulty in cloning tissue-specific and infrequently transcribed GPCRs is discussed further.
DNA Book
Authors: Kawai Jun , Hayashizaki Yoshihide
Published: September 2003

We propose herein a new method of DNA distribution, whereby DNA clones or PCR products are printed directly onto the pages of books and delivered to users along with relevant scientific information. DNA sheets, comprising water-soluble paper onto which DNA is spotted, can be bound into books. Readers can easily extract the DNA fragments from DNA sheets and amplify them using PCR. We show that DNA sheets can withstand various conditions that may be experienced during bookbinding and delivery, such as high temperatures and humidity. Almost all genes (95%–100% of randomly selected RIKEN mouse cDNA clones) were recovered successfully by use of PCR. Readers can start their experiments after a 2-h PCR amplification without waiting for the delivery of DNA clones. The DNA Book thus provides a novel method for delivering DNA in a timely and cost-effective manner. A sample DNA sheet (carrying RIKEN mouse cDNA clones encoding genes of enzymes for the TCA cycle) is included in this issue for field-testing. We would greatly appreciate it if readers could attempt to extract DNA and report the results and whether the DNA sheet was shipped to readers in good condition.
Systematic Characterization of the Zinc-Finger-Containing Proteins in the Mouse Transcriptome
Authors: Ravasi Timothy , Huber Thomas , Zavolan Mihaela , Forrest Alistair , Gaasterland Terry , Grimmond Sean ,   RIKEN GER Group,   GSL Members, Hume David A.
Published: September 2003

Zinc-finger-containing proteins can be classified into evolutionary and functionally divergent protein families that share one or more domains in which a zinc ion is tetrahedrally coordinated by cysteines and histidines. The zinc finger domain defines one of the largest protein superfamilies in mammalian genomes;46 different conserved zinc finger domains are listed in InterPro (http://www.ebi.ac.uk/InterPro). Zinc finger proteins can bind to DNA, RNA, other proteins, or lipids as a modular domain in combination with other conserved structures. Owing to this combinatorial diversity, different members of zinc finger superfamilies contribute to many distinct cellular processes, including transcriptional regulation, mRNA stability and processing, and protein turnover. Accordingly, mutations of zinc finger genes lead to aberrations in a broad spectrum of biological processes such as development, differentiation, apoptosis, and immunological responses. This study provides the first comprehensive classification of zinc finger proteins in a mammalian transcriptome. Specific detailed analysis of the SP/Krüppel-like factors and the E3 ubiquitin-ligase RING-H2 families illustrates the importance of such an analysis for a more comprehensive functional classification of large protein families. We describe the characterization of a new family of C2H2 zinc-finger-containing proteins and a new conserved domain characteristic of this family, the identification and characterization of Sp8, a new member of the Sp family of transcriptional regulators, and the identification of five new RING-H2 proteins.
GeneLynx Mouse: Integrated Portal to the Mouse Genome
Authors: Lenhard Boris , Wahlestedt Claes , Wasserman Wyeth W.
Published: September 2003

GeneLynx Mouse is a meta-database providing an extensive collection of hyperlinks to mouse gene-specific information in diverse databases available via the Internet. The GeneLynx project is based on the simple notion that given any gene-specific identifier (e.g., accession number, gene name, text, or sequence), scientists should be able to access a single location that provides a set of links to all the publicly available information pertinent to the specified gene. The recent climax in the mouse genome and RIKEN cDNA sequencing projects provided the data necessary for the development of a gene-centric mouse information portal based on the GeneLynx ideals. Clusters of RIKEN cDNA sequences were used to define the initial set of mouse genes. Like its human counterpart, GeneLynx Mouse is designed as an extensible relational database with an intuitive and user-friendly Web interface. Data is automatically extracted from diverse resources, using appropriate approaches to maximize the coverage. To promote cross-database interoperability, an indexing utility is provided to facilitate the establishment of hyperlinks in external databases. As a result of the integration of the human and mouse systems, GeneLynx now serves as a powerful comparative genomics data mining resource. GeneLynx Mouse can be freely accessed at http://mouse.genelynx.org.