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At least 127 records · Page 7Linked to original sources
PubMed1992

The population genetics of alleles affecting enzyme activity.

It is possible to predict the population genetics of allozymes by assuming that fitness is proportional to flux through a biochemical pathway. The model presented here extends previous work by incorporating two additional features of biological realism. Firstly, that more than one biochemical route may exist between any two metabolites. The major routes have been identified as the classical biochemical pathways but in the event of a mutation blocking a major route, minor routes become significant. These minor routes are named "bypass fluxes" and have profound effects on the population genetics of allozymes. Secondly, recent work has suggested that a metabolic cost is associated with enzyme synthesis; this will constitute an additional selective pressure on alleles which affect the amount of enzyme synthesized. The model generates a fitness curve which predicts the fitness associated with any level of enzyme activity. It can utilize data on null or near-null, structural or regulatory, mutations in the presence or absence of bypass fluxes. When data from natural populations of Drosophila are investigated, it is concluded that selection pressures acting on enzyme variants may be much higher than previously thought.

Animals↗
PubMed1991

Artificial neural networks for source localization in the human brain.

Source localization in the brain remains an ill-posed problem unless further constraints about the type of sources and the head model are imposed. Human head is modeled in various ways depending critically on the computing power available and/or the required level of accuracy. Sophisticated and truly representative models may yield more accurate results in general, but at the cost of prohibitively long computer times and huge memory requirements. In conventional source localization techniques, solution source parameters are taken as those which minimize an index of performance, defined relative to the model-generated and clinically measured voltages. We propose the use of a neural network in the place of commonly employed minimization algorithms such as the Simplex Method and the Marquardt algorithm, which are iterative and time consuming. With the aid of the error-backpropagation technique, a neural network is trained to compute source parameters, starting from a voltage set measured on the scalp. Here we describe the methods of training the neural network and investigate its localization accuracy. Based on the results of extensive studies, we conclude that neural networks are highly feasible as source localizers. A trained neural network's independence of localization speed from the head model, and the rapid localization ability, makes it possible to employ the most complex head model with the ease of the simplest model. No initial parameters need to be guessed in order to start the calculation, implying a possible automation of the entire localization process. One may train the network on experimental data, if available, thereby possibly doing away with head models.

Brain↗
PubMed1990

Urea kinetics and clinical evaluation of the haemodialysis patient.

Urea kinetic modelling (UKM) was performed on 62 patients in a haemodialysis unit not normally using kinetic methods. Without knowledge of the results, four nephrologists, four nurses and the patients themselves evaluated adequacy of dialysis (eAD) and daily protein intake (eDPI). Thirty-two patients had Kt/V less than 1.0, and 17 patients had Kt/V less than 0.9. Estimated improvement of the efficacy of treatment after the intervention of a physician was minor. Seven patients had a protein catabolic rate (pcr) at less than 0.8 g/kg per day. On average physicians identified five of these. Both nurses and doctors exhibited highly significant correlations between Kt/V and eAD, and between pcr and eDPI, but the correlation coefficients were generally modest (typically below 0.4). When patients evaluated themselves, no significant correlations were found. Examined individually, all four physicians' decisions about eAD correlated better with model-generated decisions than with eAD stated by their colleagues. It is concluded that UKM should be used to secure adequate and more uniform treatment prescription. There is no 'clinical standard' competing with UKM. Nurses make satisfactory evaluations compared to doctors, but the patients are unable to assess the adequacy of their dialysis or diet.

Adult↗
PubMed2025

Embed-Search-Align: DNA sequence alignment using Transformer models.

MOTIVATION: DNA sequence alignment, an important genomic task, involves assigning short DNA reads to the most probable locations on an extensive reference genome. Conventional methods tackle this challenge in two steps: genome indexing followed by efficient search to locate likely positions for given reads. Building on the success of Large Language Models in encoding text into embeddings, where the distance metric captures semantic similarity, recent efforts have encoded DNA sequences into vectors using Transformers and have shown promising results in tasks involving classification of short DNA sequences. Performance at sequence classification tasks does not, however, guarantee sequence alignment, where it is necessary to conduct a genome-wide search to align every read successfully, a significantly longer-range task by comparison. RESULTS: We bridge this gap by developing a "Embed-Search-Align" (ESA) framework, where a novel Reference-Free DNA Embedding (RDE) Transformer model generates vector embeddings of reads and fragments of the reference in a shared vector space; read-fragment distance metric is then used as a surrogate for sequence similarity. ESA introduces: (i) Contrastive loss for self-supervised training of DNA sequence representations, facilitating rich reference-free, sequence-level embeddings, and (ii) a DNA vector store to enable search across fragments on a global scale. RDE is 99% accurate when aligning 250-length reads onto a human reference genome of 3 gigabases (single-haploid), rivaling conventional algorithmic sequence alignment methods such as Bowtie and BWA-Mem. RDE far exceeds the performance of six recent DNA-Transformer model baselines such as Nucleotide Transformer, Hyena-DNA, and shows task transfer across chromosomes and species. AVAILABILITY AND IMPLEMENTATION: Please see https://anonymous.4open.science/r/dna2vec-7E4E/readme.md.

Sequence Analysis, DNA↗
PubMed1991

Structure of flagellar microtubules.

There is a widely perceived and growing need for a reliable high-resolution three-dimensional structural model of MT. One contributor to this need has been the enormous burst of new information from molecular biological manipulations of tubulin primary sequence and pattern of expression in cells. A second contributor has been the astounding progress in defining the MT-dynein motors of cytoplasmic motility. To interpret this new information in terms of MT assembly and function, we simply must have the structure of tubulin to atomic resolution and know the arrangement of tubulin in MT to an accuracy of better than 1 nm. The best experimental system for understanding the structural basis of MT-dependent motility is the eukaryotic flagellum. Therefore, the MT whose structure we need to know first is the flagellar doublet MT. The most generally accepted specific model for flagellar MT structure was proposed by Amos and Klug in 1974. The impact of their model has been enormous. It has provided the structural framework for thinking about MT function and has influenced the interpretation of a vast body of experimental observation over the intervening 15 years. As a first approximation to the structure of the native MT, in flagellar doublets and cytoplasmic singlets, it has served superbly. Now, we face an accumulation of new information on the nature of the intersubunit bond gleaned from assembly reactions of tubulin, on the nature and probable structure of nontubulin components of flagellar MT, and on the appearance of MT in their native hydrated state. We are compelled by this new evidence to look for the next approximation to the three-dimensional structure of the flagellar doublet MT. This second generation model is not yet formulated in sufficient detail to serve as a replacement for the Amos and Klug model. What we can say at this point is that the new model will be much more complex than the old one, having only axial periodicity in both A and B subfibers rather than full helical symmetry. The model must include at least one tektin filament at the medial (in the flagellum) A-B junction, and perhaps another in a location yet to be determined. It may also include other nontubulin components. The axial period of the MT itself, free of attached cross-bridging structure from the flagellum, must be at least 32.8 nm.(ABSTRACT TRUNCATED AT 400 WORDS)

Flagella↗
PubMed1990

A critical review of the use of Rogers' model within a special hospital: a single case study.

This case study presents a problematic patient who has been resident in a special hospital for mentally handicapped people for years due to a gross sexual fantasy disorder, continuous self-injurious behaviour and an array of disordered conducts which resulted in negative nursing reports. The introduction of Rogers' model, with its abstract finer conceptualizations produced an alternative framework by which to assess the patient. This holistic interactive model generated a paradigmatic shift in the nursing perceptions, at a conceptual level, which was manifested in their reporting behaviours. The results appeared to indicate a sudden and dramatic change in the patient's behaviour. However, alternative interpretations proved the more convincing on closer analysis. The use of Rogers' framework proved difficult in its practical application due to its underpinning requirements for role adoption and negotiation, both being problematic in a secure environment.

Adult↗
PubMed1976

Studies of bacterial chemotaxis in defined concentration gradients. A model for chemotaxis toward L-serine.

The details of the chemotactic response of Salmonella typhimurium to gradients of L-serine have been examined in some detail. Two relatively macroscopic techniques have been employed to measure the bacterial response. These include measurements of the average velocity as the bacterial population moves toward attractants, and measurement of the upward-to-downward flux ratio, R, in the stable preformed attractant gradients. The dependence of the average velocity on gradient appears to be hyperbolic in nature, while the flux ratio depends linearly on the gradient. These data suggest a microscopic model for the dependence of bacterial behavior on the serine gradient. The model involves a linear dependence of the mean lifetime of a bacterial trajectory on the gradient for those bacteria moving toward higher attractant concentration. Those moving toward low concentrations of attractant do not change the mean duration of their trajectories, or the speed at which a given bacterium swims through the solution. This model generates the observed dependences of the average velocity and flux ratio on gradient. Interpretation of the experimental data suggests that a gradient which increases serine concentration by a factor of 2 in 10 mm is sufficient to double the average duration of a trajectory for a bacterium moving directly up the gradient. The concentration dependence of the chemotactic response to serine is more complicated. It suggests that more than one receptor of serine may be involved in determining chemotactic behavior to this attractant.

Chemotaxis↗
PubMed1989

Problems of the third dimension.

The problems facing a pathologist or anatomist who wishes to embark on computer-assisted reconstruction of structures seen in serial light microscope sections are reviewed. They are illustrated by comparing a reconstruction of a bronchial gland made by cutting out polystyrene sheets with models generated by four computer-assisted systems, i.e. the IBAS 2000 system, the SSRCON (MRC) system, the AT-Videoplan system and the CHD (Cookson, Holman, Dykes) system. It is obvious that computer-assistance cannot solve the preparation problems of three-dimensional reconstruction (3DR) and that choosing a computer-assisted system is fraught with difficulties. It is recommended that intending purchasers of computer-assisted 3DR systems prepare material in advance to try out on the systems they are considering.

Bronchi↗
PubMed1991

Relationship of apparent systemic clearance to individual organ clearances: effect of pulmonary clearance and site of drug administration and measurement.

The relationships between apparent total-body clearance (CL) and individual organ clearances were mathematically defined with respect to the site of drug administration and measurement. The derived equations can be applied to drugs undergoing different pathways of elimination, including pulmonary clearance. A physiological pharmacokinetic model was used to test the validity of the equations. The apparent systemic clearance values obtained through the equations, using the individual organ clearance values, were identical to those calculated utilizing the model-generated data, indicating the validity of the equations. Furthermore, it was shown that the conventional estimation of CL of drugs subject to pulmonary clearance is highly dependent upon the site of drug administration and measurement. The relationships were further utilized to explain the reported CL values which are higher than the cardiac output. The equations developed here may be used to predict the contribution of different organs, such as the lungs, to the apparent systemic clearance of drugs.

Animals↗
PubMed1991

The Z-Z junction: the boundary between two out-of-phase Z-DNA regions.

The boundary between two segments of Z-DNA that differ in the phase of their syn-anti alternation about the glycosidic bond is termed a Z-Z junction. Using chemical probes and two-dimensional gel electrophoresis, we examined a Z-Z junction consisting of the sequence d[(CG)8C(CG)8] inserted into a plasmid and used energy minimization techniques to devise a three-dimensional model that is consistent with the available data. We show that both alternating CG segments undergo the B-Z transition together to form a Z-Z junction. The junction is very compact, displaying a distinctive reactivity signature at the two base pairs at the junction. In particular, the 5' cytosine of the CC dinucleotide at the junction is hyperreactive toward hydroxylamine, and the two guanines of the GG dinucleotide on the complementary strand are less reactive toward diethyl pyrocarbonate than are the surrounding Z-DNA guanines. Statistical mechanical treatment of the 2-D gel data yields a delta G for forming the Z-Z junction equal to 3.5 kcal, significantly less than the cost of a B-Z junction and approximately equal to the cost of a base out of alternation (i.e., a Z-DNA pyrimidine in the syn conformation). The computer-generated model shows little distortion of the Z helix outside of the central two base pairs, and the energy of the structure and the steric accessibility of the reactive groups are consistent with the data.

Base Sequence↗
PubMed1991

Coverage and the design of striate cortex.

Hubel and Wiesel (1977) suggested that ocular dominance and orientation columns in the macaque monkey striate cortex might be bands of uniform width that intersected orthogonally. They pointed out that if this were the case, there would be an equal allocation of cells of different orientation preference to each eye and to each point in visual space. However, orientation and ocular dominance columns have a more complex structural organization than is implied by this model: for example, iso-orientation domains do not intersect ocular dominance stripes at right angles and the two columnar systems have different periodicities. This raises the question as to how well the striate cortex manages to allocate equal numbers of neurons of different orientation preference to each eye and to each region of visual space, a factor referred to here as coverage. This paper defines a measure of uniformity of coverage, c', and investigates its dependence on several different parameters of columnar organisation. Calculations were done first using a simplified one-dimensional model of orientation and ocular dominance columns and were then repeated using more realistic two-dimensional models, generated with the algorithms described in the preceding paper (Swindale 1991). Factors investigated include the relative periodicities of the two columnar systems, the size of the cortical point image, the width of orientation tuning curves, whether columns are spatially anisotropic or not, and the role of the structural relationships between columns described by Blasdel and Salama (1986). The results demonstrate that coverage is most uniform when orientation hypercolumns are about half the size of ocular dominance hypercolumns. Coverage is most uneven when the hypercolumns are the same size, unless they are related in the way described by Blasdel and Salama, in which case coverage gets only slightly worse as the size ratio (ori/od) increases above 0.5. The minimum diameter of cortical point image that ensures reasonably uniform coverage is about twice the size of an ocular dominance hypercolumn i.e. about 1.5-2.0 mm.

Animals↗
PubMed1989

[Multivariate analysis of prognostic factors influencing survival in chronic myelogenous leukemia].

Prognostic significance of disease features obtained at the time of initial diagnosis was analyzed in 90 patients with chronic myelogenous leukemia (CML) in chronic phase. Median survival of this population was 45.9 months. Univariate analysis revealed that splenomegaly, bone marrow basophils, bone marrow blasts, peripheral blood blasts, and bone marrow eosinophils were significant prognostic factors for survival, and that peripheral blood leukocytes counts, hemoglobin concentration, performance status, age and lymphadenopathy were factors with border line significance. There were multiple interrelationship among these disease features. Multivariate regression analysis identified that age, hemoglobin concentration, and bone marrow blasts were independent primarily significant prognostic factors for survival. The Cox model generated with three variables of age, hemoglobin concentration, and percent blasts in bone marrow provided a useful representation of risk status in the population. A hazard function derived from the patients population segregated patients into three groups with significantly different survival patterns: A lower risk group, an intermediate group and a high risk group of patients with median survival of 57.8, 49.8 and 38.4 months respectively. Survival after CML blast crisis was short and overall median survival of 54 patients with CML blast crisis was 6.4 months. A sole prognostic factor for survival in blast crisis identified by multivariate analysis was blast cell type at CML blast crisis and patients with lymphoid phenotype had a good prognosis with median survival of 9.8 months. Median survival of myeloid crisis was 4.2 months. No other disease features were identified as significant prognostic factors in the present patient population.

Adult↗
PubMed2026

A trainable language model with potential to modulate translation rates in non-model organisms by generating upstream untranslated region sequence libraries.

Tuning protein expression in non-model organisms is often constrained by the lack of validated genetic parts and predictive design tools. Translational tuning through the modulation of upstream untranslated regions (5'-UTRs) offers a potentially organism-agnostic route, but existing methods typically rely on mechanistic assumptions, prior knowledge that may not be available in non-model contexts, or the screening of sequence libraries. Here, we present a simple generative approach for creating synthetic 5'-UTR libraries based solely on the genomic sequence statistics of any desired organism. The method uses a sliding-window n-gram language model applied to native 5'-UTR sequences to produce novel sequences that preserve organism-specific base distributions and motifs without hard-coding specific motifs or mechanistic rules into inflexible statistical templates. We have applied this approach to the model bacterium Escherichia coli and the non-model probiotic Limosilactobacillus reuteri. Libraries of approximately 1,000 sequences were generated for each organism, from which about 100 unique sequences were experimentally tested for translation of a fluorescent reporter protein. In both organisms, the synthetic libraries yielded a broad range of translation levels from this relatively small number of tested variants. Sequences derived from an organism's own genomic statistics provided a more uniformly distributed range of translation rates in that organism than sequences derived from the other species. Correlations of individual sequence performance across the two species were weak, and thermodynamic predictions of ribosome binding strength showed very little predictive power, especially in the non-model L. reuteri. The results demonstrate that simple statistical language model approaches applied to genomic data can generate functional translational regulatory sequence libraries without detailed mechanistic knowledge or explicit reference to consensus motifs. The approach requires minimal computational resources, avoids reproducing native sequences, and can be readily applied to any organism with a sequenced genome. This strategy may lower technical barriers to expression tuning in non-model organisms.

5' Untranslated Regions↗
PubMed1991

N.m.r. and conformational analysis of the capsular polysaccharide from Streptococcus pneumoniae type 4.

The 1H- and 13C-n.m.r. data on the capsular polysaccharide (1) produced by Streptococcus pneumoniae type 4, the depyruvated polysaccharide (2), and a tetrasaccharide (3a) derived by Smith degradation of 2 were used as constraints on a computer-generated model of the conformation of 1 and to assess the effects of the pyruvic acetal substituent on the conformation. The dynamics of the polysaccharide systems and the influence of the pyruvic acetal were investigated using 13C-n.m.r. relaxation measurements.

Amides↗
PubMed1991

Ultraviolet photoreception in carp: microspectrophotometry and behaviorally determined action spectra.

This study demonstrates correlations between u.v. sensitivity and microspectrophotometric absorption spectra determined sequentially for the same group of individuals. We used the heart-rate conditioning technique to measure spectral sensitivity of carp, a species known to have u.v.-sensitive photoreceptors. Mean spectral sensitivity (n = 3) determined with a spectrally-broad background (450 nm long pass filter) revealed a small but consistent u.v. peak (lambda max of 380 nm) in addition to the other long wavelength peaks. An intense blue-green background (490 nm) produced a more prominent u.v. peak (lambda max of 400 nm) when a 450 nm longpass filter was added to the background. Microspectrophotometric measurements of u.v.-sensitive photoreceptors from one individual, which belonged to the group used in the spectral sensitivity experiments, revealed an average lambda max of 377.5 nm (SD +/- 4.5 nm, n = 5 cells). Bleaching and dichroic measurements of these receptors ensured that we were examining typical vertebrate visual pigments and not stable photoproducts. The mean spectral sensitivity points were compared with the u.v. and blue-sensitive visual pigment absorption spectra. A linear subtractive model and ocular media absorption were used in this comparison for the various photic conditions used in the heart-rate conditioning experiments. The model successfully described the sensitivity of the test fish in two cases but in a third case there was some discrepancy. The model generated curve was broader than the spectral sensitivity of the u.v.-sensitive cone mechanism on the shortwave side even though the ocular media corrections had been accounted for.

Animals↗
PubMedDate not supplied

Dipole source localization in the study of EP generators: a critique.

(1) The decision to solve the inverse problem in terms of one or more localized generators implies the assumption of a particular generator model. This assumption permits carrying out inverse dipole estimation. However, it is perilous to justify the procedure on the basis of the result. (2) Goodness of fit is a necessary but not sufficient criterion of model adequacy. A particular quantitative inverse solution has meaning only if it is accompanied by consideration of sensitivity to small changes in all of the free modeling parameters and estimates of perturbing factors including noise and forward calculation uncertainties.

Brain Mapping↗
PubMed1990

Gadolinium-DTPA-enhanced and digitally subtracted magnetic resonance imaging of estrogen-induced pituitary lesions in rats: correlation with pituitary anatomy.

Pituitary hypertrophy and tumors were induced in male Sprague Dawley rats using estradiol-17 beta. This tumor model generates a variety of pituitary lesions which are relevant to human pituitary disease. In order to characterize these lesions, gadolinium DTPA was injected intravenously into the tail vein of estrogen treated and control rats. High resolution T1-weighted MR images, pre- and postenhancement, were obtained at 8 different time points spanning 300 days following the subcutaneous implantation of the estrogen pellets. Images with 2-mm slice thickness were made with a 2 Telsa small-bore MR imaging system. Both normal and tumorous pituitaries were found to enhance with contrast agent, but contrast uptake was not uniform. Gd-DTPA distribution was sensitive to the different types of lesions generated in the course of this study. Digital subtraction of congruent images, pre- and postcontrast, provided difference images reflecting contrast concentration and allowed identification of subtle enhancement effects. Hypertrophic pituitaries displayed uptake of contrast, but the distribution of contrast agent was nonuniform and appeared mottled. A bright rim enhancement was often seen anterior to the pituitary gland, most likely arising from the oculomotor nerves and arachnoid. Histological slices in the same anatomical plane as the MR images were obtained on the animals allowing identification of individual lesions. Cystic areas within tumors were found to give strong contrast enhancement in less than five min postinjection. Solid and hemorrhagic areas of the pituitary tumor were hypo- to isointense relative to surrounding brain and did not take up contrast agent. Significant perfusion in these areas apparently does not occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Prediction of employability in schizophrenic patients.

This study, the third of a series of reports on employability and schizophrenia, investigated the effects of both interview and non-interview variables on employability. Data on 46 chronic schizophrenic inpatients included demographic and illness-related variables, measures of psychopathology and interview-based ratings of employment skill. Latent class analysis using linear structural relations (LISREL) modelling generated the main finding namely, that interview-based measures are the strongest determinants of employability. However, other variables pertaining to illness, prior functioning and negative symptoms, exert an effect on interview performance and hence indirectly influence employability ratings and judgements.

Activities of Daily Living↗