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Genomes: Harvard's new Bauer Center for Genomics Research has an ambitious plan to bolster novel research and collaboration to exploit genome data for studies on how biological systems work. Karen Hopkin reports.
Axonal injury following cerebral ischaemia has attracted less attention than damage in grey matter. However, it is becoming increasingly recognised that axons are highly vulnerable to focal ischaemia [D. Dewar, D.A. Dawson, Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat, Acta. Neuropathol., 93 (1997) 71-77] [2]; [L. Pantoni, J.H. Garcia, J.A. Gutierrez, Cerebral white matter is highly vulnerable to ischemia, Stroke, 27 (1996) 1641-1647] [10]; [P. S. Yam, T. Takasago, D. Dewar, D.I. Graham, J. McCulloch, Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion, Brain Res., 760 (1997) 150-157] [15]. Since white matter does not contain neuronal cell bodies or synapses it is likely that the mechanisms of injury and strategies for its protection are different from those in grey matter. In order that the effect of therapeutic intervention on the protection of axons can be assessed, a method by which axonal injury can be mapped and quantified is required. For this purpose, we investigated immunocytochemical methods using amyloid precursor protein (APP) following permanent middle cerebral artery occlusion in the rat. APP is transported by fast anterograde axonal transport [E.H. Koo, S.S. Sisodia, D.R. Archer, L.J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C.L. Masters, D.L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 1561-1565] [7] and has been shown to accumulate following a variety of insults to axons, indicative of dysfunction of axonal transport [R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington, E.R. Shelton, H.W. Chan, G. Perry, W.D. Lust, Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain, Neuroreport, 4 (1993) 211-214] [4]; [T. Kawarabayashi, M. Shoji, Y. Harigaya, H. Yamaguchi, S. Hirai, Expression of APP in the early stage of brain damage, Brain Res., 563 (1991) 334-338] [5]; [N. Otsuka, M. Tomonaga, K. Ikeda, Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury, Brain Res., 568 (1991) 335-338] [9]; [K. Shigematsu, P. L. McGeer, Accumulation of amyloid precursor protein in neurons after intraventricular injection of colchicine, Am. J. Pathol., 140 (1992) 787-794] [12]. We have been able to map the topographical relationship between APP accumulation and region of infarction using immunocytochemistry and image analysis techniques. Additionally, using a semi-quantitative scoring system, we have demonstrated that there is a relationship between the amount of APP accumulation and the volume of infarction following middle cerebral artery occlusion. These methods will be useful in the future for the assessment of therapeutic interventions on the protection of axons following ischaemic injury.
MOTIVATION: Natural language processing (NLP) techniques are used to extract information automatically from computer-readable literature. In biology, the identification of terms corresponding to biological substances (e.g., genes and proteins) is a necessary step that precedes the application of other NLP systems that extract biological information (e.g., protein-protein interactions, gene regulation events, and biochemical pathways). We have developed GPmarkup (for "gene/protein-full name mark up"), a software system that automatically identifies gene/protein terms (i.e., symbols or full names) in MEDLINE abstracts. As a part of marking up process, we also generated automatically a knowledge source of paired gene/protein symbols and full names (e.g., LARD for lymphocyte associated receptor of death) from MEDLINE. We found that many of the pairs in our knowledge source do not appear in the current GenBank database. Therefore our methods may also be used for automatic lexicon generation. RESULTS: GPmarkup has 73% recall and 93% precision in identifying and marking up gene/protein terms in MEDLINE abstracts. AVAILABILITY: A random sample of gene/protein symbols and full names and a sample set of marked up abstracts can be viewed at http://www.cpmc.columbia.edu/homepages/yuh9001/GPmarkup/. Contact. hy52@columbia.edu. Voice: 212-939-7028; fax: 212-666-0140.
Right atrial reentry which does not critically depend upon activation through the cavotricuspid isthmus is considered to be a subtype of atypical flutter. Diagnosis is dependent upon demonstrating the nonparticipation of the cavotricuspid isthmus. Right atrial free wall atriotomy incisions, the superior vena cava, the inferior vena cava, electrically silent or mute areas, incomplete variants of the posterior intercaval crista terminalis line of block and other functional/anisotropic lines of block form the central barriers around which macroreentry occurs. The length, location and orientation of fixed lines of block such as atriotomy incisions are important determinants of their arrhythmogenicity. Successful catheter ablation depends upon delineating the circuit in order to choose the optimal isthmus for ablation and producing complete block across it.
Cardiac mapping of atrial activation was originally performed in animals during open chest preparations, using epicardial electrodes. The development of endocardial egg-shaped multiple electrodes provided detailed assessment of the minimum number of wavelengths required to sustain atrial fibrillation (AF), as well as the role of interatrial connections during AF. Subsequently, several studies on bi-atrial epicardial high-density mapping in animals and humans also reported on the importance of interatrial connections, as well as the specific characteristics of the left atrium as compared with the right atrium during chronic AF. Endocardial bi-atrial mapping studies using electrode catheters were reported using basket-shaped catheters carrying 64 electrodes. Animal studies suggested that septal activation was asynchronous and discordant, while a human study outlined the multiple origins of atrial ectopic beats following DC cardioversion in patients with chronic atrial fibrillation. The advent of non-fluoroscopic mapping systems significantly changed our approach to percutaneous endocardial mapping. Simultaneous bi-atrial studies using electroanatomic mapping were performed in sinus rhythm as well as in atrial flutter. These studies demonstrated the predominance of interatrial conduction over Bachmann's Bundle and the coronary sinus-left atrial connection during respectively, sinus rhythm and atrial flutter. Simultaneous bi-atrial non-contact mapping was initially performed during porcine studies and later in humans, demonstrating asynchronous and discordant septal activation both during sinus rhythm or left lateral atrial pacing. Preliminary studies from simultaneous bi-atrial non-contact mapping in humans in whom AF occurred spontaneously or was induced suggests three main types of atrial activation, consisting of left atrial drivers causing the right atrium to fibrillate following conduction over interatrial connections, the right atrium independently sustaining AF, even after pulmonary vein disconnection, and both atria fibrillating independently without activation over interatrial connections. Bi-atrial mapping has been essential for our understanding of normal and abnormal atrial activation, and ultimately may provide new approaches for ablation of atrial fibrillation.
In the past decades management of atrial fibrillation (AF) has been based mainly on drug therapy. New insights into the pathophysiology of AF initiation and maintenance have provided the background for the design of catheter based procedures. The crucial role of the pulmonary veins (PVs) as triggers of AF paved the way for successful mapping and ablation. Electrical isolation of all PVs using the circular mapping approach has been shown to be an effective procedure, with reported success rates around 70 to 80% in most series. Intracardiac echocardiography is a very helpful adjunctive tool to facilitate correct positioning of the circular catheter at the PV-left atrial junction, as well as to monitor energy delivery and assist transseptal left atrial access. PV stenosis is a potential serious complication, occurring in around 2% of cases. It presents mainly with respiratory symptoms, although it is frequently asymptomatic. Spiral computed tomography is a reliable non-invasive method for imaging the PVs and can be used to screen patients for PV stenosis after radiofrequency ablation. In symptomatic patients, PV dilatation and stenting is the preferred treatment approach. The possibility of curing AF represents a major breakthrough in invasive cardiac electrophysiology. Isolation of all PVs is a very solid endpoint for successful ablation and should be pursued in all patients. It seems to be associated with high success rates over long term follow-up. Future refinements in catheter technology should provide simpler and faster procedures and render catheter ablation of AF more widespread and accepted.
Atrial fibrillation (AF) remains an unsurmounted hurdle toward the cure of supraventricular arrhythmias. Despite its high prevalence, a definitive treatment approach has not been established. AF is triggered in most cases by early premature atrial beats and is maintained by anomalies of the substrate. Elimination or modification of either one or both may be effective in the cure of AF. Surgical ablation, which originated with the favorable results of the Maze procedure developed by Cox, has an important role in the cure of AF associated with heart diseases that require cardiac surgery. This is due to the high success rate and to the simplification of the procedure now used which has resulted in reduction of the procedural time and complications. Various techniques have been proposed, however, it is noteworthy that the posterior part of the left atrium and the ostia of pulmonary veins are involved in all approaches despite the different energy sources used (radiofrequency or cryo energy) and the different design of the intended lesion. These results imply that the posterior part of the left atrium is crucial in the genesis and maintenance of atrial fibrillation. On the other hand, it is not clear if the results of the ablation are due to the linear lesions that modify the substrate or to the electrical isolation that eliminate the triggers. A thorough electrophysiological evaluation post ablation has been performed only in few cases. Greater understanding of the mechanism of success of surgical ablation may advance the development and success of other approaches. Considering that surgical ablation is usually performed in patients with permanent AF, linear lesions modifying the substrate together with pulmonary vein isolation have shown better results than the elimination of the triggers with a pure electrical isolation of the pulmonary veins. Prevention of AF recurrences has been relatively good, however some severe complications (atrioesophagus fistula, coronary artery damage, etc.) have been reported. Considering the relatively benignity of AF in absence of associated cardiopathy, the risk of complications should discourage widespread application of surgical ablation in patients with lone AF. On the contrary it should be routinely proposed in most patients with permanent or paroxysmal AF undergoing cardiac surgery.
To help us understand how bioregulatory networks operate, we need a standard notation for diagrams analogous to electronic circuit diagrams. Such diagrams must surmount the difficulties posed by complex patterns of protein modifications and multiprotein complexes. To meet that challenge, we have designed the molecular interaction map (MIM) notation (http://discover.nci.nih.gov/mim/). Here we show the advantages of the MIM notation for three important types of diagrams: (1) explicit diagrams that define specific pathway models for computer simulation; (2) heuristic maps that organize the available information about molecular interactions and encompass the possible processes or pathways; and (3) diagrams of combinatorially complex models. We focus on signaling from the epidermal growth factor receptor family (EGFR, ErbB), a network that reflects the major challenges of representing in a compact manner the combinatorial complexity of multimolecular complexes. By comparing MIMs with other diagrams of this network that have recently been published, we show the utility of the MIM notation. These comparisons may help cell and systems biologists adopt a graphical language that is unambiguous and generally understood.
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Quantitative genetic research has produced a wealth of basic information concerning genetic influence on alcohol-related processes. Recent developments in quantitative trait locus (QTL) methodology were promptly applied to the task of individuating polygenes affecting alcohol-related attributes in animal models and a body of reliable data is gradually coming into focus as a result of replication and convergence of evidence from a variety of methods. A key issue in QTL research is the need to distinguish true positive results from the false positive results that are inherent in analytical procedures requiring large numbers of significance tests. One school of thought holds that stringent significance levels should be imposed; another suggests more modest criteria for QTL nomination, with subsequent confirmation trials with independent samples. Recombinant inbred strains and various types of intercrosses have been used in correlational designs, both for nomination and confirmation studies. Alternative experimental procedures include knockout preparations and short-term phenotypic selective breeding. We present here results from a third experimental method-that of marker-based genotypic selection--in evaluation of two nominated QTLs for alcohol acceptance in mice.
Selective genotyping is a cost-saving strategy in mapping quantitative trait loci (QTLs). When the proportion of individuals selected for genotyping is low, the majority of the individuals are not genotyped, but their phenotypic values, if available, are still included in the data analysis to correct the bias in parameter estimation. These ungenotyped individuals do not contribute much information about linkage analysis and their inclusion can substantially increase the computational burden. For multiple trait analysis, ungenotyped individuals may not have a full array of phenotypic measurements. In this case, unbiased estimation of QTL effects using current methods seems to be impossible. In this study, we develop a maximum likelihood method of QTL mapping under selective genotyping using only the phenotypic values of genotyped individuals. Compared with the full data analysis (using all phenotypic values), the proposed method performs well. We derive an expectation-maximization (EM) algorithm that appears to be a simple modification of the existing EM algorithm for standard interval mapping. The new method can be readily incorporated into a standard QTL mapping software, e.g. MAPMAKER. A general recommendation is that whenever full data analysis is possible, the full maximum likelihood analysis should be performed. If it is impossible to analyse the full data, e.g. sample sizes are too large, phenotypic values of ungenotyped individuals are missing or composite interval mapping is to be performed, the proposed method can be applied.
Mapping, and ultimately preventing, the dissemination of infectious agents is an important topic in public health. Newly developed molecular-microbiological methods have contributed significantly to recent advances in the efficient tracking of the nosocomial and environmental spread of microbial pathogens. Not only has the application of novel technologies led to improved understanding of microbial epidemiology, but the concepts of population structure and dynamics of many of the medically significant microorganisms have advanced significantly also. Currently, genetic identification of microbes is also within the reach of clinical microbiology laboratory professionals including those without specialized technology research interests. This review summarizes the possibilities for high-throughput molecular-microbiological typing in adequately equipped medical microbiology laboratories from both clinical and fundamental research perspectives. First, the development and application of methods for large-scale comparative typing of serially isolated microbial strains are discussed. The outcome of studies employing these methods allows for long-term epidemiologic surveillance of infectious diseases. Second, recent methods enable an almost nucleotide-by-nucleotide genetic comparison of smaller numbers of strains, thereby facilitating the identification of the genetic basis of, for instance, medically relevant microbiological traits. Whereas the first approach provides insights into the dynamic spread of infectious agents, the second provides insights into intragenomic dynamics and genetic functionality. The current state of technology is summarized, and future perspectives are sketched.
gamma-Irradiation of a laboratory strain of the Hawaiian species Drosophila heteroneura yielded 310 breaks in the five major acrocentric polytene chromosomes. Their map positions conform to the Poisson distribution, unlike most of the 436 natural breaks mapped in 105 closely related species endemic to Hawaii. Genome element E is longer and has more induced breaks than the others. Both in Hawaiian and related species groups, this element shows increased polymorphism and fixation of naturally occurring inversions. The X chromosome (element A) also accumulates many natural breaks; the majority of the resulting aberrations become fixed rather than remain as polymorphisms. Although size may play a small role in initial break distribution, the major effects relative to the establishment of a rearrangement in natural populations are ascribed to the interaction of selection and drift. Nonconformance of the natural breaks to the Poisson distribution appears to be due to the tendency for breaks to accumulate both in the proximal euchromatic portion of each arm and in heterochromatic regions that are not replicated in the polytene chromosomes.
MOTIVATION: The annotation of the Arabidopsis thaliana genome remains a problem in terms of time and quality. To improve the annotation process, we want to choose the most appropriate tools to use inside a computer-assisted annotation platform. We therefore need evaluation of prediction programs with Arabidopsis sequences containing multiple genes. RESULTS: We have developed AraSet, a data set of contigs of validated genes, enabling the evaluation of multi-gene models for the Arabidopsis genome. Besides conventional metrics to evaluate gene prediction at the site and the exon levels, new measures were introduced for the prediction at the protein sequence level as well as for the evaluation of gene models. This evaluation method is of general interest and could apply to any new gene prediction software and to any eukaryotic genome. The GeneMark.hmm program appears to be the most accurate software at all three levels for the Arabidopsis genomic sequences. Gene modeling could be further improved by combination of prediction software. AVAILABILITY: The AraSet sequence set, the Perl programs and complementary results and notes are available at http://sphinx.rug.ac.be:8080/biocomp/napav/. CONTACT: Pierre.Rouze@gengenp.rug.ac.be.
MOTIVATION: Function annotation of an unclassified protein on the basis of its interaction partners is well documented in the literature. Reliable predictions of interactions from other data sources such as gene expression measurements would provide a useful route to function annotation. We investigate the global relationship of protein-protein interactions with gene expression. This relationship is studied in four evolutionarily diverse species, for which substantial information regarding their interactions and expression is available: human, mouse, yeast and Escherichia coli. RESULTS: In E.coli the expression of interacting pairs is highly correlated in comparison to random pairs, while in the other three species, the correlation of expression of interacting pairs is only slightly stronger than that of random pairs. To strengthen the correlation, we developed a protocol to integrate ortholog information into the interaction and expression datasets. In all four genomes, the likelihood of predicting protein interactions from highly correlated expression data is increased using our protocol. In yeast, for example, the likelihood of predicting a true interaction, when the correlation is > 0.9, increases from 1.4 to 9.4. The improvement demonstrates that protein interactions are reflected in gene expression and the correlation between the two is strengthened by evolution information. The results establish that co-expression of interacting protein pairs is more conserved than that of random ones.
An expanded linkage map of the Vibrio cholerae classical strain 162 chromosome has been prepared using a variety of new auxotrophic mutants. The chromosome consists of a single, linear linkage group. The map consists of 17 markers, which have been ordered; 20 mutational sites, which are tentatively ordered; five markers (ura-1, ser-2, mal-1, man-1, suc-1), which are linked but unordered; and three mutations (aro-2, cys-2 and cys-6) which showed little or no linkage. A proposal is made to standardize genetic nomenclature in V. cholerae genetic studies.