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[Use of body surface heart potential mapping for registration of electrical phenomenal in the atrium].

Research on body surface potential mapping concerned predominantly the ventricular excitation process. There is only very limited data available documenting surface potential distribution during atrial electric events. The goal of this study was to establish the pattern and criteria of the atrial potential maps in the healthy population, which is substantial for a prospective usefulness of the noninvasive registrations of surface maps in atrial arrhythmias. A group of 54 subjects in whom there was no clinical evidence of cardiac dysfunction underwent a procedure of body surface potential mapping. The recordings were performed using the HPM-7100 system simultaneously from 87 leads covering the entire thorax. Isopotential maps registered during the P wave were subjected to the statistical analysis by means of the own system "Heart Map" enabling the qualitative and quantitative estimation of the atrial maps. To avoid a problem of variable heart rate, a time standardization, by the division of the P wave into 10 time intervals, was applied. In order to eliminate an interindividual variability of heart location in the thorax, a distribution of the constituent values without subordinating them to the individual electrodes was proposed. In consequence, the group-mean isopotential maps of the wave P for the normal subjects were created. According to the migration of the maximum throughout the thoracic surface during the P wave, three phases of the isopotential atrial maps were determined: phase 1 (P1-P4) comprising initial 40% of the P wave, phase 2 (P5,P6)-next 20% of the P wave and phase 3 (P7-P10)-the terminal 40% of the P wave duration. These phases reflect the successive sequences of atrial excitation. During the whole atrial depolarization the minimum of potential, changing its value, was located around lead D7. Furthermore, in the results of the analysis of the constituent values sequences, for the P wave time intervals the additional quantitive parameters were calculated, i.e. areas designated by positive and negative potential and the ratio of these areas. The presented findings revealed that surface maps give the precious insight into spread of atrial excitation. Establishing of the distribution pattern and the criteria of the atrial potential maps for normals enables to undertake the further research on the use of this technique in a various atrial pathology.

Adult↗

Distortions and fluctuations in topographic memory.

Two experiments dealing with the learning of a space by map or by navigation approached the questions of equivalency of the cognitive processes involved in spatial information and of response fluctuation. In the first experiment, 11 subjects were asked to situate, six times, 18 locations on a blank map. In the second experiment, the subjects were first given 3 min to learn a map with 12 locations marked, and then asked to reproduce it. The task was repeated six times, using three different maps. This gave us several trials per subject, so that distortion could be distinguished from response fluctuation. In Experiment 1, the range of values was the same for response inaccuracy and response fluctuation; in Experiment 2, the range was greater for response inaccuracy than for response fluctuation. The results showed that space learning by navigation and space learning by map involve different cognitive processes.

Adult↗

Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway.

Advanced glycation end products (AGEs) have been shown to play a role in tubular epithelial-myofibroblast transdifferentiation (TEMT) in diabetic nephropathy, but the intracellular signaling pathway remains unknown. We report here that AGEs signal through the receptor for AGEs (RAGE) to induce TEMT, as determined by de novo expression of a mesenchymal marker (alpha-smooth muscle actin, alpha-SMA) and loss of epithelial marker (E-cadherin), directly through the MEK1-ERK1/2 MAP kinase pathway, which is TGF-beta independent. This is supported by the following findings: AGEs induced de novo alpha-SMA mRNA expression as early as 2 hours followed by a loss of E-cadherin before TGF-beta mRNA expression at 24 hours and occurred in the absence of TGF-beta and AGE-induced activation of ERK1/2 MAP kinase at 15 minutes and TEMT at 24 hours were completely blocked by a neutralizing RAGE antibody, a soluble RAGE receptor, an ERK1/2 MAP kinase inhibitor (PD98059), and DN-MEK1, but not by a neutralizing TGF-beta antibody. Thus, this study demonstrates that AGEs activate the RAGE-ERK1/2 MAP kinase pathway to mediate the early TEMT process. The findings from this study suggest that targeting the RAGE or the ERK MAP kinase pathway may provide new therapeutic strategies for diabetic nephropathy and shed new light on the pathogenesis of diabetic nephropathy.

Actins↗

Homozygous deletions and point mutations of the Ikaros gene in gamma-ray-induced mouse thymic lymphomas.

Our previous genome-wide analysis of allelic loss for thymic lymphomas that were induced by gamma-irradiation in F1 hybrid mice between BALB/c and MSM strains suggested the centromeric region on chromosome 11 as a site harboring a tumor suppressor gene. Interestingly, to this region the mouse Ikaros gene was mapped which was postulated to participate in oncogenic process from the study of Ikaros knockout mice. Here we show fine allelic loss mapping in the vicinity of Ikaros in 191 lymphomas, indicating that the critical region of allelic loss was centered at the Ikaros locus. PCR analysis revealed that nine lymphomas failed to give PCR-amplification for either of two exon primer pairs, indicative of homozygous deletion. Six and five mutations were detected in the N-terminal zinc finger domain and the activation domain of Ikaros, respectively, and six of the eleven were frameshift or nonsense mutations that resulted in truncation of Ikaros protein. The results strongly suggest a direct role for Ikaros in development of mouse thymic lymphomas. This provides the experimental basis for further analysis of Ikaros mutations in human cancer.

Animals↗

A member of the caudal family of homeobox genes maps to the X-inactivation centre region of the mouse and human X chromosomes.

X-inactivation is the process which allows equalization of the dosage of X chromosomal genes between males and females. A specific region of the X chromosome, called the X-inactivation centre (XIC), is thought to have a key role in regulating this process. A gene, XIST, has been identified which maps to the XIC and so far has the unique property of being expressed exclusively from the inactive X chromosome. Although XIST is a good candidate for a gene involved in regulating X-inactivation there is as yet no formal proof it has such a role. Here we describe another gene, Cdx4, a member of the caudal-related family of homeobox genes, which is located within the minimal region assigned to XIC in humans. Furthermore, this gene is the closest known gene to XIST in both mouse and human. Unlike Xist, Cdx4 appears to be normally X-inactivated in mice. Although it is not clear whether the location of this gene within the XIC region is of any significance in X-inactivation, the isolation of the gene will allow further definition of the region of inactive X-specific expression surrounding XIST.

Animals↗

Proteome and proteomics for the research on protein alterations in aging.

Functional decline of tissues in aged animals is a result of cellular aging. Though any process of somatic cell aging basically depends on genomic instructions, phenotypes of aged cells are expressed in a given internal environment of each cell type that was made with translated proteins and post-translationally modified products. Therefore, research on age-dependent protein alterations in each cell type is very important in clarifying mechanisms of aging. The novel term "proteome" is a compound of "protein" and "genome," which means constitutive whole proteins including post-translationally modified products in a cell type. Proteomics is a novel strategy for analyzing proteomes. In proteomics, high resolution two-dimensional electrophoresis is exclusively performed for isolation of proteins followed by mass spectrometry for identification of proteins and determination of modifications. Thus, proteomics is becoming appreciated as a powerful tool to find out proteins responsible for cellular aging, symptoms of senility and geriatric diseases.

Aging↗

Transcriptional and posttranscriptional regulation contributes to the sex-regulated expression of two sequence-related genes at the janus locus of Drosophila melanogaster.

We investigated the structure and developmental pattern of expression of two genes clustered at the janus locus, located at 99D.3R. Data obtained from genomic and cDNA sequencing and from a combination of S1 mapping and primer extension experiments indicated a very unusual organization of this locus, which appeared to be composed of two partially overlapping genes, designated janA and janB. These two genes were found to be transcribed in the same direction. janA encoded one minor and two major transcripts. The 5' end of the janB mRNA mapped within the 3' untranslated region of the janA transcribed sequence. The overlapping region was 118 bases long. Similarities observed between these two genes with respect to both peptidic sequence and intron position strongly suggested that this locus originated from the duplication of an ancestral transcription unit. However, each of the resulting genes has acquired its own specificity of expression linked to sex determination. The janB transcript was detected only in males, and its expression at the adult stage was restricted to germ line cells. The janA gene displayed a much more complex expression; one of the major mRNAs was found in both sexes and at all stages, whereas the two other janA transcripts were expressed only in males.

Amino Acid Sequence↗

Functional mapping for genetic control of programmed cell death.

"Naturally occurring" or "programmed" cell death (PCD) in which the cell uses specialized cellular machinery to kill itself is a ubiquitous phenomenon that occurs early in organ development. Such a cell suicide mechanism that enables metazoans to control cell number and eliminate cells threatening the organism's survival has been thought to be under genetic control. In this report, we develop a novel statistical model for mapping specific genes or quantitative trait loci (QTL) that are responsible for the PCD process based on polymorphic molecular markers. This model incorporates the biological mechanisms of PCD that undergoes two different developmental stages, exponential growth and polynomial death. We derived a parametric approach to model the exponential growth and a nonparametric approach based on the Legendre function to model the polynomial death. A series of stationary and nonstationary models has been used to approximate the structure of the covariance matrix among cell numbers at a multitude of different times. The statistical behavior of our model is investigated through simulation studies and validated by a real example in rice.

Apoptosis↗

Knowledge mapping as a technique to support knowledge translation.

This paper explores the possibility of integrating knowledge mapping into a conceptual framework that could serve as a tool for understanding the many complex processes, resources and people involved in a health system, and for identifying potential gaps within knowledge translation processes in order to address them. After defining knowledge mapping, this paper presents various examples of the application of this process in health, before looking at the steps that need to be taken to identify potential gaps, to determine to what extent these gaps affect the knowledge translation process and to establish their cause. This is followed by proposals for interventions aimed at strengthening the overall process. Finally, potential limitations on the application of this framework at the country level are addressed.

Biomedical Research↗

Combining electron microscopic with x-ray crystallographic structures.

Analgorithm has been developed for placing three-dimensional atomic structures into appropriately scaled cryoelectron microscopy maps. The first stage in this process is to conduct a three-dimensional angular search in which the center of gravity of an X-ray crystallographically determined structure is placed on a selected position in the cryoelectron microscopy map. The quality of the fit is measured by the sum of the density at each atomic position. The second stage is to refine the three angles and three translational parameters for the best (usually 25 to 100) fits. Useful criteria for this refinement include the sum of densities at atomic sites, the lack of atoms in negative or low density, the absence of atomic clashes between symmetry-related positions of the atomic structure, and the distances between identifiable features in the map and their positions on the fitted atomic structure. These refinements generally lead to a convergence of the originally chosen, top scoring fits to just a few (about 3 to 8) acceptable possibilities. Usually, the best remaining fit is clearly superior to any of the others.

Cryoelectron Microscopy↗

Care maps across the continuum.

As hospital length of stay decreases and care shifts to the community, there is a need to develop approaches to ensure uniformity and continuity of care in patient groups. Care maps, multidisciplinary standards that outline the processes of care and expected outcomes within predetermined timeframes, can support a continuum of care from preadmission through hospital stay to discharge from community-based home care by clearly delineating standards across the entire episode of care. However, the development of successful care maps requires extensive collaboration, planning and evaluation.

Continuity of Patient Care↗

Genetic mapping and some characterization of the rnpA49 mutation of Escherichia coli that affects the RNA-processing enzyme ribonuclease P.

A mutant defective in the enzyme RNase P was isolated by P. SCHEDL and P. PRIMAKOFF (1973). The mutation rnpA49 found in this strain, which confers temperature sensitivity on carrier strains, was mapped by conjugation and transduction experiments and located around minute 82 of the E. coli map, with the suggested order rnpA bglB phoS rbsP ilv. As expected, the rnpA49 mutation is recessive. Even though this mutation is conditional, it is manifested at temperatures at which the carrier strains can grow.

Chromosome Mapping↗

Cholinergic depletion prevents expansion of topographic maps in somatosensory cortex.

Although the role of acetylcholine in processing stimuli in the cerebral cortex is becoming defined, the impact of cholinergic activity on the character of cortical maps remains unclear. In the somatosensory cortex, topographic maps appear capable of lifelong modifications in response to alterations in the periphery. One factor proposed to influence this adaptational ability is the presence of acetylcholine in the cortex. The studies presented here, using the 2-deoxyglucose technique, demonstrate that the unilateral removal of a digit in cats, followed by stimulation of an adjacent digit, produces a pattern of metabolic activity in the somatosensory cortex that is dramatically expanded when compared with the opposite (normal) hemisphere. In contrast, experiments in which the somatosensory cortex was depleted of acetylcholine and the animal received a similar amputation led not to patterns of expanded metabolic activity, but rather to reductions in the evoked metabolic distribution. These studies implicate acetylcholine in normal map formation and in the maintenance of the capacity of cortical maps to adapt to changes in the periphery.

Acetylcholine↗

Release of amino-terminal fragments from amyloid precursor protein reporter and mutated derivatives in cultured cells.

Abnormal proteolytic processing of amyloid precursor protein (APP) is thought to be central to the formation and deposition of beta amyloid peptide in Alzheimer's disease. A putative "secretase" activity normally releases an amino-terminal APP fragment by cleaving APP at residues within the beta amyloid peptide thereby precluding amyloidogenesis. In order to better understand the requirements for APP cleavage by secretase, we have expressed a modified cDNA construct representing the 751-amino acid isoform of APP (APP-REP) and mutated APP-REP proteins in cultured cells. Here, we show that: (a) APP-REP is predominantly associated with membranes; (b) intracellular turnover and processing of APP-REP is similar to that reported for the intact APP protein; (c) secretion appears unaltered by introduction of the glutamate to glutamine mutation found in the APP gene of patients suffering from hereditary cerebral hemorrhage with amyloidosis of Dutch origin; (d) a mutation in which the 18 juxtamembranous amino acids encompassing the secretase site are deleted also allows release of an amino-terminal fragment into the conditioned medium; and (e) kinetics of cleavage of APP-REP and its mutated derivatives are similar. These results indicate that the secretory cleavage of the extracellular amino-terminal fragments of APP-REP can occur in the presence of different novel juxtamembranous amino acid sequences.

Amino Acid Sequence↗

Prediction of contact maps by GIOHMMs and recurrent neural networks using lateral propagation from all four cardinal corners.

MOTIVATION: Accurate prediction of protein contact maps is an important step in computational structural proteomics. Because contact maps provide a translation and rotation invariant topological representation of a protein, they can be used as a fundamental intermediary step in protein structure prediction. RESULTS: We develop a new set of flexible machine learning architectures for the prediction of contact maps, as well as other information processing and pattern recognition tasks. The architectures can be viewed as recurrent neural network implemantations of a class of Bayesian networks we call generalized input-output HMMs (GIOHMMs). For the specific case of contact maps, contextual information is propagated laterally through four hidden planes, one for each cardinal corner. We show that these architectures can be trained from examples and yield contact map predictors that outperform previously reported methods. While several extensions and improvements are in progress, the current version can accurately predict 60.5% of contacts at a distance cutoff of 8 A and 45% of distant contacts at 10 A, for proteins of length up to 300.

Algorithms↗

A high-order graph generating self-organizing structure.

A large class of neural network models have their units organized in a lattice with fixed topology or generate their topology during the learning process. These network models can be used as neighborhood preserving map of the input manifold, but such a structure is difficult to manage since these maps are graphs with a number of nodes that is just one or two orders of magnitude less than the number of input points (i.e., the complexity of the map is comparable with the complexity of the manifold) and some hierarchical algorithms were proposed in order to obtain a high-level abstraction of these structures. In this paper a general structure capable to extract high order information from the graph generated by a large class of self-organizing networks is presented. This algorithm will allow to build a two layers hierarchical structure starting from the results obtained by using the suitable neural network for the distribution of the input data. Moreover the proposed algorithm is also capable to build a topology preserving map if it is trained using a graph that is also a topology preserving map.

Algorithms↗