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PubMed2025

Metagenomic analyses reveal E. coli-derived siderophores as potential signatures for breast cancer.

BACKGROUND: Breast cancer remains a leading cause of cancer-related mortality in women. Recent evidence implicates the gut microbiome and metabolites in breast cancer pathogenesis. This study explores associations between gut microbial species, their predicted metabolites, and breast cancer to uncover potential mechanistic insights. METHODS: Comprehensive metagenomic analyses were conducted on the gut microbiome of pre- and postmenopausal breast cancer patients, where microbial species were profiled through AMPHORA2 and metabolites were predicted through antiSMASH. Multivariate association analysis was used to identify significant associations between specific microbial species, predicted metabolites, and breast cancer status. A custom ensemble machine learning classifier was developed to classify pre- and postmenopausal breast cancer cases and controls based on microbial and predicted metabolite features. Additionally, a synthetic microbiome dataset was generated through MIDASim to validate the reproducibility of the ML results. Using our results, we explored the underlying dynamics of identified taxa and metabolite in breast cancer through literature and statistical support. RESULTS: Our analysis identified 471 microbial species and predicted 40 key metabolites in the metagenomic data. Multivariate analysis identified significant positive associations (p-value < 0.05) of E. coli, siderophore, and thiopeptide with breast cancer. The custom ensemble model achieved accuracy and AUC as high as 78% and 90%, respectively, in classifying pre- and postmenopausal cases and controls. The high-ranking features i.e., E. coli, siderophore, and thiopeptide were consistent with the results of the multivariate association analysis, thereby substantiating their biological significance. Using these findings, we propose a mechanistic model in which E. coli secretes siderophores under iron-limited conditions in breast cancer patients, for iron sequestration from the host, which can potentially promote angiogenesis and tumor progression. CONCLUSION: Our findings suggest that microbial iron acquisition mechanisms may play a critical role in breast cancer pathophysiology. Functional validation of these mechanisms is needed to assess therapeutic potential. This study highlights gut microbiota and their metabolites as promising targets for breast cancer research and intervention.

Breast Neoplasms↗

PubMed2006

Sub-angstrom conformational changes of a single molecule captured by AFM variance analysis.

A system's equilibrium variance can be analyzed to probe its underlying dynamics at higher resolution. Here, using single-molecule atomic-force microscope techniques, we show how the variance in the length of a single dextran molecule can be used to establish thermodynamic equilibrium and to detect conformational changes not directly observable with other methods. Dextran is comprised of a chain of pyranose rings that each undergoes an Angstrom-scale transition from a chair to boat conformation under a stretching force. Our analysis of the variance of the molecule's fluctuations verifies equilibrium throughout the force-extension curve, consistent with the expected thermodynamic ensemble. This validates further analysis of the variance in the transition region, which reveals an intermediate conformation between the chair and the boat on the sub-Angstrom scale. Our test of thermal equilibrium as well as our variance analysis can be readily extended to a wide variety of molecules, including proteins.

Analysis of Variance↗

PubMed2006

Protective clothing in hot environments.

The high level of protection required by personal protective clothing (PPC) severely impedes heat exchange by sweat evaporation. As a result work associated with wearing PPC, particularly in hot environments, implies considerable physiological strain and may render workers exhausted in a short time. Recent development of algorithms for describing the heat transfer, accounting for pumping and wind effects, comprises improvement of the prediction of thermal stress. Realistic corrections can then be made to the available measures of thermal insulation and evaporative resistance of a given clothing ensemble. Currently this information is incorporated in international standards for assessment of thermal environments. Factors, such as directional radiation and wetting of layers, were studied in a recently completed EU research project. The development of advanced thermal manikins and measurement procedures should provide better measures for predictive models. As with all methods and models, the results need validation in realistic wear trials in order to prove their relevance and accuracy.

Europe↗

PubMed2006

Efficiency of liquid cooling garments: prediction and manikin measurement.

INTRODUCTION: We studied the efficiency of liquid cooling garments (LCG) and their relationship to the insulation of outer clothing, perfusate inlet temperatures, and environmental conditions by both theoretical analysis and thermal manikin (TM) testing. METHODS: An equation to estimate LCG cooling efficiency was developed on the basis of energy balance. Cooling efficiency is a function of the thermal resistance between the TM skin and perfusate in the LCG, the thermal resistance between the environment and the perfusate, and TM skin, ambient, and perfusate temperatures. Three ensembles, a cooling vest (CV) only, CV plus a battle dress uniform (CVB), and CVB plus a battle dress overgarment (CVO), were tested on a sweating TM in dry and wet conditions. The TM surface temperature was maintained at 33 degrees C and the environment was 30 degrees C and 50% RH. The LCG heat removal from the TM was calculated using the power inputs to the TM with and without perfusate flow. RESULTS: The cooling efficiency was increased from approximately 0.45 for CV to approximately 0.70 for CVO in dry experiments and from approximately 0.53 for CV to 0.78 for CVO in wet experiments. CONCLUSION: With additional outer clothing layers, higher thermal resistances increased the rate of heat removal from the TM surface, and decreased heat gain from the ambient environment, thus increasing efficiency. The perfusate inlet temperature had minimal influence on the efficiency. The equations developed can predict cooling efficiency and heat removal rates under a wider range of environmental conditions.

Body Temperature Regulation↗

PubMed2004

Predicting interactions of winged-helix transcription factors with DNA.

Determining protein-DNA interactions is important for understanding gene regulation, DNA repair and chromatin structure. Unfortunately, the structures of DNA-bound complexes are often difficult to obtain experimentally, so the development of computational methods that provide good models of these complexes would be valuable. Here, we present a rigid-body docking approach using the computer program DOT. DOT performs a complete, six-dimensional search of all orientations for two rigid molecules and calculates the interaction energy as the sum of electrostatic and van der Waals terms. DOT was applied to three winged-helix transcription factors that share similar DNA-binding structural motifs but bind DNA in different ways. Docking with linear B-form DNA models accomplished several objectives; it (1) distinguished the different ways the transcription factors bind DNA, (2) identified each protein's DNA-binding site and the DNA orientation at the site and (3) gave at least one solution among the three best-ranked that shows the protein side chain-DNA base interactions responsible for recognition. Furthermore, the ensemble of top-ranked, docked linear B-DNA fragments indicated the DNA bending induced upon protein binding. Docking linear B-DNA to structures of the transcription factor FadR suggests that the allosteric, conformational change induced upon effector binding results in loss of the ability to bend DNA as well as loss of sequence-specific interactions with DNA. The electrostatic energy term calculated by DOT is comparable to the electrostatic binding energy calculated by Poisson-Boltzmann methods. Our results show rigid-body docking that includes a rigorous treatment of the electrostatic interaction energy can be effective in predicting protein-DNA interactions.

Bacterial Proteins↗

PubMed1997

Tensioactivity and supramolecular organization of the palmitoyl prodrug of timolol.

PURPOSE: To improve the bioavailability of the ocular drug timolol by facilitating its transport through the cornea, an amphiphilic prodrug was synthesized via the addition of a palmitic chain by esterification. The present study was undertaken to investigate the physicochemical and tensioactive properties of the prodrug. METHODS: The amphiphilic properties of the prodrug were firstly investigated by the Wilhelmy plate method. The textures generated by the supramolecular organizations of the ester were visualized by optical microscopy. RESULTS: The prodrug clearly decreased the surface tension. Optical microscopy provided excellent evidence for the existence of lyotropic liquid crystalline phases: two isotropic but organized phases and a birefringent lamellar phase. CONCLUSIONS: The results from the ensemble of studies undertaken to determine the amphiphilic properties of the prodrug were all in accord with its ability to form liquid crystalline phases. The liquid crystalline state of the prodrug is believed to introduce a delay in the drug pharmacological effect.

Adrenergic beta-Antagonists↗

PubMed2004

Bridging continuum and statistical thermodynamics via equations of state and the density of states.

The connection between molecular force fields and equations of state (EoS) is typically established at the level of predicted quantities, e.g., by comparing simulation data and EoS data. In this paper we show how an EoS can be used to extract the density of states (Omega) of a system thus establishing a deeper connection between EoSs and statistical thermodynamics. We also show how such an EoS Omega can be used to aid molecular simulation methods designed to map out Omega (like the multicanonical approach). Central to the implementation of these ideas is the fact that the configurational Omega is related to thermodynamic properties accessible by an EoS via Boltzmann's equation. Sample calculations are presented for the Omega relevant to isothermal-isobaric and grand canonical ensemble simulations using the hard-sphere system and the Lennard-Jones system as model fluids, and the Carnahan-Starling EoS and a cubic EoS, respectively, as thermodynamic models.

Journal Article↗

PubMed2002

Computational antisense oligo prediction with a neural network model.

MOTIVATION: The expression of a gene can be selectively inhibited by antisense oligonucleotides (AOs) targeting the mRNA. However, if the target site in the mRNA is picked randomly, typically 20% or less of the AOs are effective inhibitors in vivo. The sequence properties that make an AO effective are not well understood, thus many AOs need to be tested to find good inhibitors, which is time consuming and costly. So far computational models have been based exclusively on RNA structure prediction or motif searches while ignoring information from other aspects of AO design into the model. RESULTS: We present a computational model for AO prediction based on a neural network approach using a broad range of input parameters. Collecting sequence and efficacy data from AO scanning experiments in the literature generated a database of 490 AO molecules. Using a set of derived parameters based on AO sequence properties we trained a neural network model. The best model, an ensemble of 10 networks, gave an overall correlation coefficient of 0.30 (p=10(-8)). This model can predict effective AOs (>50% inhibition of gene expression) with a success rate of 92%. Using these thresholds the model predicts on average 12 effective AOs per 1000 base pairs, making it a stringent yet practical method for AO prediction.

Algorithms↗

PubMed2000

Distillation of Greenberger-Horne-Zeilinger states by selective information manipulation.

Methods for distilling Greenberger-Horne-Zeilinger (GHZ) states from arbitrary entangled tripartite pure states are described. These techniques work for virtually any input state. Each technique has two stages which we call primary and secondary distillations. Primary distillation produces a GHZ state with some probability, so that when applied to an ensemble of systems a certain percentage is discarded. Secondary distillation produces further GHZs from the discarded systems. These protocols are developed with the help of an approach to quantum information theory based on absolutely selective information, which has other potential applications.

Information Theory↗

PubMed2004

Predicting the threshold of pulse-train electrical stimuli using a stochastic auditory nerve model: the effects of stimulus noise.

The incorporation of low levels of noise into an electrical stimulus has been shown to improve auditory thresholds in some human subjects (Zeng et al., 2000). In this paper, thresholds for noise-modulated pulse-train stimuli are predicted utilizing a stochastic neural-behavioral model of ensemble fiber responses to bi-phasic stimuli. The neural refractory effect is described using a Markov model for a noise-free pulse-train stimulus and a closed-form solution for the steady-state neural response is provided. For noise-modulated pulse-train stimuli, a recursive method using the conditional probability is utilized to track the neural responses to each successive pulse. A neural spike count rule has been presented for both threshold and intensity discrimination under the assumption that auditory perception occurs via integration over a relatively long time period (Bruce et al., 1999). An alternative approach originates from the hypothesis of the multilook model (Viemeister and Wakefield, 1991), which argues that auditory perception is based on several shorter time integrations and may suggest an NofM model for prediction of pulse-train threshold. This motivates analyzing the neural response to each individual pulse within a pulse train, which is considered to be the brief look. A logarithmic rule is hypothesized for pulse-train threshold. Predictions from the multilook model are shown to match trends in psychophysical data for noise-free stimuli that are not always matched by the long-time integration rule. Theoretical predictions indicate that threshold decreases as noise variance increases. Theoretical models of the neural response to pulse-train stimuli not only reduce calculational overhead but also facilitate utilization of signal detection theory and are easily extended to multichannel psychophysical tasks.

Algorithms↗

PubMed2004

"Proprioceptive signature" of cursive writing in humans: a multi-population coding.

The goal of the present study was to investigate the firing behavior of populations of muscle spindle afferents in all the muscles acting on the ankle while this joint was being subjected to "writing-like" movements. First it was proposed to determine whether the ensemble of muscle spindles give rise to a unique, specific, and reproducible feedback information characterizing each letter, number or short word. Secondly, we analyzed how the proprioceptive feedback on the whole encodes the spatial and temporal characteristics of writing movements using the "vector population model". The unitary activity of 51 primary and secondary muscle spindle afferents was recorded in the tibial and common peroneal nerves at the level of the popliteal fossea, using the microneurographic method. The units recorded from belonged to the tibialis anterior, the extensor digitorum longus, the extensor hallucis longus, the peroneus lateralis, the gastrocnemius-soleus and the tibialis posterior muscles. The "writing-like" movements were randomly imposed at a "natural" velocity via a computer-controlled machine in a two-dimensional space. In general, muscle spindle afferents from any of the six muscles responded according to the tuning properties of the parent muscle, i.e. increasing their discharge rate during the phases where the direction of movement was within the preferred sensory sector of the parent muscle. The whole trajectory of the writing movements was coded in turn by the activity of Ia afferents arising from all the muscles acting on the joint. Both single afferent responses and population responses were found to be highly specific and reproducible with each graphic sign. The complex multi-muscle afferent pattern involved, with its timing and distribution in the muscle space, seems to constitute a true "proprioceptive signature" for each graphic symbol. The ensemble of muscle spindle afferents were therefore found to encode the instantaneous direction and velocity of writing movements remarkably accurately. It was concluded that the proprioceptive feedback from all the muscles with which the moving joint is equipped provides the CNS with highly specific information that might contribute to a graphic sign identification process.

Action Potentials↗

PubMed1993

"Ensemble" iterative relaxation matrix approach: a new NMR refinement protocol applied to the solution structure of crambin.

The structure in solution of crambin, a small protein of 46 residues, has been determined from 2D NMR data using an iterative relaxation matrix approach (IRMA) together with distance geometry, distance bound driven dynamics, molecular dynamics, and energy minimization. A new protocol based on an "ensemble" approach is proposed and compared to the more standard initial rate analysis approach and a "single structure" relaxation matrix approach. The effects of fast local motions are included and R-factor calculations are performed on NOE build-ups to describe the quality of agreement between theory and experiment. A new method for stereospecific assignment of prochiral groups, based on a comparison of theoretical and experimental NOE intensities, has been applied. The solution structure of crambin could be determined with a precision (rmsd from the average structure) of 0.7 A on backbone atoms and 1.1 A on all heavy atoms and is largely similar to the crystal structure with a small difference observed in the position of the side chain of Tyr-29 which is determined in solution by both J-coupling and NOE data. Regions of higher structural variability (suggesting higher mobility) are found in the solution structure, in particular for the loop between the two helices (Gly-20 to Pro-22).

Amino Acid Sequence↗

PubMed2005

Simulating nonequilibrium quantum fields with stochastic quantization techniques.

We present lattice simulations of nonequilibrium quantum fields in Minkowskian space-time. Starting from a nonthermal initial state, the real-time quantum ensemble in (3 + 1) dimensions is constructed by a stochastic process in an additional (5th) "Langevin-time." For the example of a self-interacting scalar field, we show how to resolve apparent unstable Langevin dynamics and compare our quantum results with those obtained in classical field theory. Such a direct simulation method is crucial for our understanding of collision experiments of heavy nuclei or other nonequilibrium phenomena in strongly coupled quantum many-body systems.

Journal Article↗

PubMed2006

Optimization and computational evaluation of a series of potential active site inhibitors of the V82F/I84V drug-resistant mutant of HIV-1 protease: an application of the relaxed complex method of structure-based drug design.

The Relaxed Complex method, an approach to structure-based drug design that incorporates the flexibilities of both the ligand and target protein, was applied to the immunodeficiency virus protease system. The control cases used AutoDock3.0.5 to dock a fully flexible version of the prospective drug JE-2147 (aka SM-319777 or KNI-764) to large ensembles of conformations extracted from conventional, all atom, explicitly solvated molecular dynamic simulations of the wild type, and the V82F/I84V drug-resistant mutant of HIV-1 protease. The best set of run parameters from the control cases produced robust results when used against 2200 different conformations of the wild-type HIV-1 protease or against 2200 conformations of the mutant. The results of the control cases, the published advice from experts, and structural intuition were used to design a new series of 23 potential active site inhibitors. The compounds were evaluated by docking them against 700 different conformations of the V82F/I84V mutant. The results of this first round of lead optimization were quite promising. Approximately one-third of that series performed at least slightly better than the parent compound, and four of those compounds displayed significantly better binding affinities against that drug-resistant mutant (within our computational model).

Amino Acid Substitution↗

PubMed1987

Mechanisms of closure of cardiac sodium channels in rabbit ventricular myocytes: single-channel analysis.

We have examined the kinetics of closure of sodium channels using single-channel recordings in cell-attached and excised membrane patches of rabbit ventricular myocytes. Sodium-channel closure was dependent on membrane potential. The closing rate initially decreased with depolarization. The rate then passed through a minimum and increased at strongly depolarized potentials. We attempted to determine the separate voltage dependence of the deactivation and inactivation rate constants using the method of Aldrich, Corey, and Stevens. In a majority of experiments, the method did not give internally consistent results. As an alternative approach, batrachotoxin was used to remove inactivation and determine the voltage dependence of deactivation rate. The deactivation rate decreased with depolarization. To account for the increase in the closing rate at strongly depolarized test potentials, one must postulate voltage dependence of inactivation. The ensemble average current relaxed with a time course that was usually best described by the sum of two exponentials. The larger of the two rate constants that described the relaxation was strongly voltage-dependent, increasing with depolarization. The larger rate constant may reflect voltage-dependent inactivation. We found evidence of two possible mechanisms for the slow component of relaxation: 1) cardiac sodium channels may open repetitively during a given depolarizing epoch, and 2) channels may return from the inactivated state with low probability and burst for as much as 200 msec with open times that are longer than those during usual gating. The slow component appears to be more prominent in cardiac muscle than in nerve and may play an important role in the control of the action potential duration and the inotropic state of the heart.

Animals↗

PubMed1992

Protective clothing against cold--performance standards as method for preventive measures.

Survival, function and comfort in the cold are dependent on a rational and cautious use of protective measures to reduce and control heat losses. International standards are now available for establishing a basis for the rational assessment of protection requirements and the subsequent selection of appropriate clothing. Protection requirements may be readily calculated by the IREQ-index (ISO/TR-11079), which specifies required resultant clothing insulation for given conditions. Performance of selected clothing ensemble can be tested by measuring the insulation value on a moveable, thermal manikin according to prEN-342. Similarly, performance of protective gloves against cold may be tested with a heated hand model (prEN-511). It is important to emphasize that the outlined procedure should only be applied as a guide-line for action. Due to considerable individual variation in capacities, preference and demand, room must be available for behavioral adjustments, as well as clothing must be flexible enough to accommodate these adjustments.

Cold Climate↗

PubMed1991

1H- and natural abundance 15N-NMR studies of a derivative of a rabies glycoprotein fragment.

Using a combination of one- and two-dimensional methods, 1H- and 15N-nmr spectroscopy has been employed to perform the complete assignment and the structural determination of the immunogenic undecapeptide CTTTNSRGTTT in DMSO solution. Nuclear Overhauser enhancement spectroscopy experiments indicated the presence of secondary structures, mainly turn-like structures, which only represent a family, albeit a dominant one, of an ensemble of conformations available to the peptide. Since reverse turns may play an important role as intermediates in protein folding, the experimental observations described here may link the immunological and theoretical approaches to protein folding.

Amino Acid Sequence↗

PubMed2003

DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones.

We have designed DOP-PCR primers specifically for the amplification of large insert clones for use in the construction of DNA microarrays. A bioinformatic approach was used to construct primers that were efficient in the general amplification of human DNA but were poor at amplifying E. coli DNA, a common contaminant of DNA preparations from large insert clones. We chose the three most selective primers for use in printing DNA microarrays. DNA combined from the amplification of large insert clones by use of these three primers and spotted onto glass slides showed more than a sixfold increase in the human to E. coli hybridization ratio when compared to the standard DOP-PCR primer, 6MW. The microarrays reproducibly delineated previously characterized gains and deletions in a cancer cell line and identified a small gain not detected by use of conventional CGH. We also describe a method for the bulk testing of the hybridization characteristics of chromosome-specific clones spotted on microarrays by use of DNA amplified from flow-sorted chromosomes. Finally, we describe a set of clones selected from the publicly available Golden Path of the human genome at 1-Mb intervals and a view in the Ensembl genome browser from which data required for the use of these clones in array CGH and other experiments can be downloaded across the Internet.

Animals↗