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At least 1,261 records · Page 70Linked to original sources
PubMed1996

Refined structure of lac repressor headpiece (1-56) determined by relaxation matrix calculations from 2D and 3D NOE data: change of tertiary structure upon binding to the lac operator.

The solution structure of the DNA binding domain of lac repressor (headpiece 1-56; HP56) has been refined using data from 2D and 3D NMR spectroscopy. The structure was derived from 1546 restraints (giving an average of 27.6 per residue), comprising 389 intraresidual, 402 sequential, 385 medium range and 325 long range distance restraints and also 30 phi and 15 chi 1 dihedral angle restraints. The structures were determined by the method of direct refinement against nuclear Overhauser enhancement peak volumes with the program DINOSAUR. The final set of 32 selected structures displayed an r.m.s. deviation from the average of 0.43(+/-0.08) A angstroms (backbone) and 0.95(+/-0.08) angstroms (all heavy atoms) for the best defined region of the protein (residues 3 to 49). The ensemble R-factor was 0.35, which indicates close correspondence with the experimental data. The structures revealed good stereochemical qualities. The conformations of the NMR structures of free and DNA complexed lac repressor headpiece were compared. The regions comprising the secondary structure elements show close correspondence for both conformations. However, the conformation of the loop between helix II and III changes considerably upon complexation of the headpiece. This change in the conformation of the loop in lac HP56 is essential for binding of the side-chains of residues Asn25 and His29 to the lac operator DNA. Finally, the lac headpiece residues that are intolerant to mutations were analysed. Most of these mutation-sensitive residues are important for a correct folding of the headpiece region, and a number of these residues are also involved in contacting the operator DNA.

Crystallography, X-Ray↗
PubMed1996

The role of high-order phase correlations in texture processing.

Isodipole textures are pairs of texture ensembles whose autocorrelations, and hence power spectra, are equal. Examples of readily discriminable isodipole textures are well known. Such discriminations appear to require feature extraction, since the isodipole condition eliminates ensemble differences in spatial frequency content. We studied the effects of phase decorrelation on VEP indices of discrimination of isodipole texture pairs. Phase decorrelation, which ranged from 0.125 pi radians (slight randomization) to pi radians (complete randomization), was introduced in two ways: by independent jittering of each spatial Fourier component, and by a product method, which preserved correlations among certain quadruples of spatial Fourier components, despite pairwise decorrelation. For the even/random isodipole texture pair, independent phase decorrelation greater than 0.5 pi radians markedly reduced VEP indices of texture discrimination for all check sizes, and eliminated them entirely for check sizes of 8 min or greater. However, the product method preserved texture discrimination signals even with complete pairwise randomization of spatial phases. For the triangle/random isodipole texture pair, both kinds of phase decorrelation eliminated VEP indices of texture discrimination. These results imply that isodipole texture discrimination is based on fundamentally local processing, and not on global Fourier amplitudes-since the phase manipulations which eliminate texture discrimination preserve the Fourier amplitudes. The dependence of the antisymmetric response component (the odd harmonics) on phase decorrelation and texture type is consistent with a previously proposed model for feature extraction, and leads to constraints on how texture processing is modulated by contrast. The limited contribution of global spectral characteristics for small checks is consistent with a previously identified breakdown in scale-invariant processing.

Adult↗
PubMed2026

Linking MRI radiomics to transcriptomics-based radiosensitivity in lower-grade glioma: A radiogenomic framework.

BACKGROUND: RSI is a transcriptomics-based biomarker associated with radiotherapy outcomes, but its clinical application is constrained by the requirement for tumor tissue and RNA sequencing. This study investigates whether MRI-derived radiomic features can reflect RSI-defined intrinsic radiosensitivity in lower-grade glioma.This addresses a critical gap arising from the limited availability of matched imaging and genomic data in routine clinical practice. METHODS: MRI-derived radiomic features were extracted from FLAIR images of lower-grade glioma patients obtained from TCIA and matched with transcriptomic data from TCGA. A total of 107 patients with both MRI and RNA sequencing data were included in the radiogenomic analysis. Radiomic features were ranked using a Borda-based ensemble feature selection strategy. Five supervised machine-learning classifiers were trained to predict RSI-based radiosensitivity classification, and model interpretability was assessed using SHAP within radiogenomic framework. RESULTS: Classification performance increased with feature number and stabilized at compact subset of 13 radiomic features. Logistic regression showed stable performance with an AUC of 0.82 (95 % CI: 0.71-0.93). SHAP analysis indicated that heterogeneity-related texture features were dominant contributors to model predictions, with many associated with the RR phenotype, while others were linked to the RS phenotype. CONCLUSION: An MRI-based radiomic signature enables non-invasive prediction of RSI-defined radiosensitivity in lower-grade glioma. Rather than offering an immediately deployable clinical tool, this study establishes a proof-of-concept radiogenomic framework demonstrating that intrinsic radiosensitivity, traditionally assessed through invasive molecular assays, can be approximated using quantitative imaging features. These findings highlight the potential of imaging-based radiosensitivity assessment and provide a foundation for future radiogenomic investigations.

Lower-grade glioma↗
PubMed2003

Aromatic and methyl NOEs highlight hydrophobic clustering in the unfolded state of an SH3 domain.

The N-terminal SH3 domain of Drosophila drk (drkN SH3 domain) exists in equilibrium between a folded (F(exch)) state and a relatively compact unfolded (U(exch)) state under nondenaturing conditions. Selectively labeled samples of the domain have been analyzed by NOESY NMR experiments to probe residual hydrophobic clustering in the U(exch) state. The labeling strategy included selective protonation of aromatic rings or delta-methyl groups on Ile and Leu residues in a highly deuterated background. Combined with long mixing times, the methods permitted observation of significant numbers of long-range interactions between hydrophobic side chains, providing evidence for multiple conformers involving non-native hydrophobic clusters around the Trp 36 indole. Comparison of these data with previously reported HN-HN NOEs yields structural insight into the diversity of structures within the U(exch) ensemble in the drkN SH3 domain. Many of the HN-HN NOEs are consistent with models containing compact residual nativelike secondary structure and greater exposure of the Trp 36 indole to solvent, similar to kinetic intermediates formed in the hierarchic condensation model of folding. However, the methyl and aromatic NOE data better fit conformations with non-native burial of the Trp indole surrounded by hydrophobic groups and more loosely formed beta-structure; these structural characteristics are more consistent with those of kinetic intermediates formed during the hydrophobic collapse mechanism of folding. This suite of NOE data provides a more complete picture of the structures that span the U(exch) state ensemble, from conformers with non-native structure but long-range contacts to those that are highly nativelike. Together, the results are also consistent with the folding funnel view involving multiple folding pathways for this molecule.

Animals↗
PubMed1998

Conformational energy penalties of protein-bound ligands.

The conformational energies required for ligands to adopt their bioactive conformations were calculated for 33 ligand-protein complexes including 28 different ligands. In order to monitor the force field dependence of the results, two force fields, MM3* and AMBER*, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessible surface (GB/SA) solvation model. The protein-bound conformations were relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand-protein complexes studied, the conformational energies of the bioactive conformations were calculated to be < or = 3 kcal/mol. It is demonstrated that the aqueous conformational ensemble for the unbound ligand must be used as a reference state in this type of calculations. The calculations for the ligand-protein complexes with conformational energy penalties of the ligand calculated to be larger than 3 kcal/mol suffer from uncertainties in the interpretation of the experimental data or limitations of the computational methods. For example, in the case of long-chain flexible ligands (e.g. fatty acids), it is demonstrated that several conformations may be found which are very similar to the conformation determined by X-ray crystallography and which display significantly lower conformational energy penalties for binding than obtained by using the experimental conformation. For strongly polar molecules, e.g. amino acids, the results indicate that further developments of the force fields and of the dielectric continuum solvation model are required for reliable calculations on the conformational properties of this type of compounds.

Binding Sites↗
PubMed2000

Sequence-specific binding of counterions to B-DNA.

Recent studies by x-ray crystallography, NMR, and molecular simulations have suggested that monovalent counterions can penetrate deeply into the minor groove of B form DNA. Such groove-bound ions potentially could play an important role in AT-tract bending and groove narrowing, thereby modulating DNA function in vivo. To address this issue, we report here (23)Na magnetic relaxation dispersion measurements on oligonucleotides, including difference experiments with the groove-binding drug netropsin. The exquisite sensitivity of this method to ions in long-lived and intimate association with DNA allows us to detect sequence-specific sodium ion binding in the minor groove AT tract of three B-DNA dodecamers. The sodium ion occupancy is only a few percent, however, and therefore is not likely to contribute importantly to the ensemble of B-DNA structures. We also report results of ion competition experiments, indicating that potassium, rubidium, and cesium ions bind to the minor groove with similarly weak affinity as sodium ions, whereas ammonium ion binding is somewhat stronger. The present findings are discussed in the light of previous NMR and diffraction studies of sequence-specific counterion binding to DNA.

Base Sequence↗
PubMed1988

Physiological responses to the wearing of fire fighter's turnout gear with neoprene and GORE-TEX barrier liners.

This study examined the physiological effects of performing moderate and high intensity work while wearing fire fighter's turnout gear with either a neoprene or GORE-TEX barrier liner. Eight healthy men, experienced with the use of respirators and protective clothing, each performed moderate and high intensity treadmill exercise (44% and 71% of maximum work capacity) in a double-blind study at 27.6 degrees C (50% RH) while wearing complete fire fighter's turnout gear (weighing 23 kg) with either a neoprene or GORE-TEX barrier liner. Physiological measurements obtained included minute ventilation, heart rate, skin temperature, rectal temperature and sweat rate. Subjective evaluations of perceived exertion, comfort, clothing breathability, temperature and perspiration also were obtained. Tests were terminated (tolerance time) when objective or subjective signs of near maximal stress were observed (i.e., 90% of the maximum heart rate, rectal temperature of 39 degrees C, dizziness, etc.). Mean tolerance times for the moderate intensity exercise were 27.4 (+/- 7.3 S.D.) and 30.9 (+/- 7.9) min, respectively, for the neoprene and GORE-TEX barrier liners and at the high intensity were 7.2 (+/- 2.1) and 7.5 (+/- 2.3) min, respectively. Analysis of variance indicated that significant differences caused by liner were observed in skin temperature (0.6 degrees C higher with the neoprene ensemble). No significant differences caused by liner were seen in tolerance time, heart rate, sweat rate or subjective ratings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Tracing the evolution of RNA structure in ribosomes.

The elucidation of ribosomal structure has shown that the function of ribosomes is fundamentally confined to dynamic interactions established between the RNA components of the ribosomal ensemble. These findings now enable a detailed analysis of the evolution of ribosomal RNA (rRNA) structure. The origin and diversification of rRNA was studied here using phylogenetic tools directly at the structural level. A rooted universal tree was reconstructed from the combined secondary structures of large (LSU) and small (SSU) subunit rRNA using cladistic methods and considerations in statistical mechanics. The evolution of the complete repertoire of structural ribosomal characters was formally traced lineage-by-lineage in the tree, showing a tendency towards molecular simplification and a homogeneous reduction of ribosomal structural change with time. Character tracing revealed patterns of evolution in inter-subunit bridge contacts and tRNA-binding sites that were consistent with the proposed coupling of tRNA translocation and subunit movement. These patterns support the concerted evolution of tRNA-binding sites in the two subunits and the ancestral nature and common origin of certain structural ribosomal features, such as the peptidyl (P) site, the functional relay of the penultimate stem helix of SSU rRNA, and other structures participating in ribosomal dynamics. Overall results provide a rare insight into the evolution of ribosomal structure.

Animals↗
PubMed1995

Onset timing of electromyographic activity in the vastus medialis oblique and vastus lateralis muscles in subjects with and without patellofemoral pain syndrome.

BACKGROUND AND PURPOSE: Inappropriate neural control of the quadriceps femoris muscle group has been implicated in patellofemoral pain syndrome (PFPS). This study investigated the timing of initial electromyographic (EMG) activity of the vastus medialis oblique muscle (VMO) and the vastus lateralis muscle (VL) in asymptomatic subjects and subjects with PFPS during reflex and voluntary muscle activity. SUBJECTS: Fifteen symptomatic subjects (SYMP group) (9 with bilateral symptoms) and 12 asymptomatic subjects (ASYMP group) participated. Both knees were tested in the ASYMP group and only the symptomatic knees were tested in the SYMP group, resulting in a total of 24 data sets from each group. METHODS: Electromyographic data were recorded from the VMO and VL under three conditions: reflex knee extension (RFLX) elicited by a patellar tendon tap, and active knee extension in non-weight-bearing (NWB) and weight-bearing (WB) situations. For each condition, EMG activity onset times for the VMO and VL were determined from ensemble averages of four trials. RESULTS: There were no differences between the SYMP and ASYMP groups with respect to the relative timing of initial VMO and VL activity under any of the three conditions tested. Mean timing differences for both groups were less than 0.25 milliseconds under reflex conditions and less than 4 milliseconds for active knee extension under both WB and NWB conditions. CONCLUSION AND DISCUSSION: These findings contradict a previous report of differences in reflex timing related to PFPS. Differences in the relative timing of onset of EMG activity of the VMO and VL during voluntary knee extension were not significant between SYMP and ASYMP groups, and were not related to the relative timing differences observed during reflex testing.

Adolescent↗
PubMed1998

Impedance cardiography applied to maximal arm cranking exercise: a matter of sampling and processing strategy.

PURPOSE: A new ensemble-averaging (EA) approach was developed with the goal of investigating central hemodynamics by transthoracic impedance cardiography during maximal arm cranking. This EA procedure of the first time derivative of impedance changes (dZ/dt) over several cardiac cycles differs from previously reported techniques with respect to cycle selection strategy, according to fixed criteria, and processing methods. METHODS: First, the primary elements of the Kubicek stroke volume (SV) formula, as determined by EA, were compared with the values determined by the standard hand-processing (HP) method over a large range of cardiac outputs. RESULTS: Results showed a very high reliability for ventricular ejection time (r = 0.996), (dZ/dt)min (r = 0.995), SV (r = 0.977), and heart rate (r = 0.999). Second, the EA procedure was applied to six subjects performing a continuous, multistage arm cranking test to volitional fatigue. The present technique allowed for an effective filtering of movement and breathing artifacts of the original signal. Thus, interpretation of the dZ/dt wave form was convenient, even at maximal arm cranking power outputs up to 120 W. Stroke volume ranged from 63.83 to 127.18 mL.beat-1, showing no significant variations with oxygen consumption. Cardiac output increased linearly with oxygen uptake, reaching a mean maximal value of 16 L.min-1. CONCLUSION: The present procedure opens a new field of application to impedance cardiography, permitting to measure cardiac output during maximal arm cranking exercise.

Adult↗
PubMed2005

Noise characterization of block-iterative reconstruction algorithms: II. Monte Carlo simulations.

In Soares et al. (2000), the ensemble statistical properties of the rescaled block-iterative expectation-maximization (RBI-EM) reconstruction algorithm and rescaled block-iterative simultaneous multiplicative algebraic reconstruction technique (RBI-SMART) were derived. Included in this analysis were the special cases of RBI-EM, maximum-likelihood EM (ML-EM) and ordered-subset EM (OS-EM), and the special case of RBI-SMART, SMART. Explicit expressions were found for the ensemble mean, covariance matrix, and probability density function of RBI reconstructed images, as a function of iteration number. The theoretical formulations relied on one approximation, namely that the noise in the reconstructed image was small compared to the mean image. In this paper, we evaluate the predictions of the theory by using Monte Carlo methods to calculate the sample statistical properties of each algorithm and then compare the results with the theoretical formulations. In addition, the validity of the approximation will be justified.

Algorithms↗
PubMed1993

Biological rhythms as organization and information.

While it is generally acknowledged that modern science began with the quantification of time in the measurement of linear physical processes in space by Galileo and Newton, the biological sciences have only recently developed appropriate experimental and mathematical methods for the description of living systems in terms of processes of non-linear, recursive dynamics. We now recognize that living organisms have patterns of exquisitely timed processes that are as intricate as their spatial structure and organization. Self-similarities of life processes in time and space have evolved to generate an ensemble of oscillators within which analogous functions may be discerned on many different time scales. The increasing complexity of periodic relationships on and between the many levels of biological organization are uncovered by current research. Recent efforts to reformulate the foundation of physics from the quantum to the cosmological level by using the concept of information as the common denominator integrating time, structure and energy remind us of an apparently analogous suggestion in the chronobiological literature which also describes the periodic dynamics of living systems as information processing. In this paper we review the periodic processes of living systems on all levels from the molecular, genetic and cellular to the neuroendocrinological, behavioural and social domains. Biological rhythms may be conceptualized as the evolution of ever more complex dynamics of information transduction that optimize the temporal integrity, development, and survival of the organism.

Animals↗
PubMed2000

A lesion detectability simulation method for digital x-ray imaging.

A simulation method is described in this work that aids in quantifying the upper limits of lesion detectability as a function of lesion size, lesion contrast, pixel size, and x-ray exposure for digital x-ray imaging systems. The method entails random lesion placement with subsequent simulated imaging on idealized x-ray detectors with no additive noise and 100% quantum detective efficiency. Lesions of different size and thickness were simulated. Mean (expectation) lesion signal-to-noise ratios (LSNRs) were calculated and receiver operating characteristic (ROC) curves were constructed based on LSNR ensembles. Mean (expectation) values of the areas under the ROC curves were calculated for lesions of varying size on pixel arrays of varying size at different exposures. Analyses were performed across several parameters, including lesion size, pixel size, and exposure levels representative of various areas of radiography. As expected, lesion detectability increased with lesion size, contrast, pixel size, and exposure. The model suggests that lesion detectability is strongly dependent on the relative alignment (phase) of the lesion with the pixel matrix for lesions on the order of the pixel size.

Biophysical Phenomena↗
PubMed1999

Efficacy of air and liquid cooling during light and heavy exercise while wearing NBC clothing.

BACKGROUND: Studies, to date, have not revealed the extent to which the heat strain of continuous heavy exercise while wearing NBC protective clothing can be reduced by providing liquid- or air-cooling and whether one system is more effective than the other in aiding heat transfer from the body and the clothing. It was of interest to know to what extent present-day cooling technologies can reduce the heat strain of light and heavy exercise in NBC clothing and to compare these reductions to other strategies that have employed changes in clothing design. HYPOTHESIS: It was hypothesized that there would be no difference between the liquid and air cooling systems and that sufficient cooling power would be delivered to the body to reduce the heat strain of heavy exercise to a level similar to that experienced with light exercise when no cooling was provided. METHODS: Eight males performed 6 randomized exposures for a maximum of 3 h at 40 degrees C and 30% relative humidity that involved either light (L) (walking at 3.5 km x h(-1) or heavy (H) (walking at 4.8 km x h(-1) and a 5% grade) exercise while wearing the NBC protective clothing ensemble with no cooling (N), liquid (L) or air (A) cooling. RESULTS: For L exercise, tolerance time was significantly increased from 100 min with N to the maximum of 3 h with either cooling system. There was no difference between L and A cooling in the extent of the changes in rectal temperature, heart rate and heat flow. For H exercise, tolerance time was significantly increased 150% from 57 min with N to 149 min with L and 140 min with A. These latter values for HL and HA were not different from each other but both were significantly greater than L exercise with N. Rectal temperature increased more quickly during HL compared with HA during the first 60 min of exposure but there were no differences between cooling trials for the remainder of the heat exposure. CONCLUSIONS: It was concluded that sufficient cooling power could be delivered to the body to effectively reduce the heat strain of wearing NBC protective clothing during heavy exercise in a hot environment to a level comparable to or slightly lower than that experienced with light exercise and no cooling.

Air↗
PubMed2002

Rapid generation of a representative ensemble of N-glycan conformations.

Glycosylated proteins are ubiquitous components of extracellular matrices and cellular surfaces where their oligosaccharide moieties are implicated in a wide range of cell-cell and cell-matrix recognition events. Glycans constitute highly flexible molecules. Only a small number of glycan X-ray structures is available for which sufficient electron density for an entire oligosaccharide chain has been observed. An unambiguous structure determination based on NMR-derived geometric constraints alone is often not possible. Time consuming computational approaches such as Monte Carlo calculations and molecular dynamics simulations have been widely used to explore the conformational space accessible to complex carbohydrates. The generation of a comprehensive data base for N-glycan fragments based on long time molecular dynamics simulations is presented. The fragments are chosen in such a way that the effects of branched N-glycan structures are taken into account. The prediction database constitutes the basis of a procedure to generate a complete set of all possible conformations for a given N-glycan. The constructed conformations are ranked according to their energy content. The resulting conformations are in reasonable agreement with experimental data. A web interface has been established (http://www.dkfz.de/spec/glydict/), which enables to input any N-glycan of interest and to receive an ensemble of generated conformations within a few minutes.

Carbohydrate Conformation↗
PubMedDate not supplied

Sensitivity analysis of kernel estimates: implications in nonlinear physiological system identification.

Many techniques have been developed for the estimation of the Volterra/Wiener kernels of nonlinear systems, and have found extensive application in the study of various physiological systems. To date, however, we are not aware of methods for estimating the reliability of these kernels from single data records. In this study, we develop a formal analysis of variance for least-squares based nonlinear system identification algorithms. Expressions are developed for the variance of the estimated kernel coefficients and are used to place confidence bounds around both kernel estimates and output predictions. Specific bounds are developed for two such identification algorithms: Korenberg's fast orthogonal algorithm and the Laguerre expansion technique. Simulations, employing a model representative of the peripheral auditory system, are used to validate the theoretical derivations, and to explore their sensitivity to assumptions regarding the system and data. The simulations show excellent agreement between the variances of kernel coefficients and output predictions as estimated from the results of a single trial compared to the same quantities computed from an ensemble of 1000 Monte Carlo runs. These techniques were validated with white and nonwhite Gaussian inputs and with white Gaussian and nonwhite non-Gaussian measurement noise on the output, provided that the output noise source was independent of the test input.

Algorithms↗
PubMed2001

RNA folding pathway functional intermediates: their prediction and analysis.

The massively parallel genetic algorithm (GA) for RNA structure prediction uses the concepts of mutation, recombination, and survival of the fittest to evolve a population of thousands of possible RNA structures toward a solution structure. As described below, the properties of the algorithm are ideally suited to use in the prediction of possible folding pathways and functional intermediates of RNA molecules given their sequences. Utilizing Stem Trace, an interactive visualization tool for RNA structure comparison, analysis of not only the solution ensembles developed by the algorithm, but also the stages of development of each of these solutions, can give strong insight into these folding pathways. The GA allows the incorporation of information from biological experiments, making it possible to test the influence of particular interactions between structural elements on the dynamics of the folding pathway. These methods are used to reveal the folding pathways of the potato spindle tuber viroid (PSTVd) and the host killing mechanism of Escherichia coli plasmid R1, both of which are successfully explored through the combination of the GA and Stem Trace. We also present novel intermediate folds of each molecule, which appear to be phylogenetically supported, as determined by use of the methods described below.

Algorithms↗
PubMed2006

Analysis of EMG patterns of control subjects and subjects with ACL deficiency during an unanticipated walking cut task.

PURPOSE: The purpose of this study was to describe the muscle activation patterns of the vastus lateralis (VL), medial hamstrings (MH) and lateral hamstrings (LH) associated with subjects that were anterior cruciate ligament (ACL) deficient and controls. METHODS: A total of 54 subjects participated in this study including 25 ACL deficient subjects subdivided into copers (n=9) and non-copers (n=16) using clinical criteria. Muscle activation patterns were recorded at 1000 Hz during an unanticipated side step cut task. The root mean square processed data (time constant 11 ms) were ensemble averaged from 20% of stance before heel strike to toe off. Using the first five harmonics of the Fourier Coefficients as features, muscle activation patterns were divided using a cluster analysis algorithm. RESULTS: A majority (76-93%) of control subjects used three muscle activation patterns for each muscle. The coper group preferentially used a particular VL and MH activation pattern >2 times more frequently than controls. The non-coper group also preferentially used a MH activation pattern >2 times more frequently than controls and utilized a unique MH and LH activation pattern, distinct from the copers and controls. CONCLUSIONS: Specific muscle activation patterns distinguish subsets of subjects that are healthy and injured, suggesting possible patterns of muscle activation that contribute to coping status.

Adaptation, Physiological↗