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PubMed2005

Refined repetitive sequence searches utilizing a fast hash function and cross species information retrievals.

BACKGROUND: Searching for small tandem/disperse repetitive DNA sequences streamlines many biomedical research processes. For instance, whole genomic array analysis in yeast has revealed 22 PHO-regulated genes. The promoter regions of all but one of them contain at least one of the two core Pho4p binding sites, CACGTG and CACGTT. In humans, microsatellites play a role in a number of rare neurodegenerative diseases such as spinocerebellar ataxia type 1 (SCA1). SCA1 is a hereditary neurodegenerative disease caused by an expanded CAG repeat in the coding sequence of the gene. In bacterial pathogens, microsatellites are proposed to regulate expression of some virulence factors. For example, bacteria commonly generate intra-strain diversity through phase variation which is strongly associated with virulence determinants. A recent analysis of the complete sequences of the Helicobacter pylori strains 26695 and J99 has identified 46 putative phase-variable genes among the two genomes through their association with homopolymeric tracts and dinucleotide repeats. Life scientists are increasingly interested in studying the function of small sequences of DNA. However, current search algorithms often generate thousands of matches -- most of which are irrelevant to the researcher. RESULTS: We present our hash function as well as our search algorithm to locate small sequences of DNA within multiple genomes. Our system applies information retrieval algorithms to discover knowledge of cross-species conservation of repeat sequences. We discuss our incorporation of the Gene Ontology (GO) database into these algorithms. We conduct an exhaustive time analysis of our system for various repetitive sequence lengths. For instance, a search for eight bases of sequence within 3.224 GBases on 49 different chromosomes takes 1.147 seconds on average. To illustrate the relevance of the search results, we conduct a search with and without added annotation terms for the yeast Pho4p binding sites, CACGTG and CACGTT. Also, a cross-species search is presented to illustrate how potential hidden correlations in genomic data can be quickly discerned. The findings in one species are used as a catalyst to discover something new in another species. These experiments also demonstrate that our system performs well while searching multiple genomes -- without the main memory constraints present in other systems. CONCLUSION: We present a time-efficient algorithm to locate small segments of DNA and concurrently to search the annotation data accompanying the sequence. Genome-wide searches for short sequences often return hundreds of hits. Our experiments show that subsequently searching the annotation data can refine and focus the results for the user. Our algorithms are also space-efficient in terms of main memory requirements. Source code is available upon request.

Algorithms↗
PubMed2026

A conserved distal-tail helical extension defines a tailspike attachment architecture in Gram-negative siphophages.

Rapid growth of bacteriophage genome collections has outpaced functional annotation of tail-tip proteins, limiting comparative analysis of host-recognition structures. Starting from a shared distal-tail gene organization in the Salmonella phages 9NA and Jersey, I developed a morphogenetic bioinformatic framework integrating gene synteny, sequence comparison, profile hidden Markov model (HMM) screening, structural evidence, structure-aware searching, and AlphaFold modeling. Comparison with the experimentally characterized lambda and Sf11 tail assemblies identified a predominantly alpha-helical C-terminal extension of the distal-tail (DT) protein associated with tailspike attachment, termed the distal-tail helical extension (DT-helix). Screening 541,986 proteins from 5167 complete NCBI RefSeq tailed-phage genomes, followed by evidence-based evaluation of sequence, genomic context, and structural architecture, identified 165 curated DT-helical-extension-associated phages. Their DT proteins segregated into six sequence groups. In the four principal multi-member groups, cognate tailspikes showed group-specific conservation in proximal N-terminal regions but substantially greater downstream diversity, consistent with sequence constraint at the DT-tailspike attachment boundary. A complementary ProstT5/Foldseek search supported the established groups but revealed no convincing additional highly divergent family. Together with the experimentally characterized Sf11 attachment interface, these findings define a recurrent morphogenetic architecture linking conserved distal-tail scaffolds to more variable receptor-binding proteins across siphophages infecting Gram-negative bacteria. Although universal exchangeability is not established, the identified scaffold-receptor-binding boundaries provide a framework for molecular characterization and rational phage engineering. Accession-level information for the 165 curated phages is available through PhageTailDB.

Viral Tail Proteins↗
PubMed1983

Hidden overflow pathway to L-phenylalanine in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is representative of a large group of pseudomonad bacteria that possess coexisting alternative pathways to L-phenylalanine (as well as to L-tyrosine). These multiple flow routes to aromatic end products apparently account for the inordinate resistance of P. aeruginosa to end product analogs. Manipulation of carbon source nutrition produced a physiological state of sensitivity to p-fluorophenylalanine and m-fluorophenylalanine, each a specific antimetabolite of L-phenylalanine. Analog-resistant mutants obtained fell into two classes. One type lacked feedback sensitivity of prephenate dehydratase and was the most dramatic excretor of L-phenylalanine. The presence of L-tyrosine curbed phenylalanine excretion to one-third, a finding explained by potent early-pathway regulation of 3-deoxy-D-arabinoheptulosonate 7-phosphate (DAHP) synthase-Tyr (a DAHP synthase subject to allosteric inhibition by L-tyrosine). The second class of regulatory mutants possessed a completely feedback-resistant DAHP synthase-Tyr, the major species (greater than 90%) of two isozymes. Deregulation of DAHP synthase-Tyr resulted in the escape of most chorismate molecules produced into an unregulated overflow route consisting of chorismate mutase (monofunctional), prephenate aminotransferase, and arogenate dehydratase. In the wild type the operation of the overflow pathway is restrained by factors that restrict early-pathway flux. These factors include the highly potent feedback control of DAHP synthase isozymes by end products as well as the strikingly variable abilities of different carbon source nutrients to supply the aromatic pathway with beginning substrates. Even in the wild type, where all allosteric regulation in intact, some phenylalanine overflow was found on glucose-based medium, but not on fructose-based medium. This carbon source-dependent difference was much more exaggerated in each class of regulatory mutants.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1989

Clinical radiobiology of malignant melanoma.

Tumor-control probability (TCP) was analyzed in a series of 121 patients having 239 histologically proven recurrent or metastatic malignant melanomas. These were treated with fractionated radiotherapy with various doses per fraction, total doses, and overall times. Cutaneous lesions (127, 53%) were treated with electron beams, and more deeply seated tumors (112, 47%) with 60Co or 4-8 MV X-rays. The fraction size was highly variable, and this permitted determination of the alpha/beta ratio in the multifraction linear-quadratic model, which was estimated at 0.57 Gy with 95% confidence limits [-1.07, 2.5] Gy. Treatment time had no demonstrable influence on TCP. Thus this tumor exhibits the fractionation sensitivity characteristic of a late-responding normal tissue, suggesting that an adequate fractionation schedule for malignant melanomas would be characterized by larger-than-conventional doses per fraction, possibly about 6 Gy per fraction. This is consistent with the conclusions of other authors. Tumor size, evaluated as mean tumor diameter, S, had a major impact on TCP: the number of target cells increased as a power function of S with exponent 0.72 (95% confidence limits [0.49, 0.94]. In fact, a considerable amount of the heterogeneity in the dose-response data could be removed by accounting for size. Thus, the weak or absent dose response became highly significant. When a patient had multiple lesions, the responses of these to radiotherapy tended to be similar, thus implying that results were significantly influenced by a "hidden parameter" (such as inherent radiosensitivity or immunological status). A test of the predictive value of the TCP-model was performed in a different series of 183 cutaneous and lymph node malignant melanomas. The observed dose-response relationship in this data set was in good agreement with the model prediction. A chi-square test for goodness-of-fit showed that the variation between predicted and observed results could be explained by the binomial variation on quantal response data.

Cobalt Radioisotopes↗
PubMed1989

Characterization of pre-rRNA components in ribosomal precursor particles from macronuclei of Tetrahymena thermophila.

Ribosomal precursor particles were extracted from purified macronuclei of Tetrahymena thermophila and separated in sucrose gradients. The RNA components of major particle fractions were isolated and analyzed by Northern blot hybridization using cloned rDNA fragments. A tentative scheme of preribosome maturation was established based on the RNA constituents and corresponding processing steps occurring in the different particle classes. The primary transcript of ribosomal genes, the unspliced precursor rRNA, was found in some experiments in the upper region (less than 40S) of sucrose gradients run for short times. This is in accordance with earlier results by others indicating that slowly sedimenting ribonucleoprotein (RNP) structures may exist as a transitory stage of preribosome formation. Usually, however, unspliced pre-rRNA was only found in 80S preribosomes, where splicing occurred as indicated by the presence of splice intermediates and products only in this fraction. In addition, the further processing of spliced pre-rRNA at three major sites in variable temporal order took place in the 80S preribosomes, i.e., (i) the cleavage at or near the 5'end of the 17S rRNA sequence, (ii) the central cleavage in the internal transcribed spacer (ITS2) between the 5.8S and 26S rRNA sequence, and (iii) the cleavage in the ITS1 at or near the 3' end of the 17S rRNA sequence. Only the latter event was found to result more or less immediately in the division of the 80S preribosomes into separate precursors (p40S and 60S) of the small and large ribosomal subunits. If the alternative pre-rRNA cleavage site in the ITS2 was used first the 80S preribosomes retained their integrity. The conversion of the p40S precursors into nuclear 40S subribosomal particles was correlated with the processing of pre-17S rRNA into 17S rRNA. In the 60S ribosomal precursor particles the processing of pre-26S rRNA, including the formation of precursors (ITS and 7S RNA) to 5.8S rRNA, occurred. A substantial proportion of 26S rRNA molecules isolated from these particles already contained the central hidden break as indicated by the presence of 26S rRNA alpha- and beta-subfragments. The major pre-rRNA processing by-products, IVS and ETS RNA, were partly associated with preribosomes and partly present as free RNAs in the supernatant of sucrose gradients. This indicates that they are liberated and degraded mainly outside the particles in which they are formed. In contrast, the initiation fragment (IF), a small promoter-proximal transcript, was exclusively associated with large particles.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Three-dimensional analysis of the casting accuracy of one-piece, osseointegrated implant-retained prostheses.

The three-dimensional distortions of implant frameworks of two designs, reflecting the early "Toronto" U-shaped design and a current L-shaped design, were measured. A conventional commercial laboratory one-piece casting method, using a silver-palladium alloy, was used. Distortion was defined by five displacement variables for the centroids of each of five gold cylinders incorporated in each casting: three orthogonal translational displacements (dx, dy, and dz) and two rotational displacements (d theta x and d theta y). A computerized coordinate measuring machine was used. Overall translational displacements measured were -17.4 +/- 15 microns for dx, 6.1 +/- 7.1 microns for dy, and -0.1 +/- 1.7 microns for dz. The overall global translational displacement, dR, was 20.2 +/- 14.5 microns. Overall rotational displacements were -0.098 +/- 0.109 degrees for d theta x and -0.020 +/- 0.097 degrees for d theta y, giving an average absolute angular change, d theta R, of 0.158 +/- 0.077 degrees. No significant differences were found between U- and L-shaped castings, except for dy values for cylinders 2, 3, and 4, and d theta x values for cylinder 1. Cylinder location within the arch was associated with a specific direction and magnitude of translational and rotational displacement. Even small rotational displacements may manifest large gap appearances with the one-screw test because of the "moment arm" effect. However, other rotational displacements may be hidden, depending on the direction of tilt and the moment arm length.

Analysis of Variance↗
PubMed1995

Improved analysis of heart rate variability by methods of nonlinear dynamics.

The traditional analysis of heart rate variability (HRV) in the time and frequency domains seems to be an independent predictive marker for sudden cardiac death. Because the usual applied methods of HRV analysis describe only linear or strong periodic phenomena, the authors have developed new methods of HRV analysis based on nonlinear dynamics. In that way, parameters are extracted that quantify more complex processes and their complicated relationships. These methods are symbolic dynamics that describes the beat-to-beat dynamics and renormalized entropy that compares the complexity of power spectra on a normalized energy level. In an initial investigation, the HRV of 35 healthy subjects and 39 cardiac patients have been analyzed. Using discriminant functions, the authors found an optimal (100%) differentiation between the group of healthy subjects (even using only an age-matched subgroup of 12 subjects) and that of patients after myocardial infarction with a high electrical risk (Lown 4b). Applying this discriminant function to a group of patients with low electrical risk, four patients show the same behavior indicative of a high risk score, which might be a sign for a hidden high risk, two patients show healthy behavior, and the remaining patients show a separate pattern. The use of new methods of nonlinear dynamics in combination with parameters of the time and frequency domains in HRV offers possibilities for improved classification of HRV behavior. It is suggested that this could lead to a more detailed classification of individual high risk.

Adult↗
PubMed1993

Probing the combining site of an anti-carbohydrate antibody by saturation-mutagenesis: role of the heavy-chain CDR3 residues.

The carbohydrate-binding site in Fab fragments of an antibody specific for Salmonella serogroup B O-polysaccharide has been probed by site-directed mutagenesis using an Escherichia coli expression system. Of the six hypervariable loops, the CDR3 of the heavy chain was selected for exhaustive study because of its significant contribution to binding-site topography. A total of 90 mutants were produced and screened by an affinity electrophoresis/Western blotting method. Those of particular interest were further characterized by enzyme immunoassay, and on this basis seven of the mutant Fabs were selected for thermodynamic characterization by titration microcalorimetry. With regard to residues that hydrogen bond to ligand through backbone interactions, Gly102H could not be substituted, while several side chains could be introduced at Gly100H and Tyr103H with relatively little effect on antigen binding. There was, however, a preference for nonpolar side chains at position 103H. Substitution of His101H with carboxylate and amide side chains gave mutants with binding affinities approaching that of the wild type; complete side-chain removal by mutation to Gly was tolerated with a 10-fold reduction in binding constant. Analysis of binding by titration microcalorimetry revealed some dramatic thermodynamic changes hidden by the similarity of the binding constants. Similar effects were observed with residue changes in an Arg-Asp salt-bridge at the base of the loop. These results indicate that alterations to higher affinity anti-carbohydrate antibodies are characterized by an enthalpy-entropy compensation factor which allows for fundamental changes in the nature of the binding interactions but impedes engineering for increases in affinity.

Amino Acid Sequence↗
PubMed2003

Artificial intelligence in predicting bladder cancer outcome: a comparison of neuro-fuzzy modeling and artificial neural networks.

PURPOSE: New techniques for the prediction of tumor behavior are needed, because statistical analysis has a poor accuracy and is not applicable to the individual. Artificial intelligence (AI) may provide these suitable methods. Whereas artificial neural networks (ANN), the best-studied form of AI, have been used successfully, its hidden networks remain an obstacle to its acceptance. Neuro-fuzzy modeling (NFM), another AI method, has a transparent functional layer and is without many of the drawbacks of ANN. We have compared the predictive accuracies of NFM, ANN, and traditional statistical methods, for the behavior of bladder cancer. EXPERIMENTAL DESIGN: Experimental molecular biomarkers, including p53 and the mismatch repair proteins, and conventional clinicopathological data were studied in a cohort of 109 patients with bladder cancer. For all three of the methods, models were produced to predict the presence and timing of a tumor relapse. RESULTS: Both methods of AI predicted relapse with an accuracy ranging from 88% to 95%. This was superior to statistical methods (71-77%; P < 0.0006). NFM appeared better than ANN at predicting the timing of relapse (P = 0.073). CONCLUSIONS: The use of AI can accurately predict cancer behavior. NFM has a similar or superior predictive accuracy to ANN. However, unlike the impenetrable "black-box" of a neural network, the rules of NFM are transparent, enabling validation from clinical knowledge and the manipulation of input variables to allow exploratory predictions. This technique could be used widely in a variety of areas of medicine.

Artificial Intelligence↗
PubMed2000

A model that accounts for activity prior to sensory inputs and responses during matching-to-sample tasks.

Neural network models were examined during delayed matching-to-sample tasks (DMS), and neurons in a monkey's prefrontal cortex were studied during the performance of comparable tasks. In DMS, various input stimuli follow a sample stimulus, and an output should occur whenever the sample reappears. Our previous models have been restricted to certain kinds of inputs, outputs, and temporal patterns. Here, we generalized the models by training them on both spatial and nonspatial inputs, spatial and nonspatial outputs, and both fixed and variable interstimulus intervals. Two versions of DMS were presented to both the model and the monkey, both involving nonspatial samples: (1) Two stimuli simultaneously appeared at a variable interval after the sample; and (2) A series of single stimuli appeared at fixed intervals after the sample. Both versions required identical spatial responses, reflecting the direction (left or right) of the matching stimulus relative to a central origin. Thus, these two versions of DMS involved the same samples, memory, and responses, but established different response contexts. Our analysis focused on unit activity prior to stimuli, as well as that prior to responses, termed anticipatory and response-related activity, respectively. In both the model and the monkey, anticipatory activity occurred only for fixed interstimulus intervals. In the model, we could determine that anticipatory activity acted either like a filter to suppress inappropriate responses or it served to enhance the network's general readiness to respond. As for response-related activity, units in both the model and the monkey showed directional selectivity and had a strong dependence on response context. In the model, we could show that this activity contributed both to the suppression of inappropriate responses and to the generation of correct ones. None of the model's hidden units contributed exclusively to computing the direction of match output. Instead, their response-related activity contributed to the computation of both the match decision and the correct response direction.

Animals↗
PubMed1992

[3-dimensional topographic analysis of the papilla as a component of glaucoma diagnosis].

Three-dimensional topography of the optic nerve head can be objectively described by means of quantitative parameter values. Owing to interindividual variability in the disc configuration, new structural variables, such as the relative height of the peripapillary retinal nerve fiber layer in stereo-videography and height variations in the contour line along the disc border in laser scanning tomography, have been shown to differentiate normal optic discs and optic nerve heads with pathological alterations better than standard volumetric data. Using laser scanning tomography, the effect of age on the parameter values of disc area, rim area and the ratio of the cup-to-disc area was evaluated in 61 healthy subjects (age 14 to 77) who had normal visual fields on computerized static perimetry. The rim area decreased with age (rs = -0.26, P < 0.05); the ratio of the cup area to disc area increased (rs = 0.25; P < 0.05). No relationship was found between patient age and disc area (Spearman correlation). Although the coefficients of correlation are rather small, they may reflect the physiological age-related decline in axonal count. The high resolution of strictly confocal laser scanning microscopy allows for visualization of nerve fiber bundle defects underneath a surface of regular reflectivity. The existence of such hidden nerve fiber bundle defects has been postulated before on the basis of experimental studies and may be an early morphological sign of glaucomatous damage.

Glaucoma↗
PubMed1996

Simultaneously recorded single units in the frontal cortex go through sequences of discrete and stable states in monkeys performing a delayed localization task.

To test whether spiking activity of six to eight simultaneously recorded neurons in the frontal cortex of a monkey can be characterized by a sequence of discrete and stable states, neuronal activity is analyzed by a hidden Markov model (HMM). Using the HMM method, we are able to detect distinct states of neuronal activity within which firing rates are approximately stationary. Transitions between states, as expressed by concomitant changes in the firing rates of several units, occur quite abruptly. The significance and consistency of the states are confirmed by comparison with simulated data. The detected states are specific to a monkey's response in a delayed localization task, allowing correct prediction of the response in approximately 90% of the trials. Similar predictive power is achieved by a model based simply on the response histograms (PSTH) of the units. The two models reach this predictive ability with different time courses: the PSTH model gains predictive power with a higher rate in the first second of the delay, and the HMM gains predictive power with higher rate in the next 3 sec. In this later period, conventional methods such as the PSTH cannot detect any firing rate modulations, but the HMM successfully captures transitions between distinct states that are specific to the monkey's behavioral response and occur at highly variable times from trial to trial. Our results suggest that neuronal activity in this later period is described best as transitions among distinct states that may reflect discrete steps in the monkey's mental processes.

Animals↗
PubMedDate not supplied

Nursing time and work in an acute rehabilitation setting.

Nursing staffing has long been recognized as a significant variable in a hospital budget even through the era of increased productivity and efficiency. In addition, patient acuity has been rising, and increasing demands on nursing personnel have been documented. These increased demands have affected nurse staffing, patient outcomes, and nurse retention, all of which have an impact on our healthcare system. Therefore, it is imperative that nursing time and work be examined in the acute rehabilitation setting--a setting in which research has been sparse. To estimate patient acuity, the activities of nursing personnel must be examined to establish timeframes for the care needed by patients. Previous studies have examined time and work according to pre-established patient acuity categories. California has passed legislation that requires mandatory nurse-staffing ratios in response to the concerns about the adequacy of patient care and safety. We did this study to assess the time and work related to patients with different diagnoses that are typically found in a rehabilitation unit. The data collected can be used to develop a patient acuity system. This study sought to identify how nurses spend their time so that hidden costs and important interventions can be addressed by an institution's administration.

Acute Disease↗
PubMed2000

Hidden Markov modeling for single channel kinetics with filtering and correlated noise.

Hidden Markov modeling (HMM) can be applied to extract single channel kinetics at signal-to-noise ratios that are too low for conventional analysis. There are two general HMM approaches: traditional Baum's reestimation and direct optimization. The optimization approach has the advantage that it optimizes the rate constants directly. This allows setting constraints on the rate constants, fitting multiple data sets across different experimental conditions, and handling nonstationary channels where the starting probability of the channel depends on the unknown kinetics. We present here an extension of this approach that addresses the additional issues of low-pass filtering and correlated noise. The filtering is modeled using a finite impulse response (FIR) filter applied to the underlying signal, and the noise correlation is accounted for using an autoregressive (AR) process. In addition to correlated background noise, the algorithm allows for excess open channel noise that can be white or correlated. To maximize the efficiency of the algorithm, we derive the analytical derivatives of the likelihood function with respect to all unknown model parameters. The search of the likelihood space is performed using a variable metric method. Extension of the algorithm to data containing multiple channels is described. Examples are presented that demonstrate the applicability and effectiveness of the algorithm. Practical issues such as the selection of appropriate noise AR orders are also discussed through examples.

Algorithms↗
PubMedDate not supplied

Tracheobronchial foreign bodies in adults--experience of the Bronchology Unit of Centro Hospitalar de Vila Nova de Gaia.

INTRODUCTION: Foreign body aspiration (FBA) is frequent in children but uncommon in adults it's and often remains hidden for long periods of time. A high index of suspicion is essential for the correct diagnosis of this condition. Early extraction of FB avoids sequelae and complications. METHODS: Retrospective study of FBA cases in adults that occurred in a 20 year period (1985-2005). The authors reviewed of the clinical records of all patients admitted with the diagnosis of foreign body in the airway in that time period. RESULTS: In that period of time 77 FB were extracted. Male:female ratio was 68:32%, mean age was 51.4 years and mean delay between FB aspiration and removal 401 days (min: 3 h, max: 21 years). Most common clinical presentations: acute asphyxia in 28%, persistent cough 22%. Nature of FB: bone fragments 33%, vegetable matter 31%. The majority of FBs (61%) was lodged in the right bronchial tree; 26% were radiopaque. Rigid bronchoscopy was performed in 75 cases and fiberoptic bronchoscopy in only two. Two patients needed two bronchoscopies for FB removal. There were no complications, need for surgery or relevant sequelae. CONCLUSIONS: FBA may happen at any age. In adults the clinical presentation is variable and the FBA episode is often missed, delaying the diagnosis. Rigid bronchoscopy proved to be an efficient and safe procedure. FBA must be a diagnostic hypothesis when studying an adult with long standing respiratory complaints.

Adolescent↗
PubMed2006

Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche.

CONTEXT: Age at menarche (AAM) is an important anthropological variable that has major implications for a woman's health later in life. Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown. OBJECTIVE: The objective of this study was to identify the quantitative trait loci (QTL) underlying the variations in AAM. METHODS: We performed a large-scale, genomewide, linkage scan in 2461 Caucasian women from 402 pedigrees. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction. RESULTS: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD, 3.70); the other two suggestive linkages were on 22q11 (LOD, 2.68) and 11q23 (LOD, 1.98), respectively. We also detected significant epistatic interaction between genomic regions 22q13 and 3q13. CONCLUSIONS: The identification of QTL and epistatic interaction in a large female sample laid a foundation for independent replication and fine-mapping studies as well as positional and functional candidate gene studies aimed at finding the causal genetic variants and hidden mechanisms concerning the variations in AAM.

Age Factors↗
PubMed2002

Patterns of motor disability in very preterm children.

Motor development in very preterm children differs in several important ways from that of children born at full term. Variability is common, although the anatomic and physiologic bases for that variability are often poorly understood. Motor patterns over the first postnatal year may depend on behaviours learned during often long periods of neonatal intensive care. The normal pattern of development may be modified by disturbances of brain function caused both by the interruption of normal brain maturation ex-utero and the superimposition of focal brain injuries following very preterm birth. Abnormal patterns of development over the first year may evolve into clear neuromotor patterns of cerebral palsy or resolve, as "transient dystonias." Cerebral palsy is associated with identified patterns of brain injury secondary to ischaemic or haemorrhagic lesions, perhaps modified by activation of inflammatory cytokines. Cerebral palsy rates have not fallen as might be expected over the past 10 years as survival has improved, perhaps because of increasing survival at low gestations, which is associated with the highest prevalence of cerebral palsy. Children who escape cerebral palsy are also at risk of motor impairments during the school years. The relationship of these impairments to perinatal factors or to neurological progress over the first postnatal year is debated. Neuromotor abnormalities are the most frequent of the "hidden disabilities" among ex-preterm children and are thus frequently associated with poorer cognitive ability and attention deficit disorders. Interventions to prevent cerebral palsy or to reduce these late disabilities in very preterm children are needed.

Age Factors↗
PubMed2001

GeneMarkS: a self-training method for prediction of gene starts in microbial genomes. Implications for finding sequence motifs in regulatory regions.

Improving the accuracy of prediction of gene starts is one of a few remaining open problems in computer prediction of prokaryotic genes. Its difficulty is caused by the absence of relatively strong sequence patterns identifying true translation initiation sites. In the current paper we show that the accuracy of gene start prediction can be improved by combining models of protein-coding and non-coding regions and models of regulatory sites near gene start within an iterative Hidden Markov model based algorithm. The new gene prediction method, called GeneMarkS, utilizes a non-supervised training procedure and can be used for a newly sequenced prokaryotic genome with no prior knowledge of any protein or rRNA genes. The GeneMarkS implementation uses an improved version of the gene finding program GeneMark.hmm, heuristic Markov models of coding and non-coding regions and the Gibbs sampling multiple alignment program. GeneMarkS predicted precisely 83.2% of the translation starts of GenBank annotated Bacillus subtilis genes and 94.4% of translation starts in an experimentally validated set of Escherichia coli genes. We have also observed that GeneMarkS detects prokaryotic genes, in terms of identifying open reading frames containing real genes, with an accuracy matching the level of the best currently used gene detection methods. Accurate translation start prediction, in addition to the refinement of protein sequence N-terminal data, provides the benefit of precise positioning of the sequence region situated upstream to a gene start. Therefore, sequence motifs related to transcription and translation regulatory sites can be revealed and analyzed with higher precision. These motifs were shown to possess a significant variability, the functional and evolutionary connections of which are discussed.

Algorithms↗