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Comprehensive comparisons of the current human, mouse, and rat RefSeq, Ensembl, EST, and FANTOM3 datasets: identification of new human genes with specific tissue expression profile.

Our understanding of functional genetic elements in the genomes is continuously growing and new entries are entered in various databases on a regular basis. We have here merged the genetic elements in RefSeq, Ensembl, FANTOM3, HINV, and NCBI:s ESTdb using the genome assemblies in order to achieve a comprehensive picture of the current status of the identity and gene number in human, mouse, and rat. The number of human protein coding genes has not increased (25,043) while the increased sequencing of mouse transcripts has provided the considerably higher number of protein coding genes (31,578) in mouse. The results indicate large discrepancies between the datasets, as considerable numbers of unique transcripts can be found in each dataset. Despite the high number of ncRNA (38,129 in mouse) there are also almost 20,000 EST clusters in both mouse and humans with more than one EST that do not overlap any transcript suggesting that several new genetic elements are still to be found. We also demonstrated presence of new genes by identifying new human ones that have specific tissue profiles, using RT-PCR on rat tissues.

Animals↗

Comparative multiresolution wavelet analysis of ERP spectral bands using an ensemble of classifiers approach for early diagnosis of Alzheimer's disease.

Early diagnosis of Alzheimer's disease (AD) is becoming an increasingly important healthcare concern. Prior approaches analyzing event-related potentials (ERPs) had varying degrees of success, primarily due to smaller study cohorts, and the inherent difficulty of the problem. A new effort using multiresolution analysis of ERPs is described. Distinctions of this study include analyzing a larger cohort, comparing different wavelets and different frequency bands, using ensemble-based decisions and, most importantly, aiming the earliest possible diagnosis of the disease. Surprising yet promising outcomes indicate that ERPs in response to novel sounds of oddball paradigm may be more reliable as a biomarker than the more commonly used responses to target sounds.

Aged↗

Ensemble spontaneous activity in the guinea-pig cochlear nerve.

Spectral analysis of electrical noise recorded from the round window (RW) of the cochlea is referred to as the ensemble spontaneous activity (ESA) of the cochlear nerve. The ESA is considered to represent the summed spontaneous activity of single fibers of the auditory nerve and changes in the spectral characteristics of the ESA have been observed in humans with tinnitus. Experiments were undertaken to determine the relationship of the ESA to auditory neurotransmission. The ESA consisted of energy centered at approximately 900 Hz, similar to the spectral peak of single auditory neuron discharges. The amplitude of the ESA was correlated with good auditory sensitivity in the 12-30 kHz region of the cochlea. Constant pure tones of 12-22 kHz suppressed the ESA reducing its amplitude in a frequency and intensity dependent manner implying that the ESA recorded at the RW is generated or dominated by neurons in the basal region of the cochlea. The ESA was significantly suppressed by round window perfusion of the P2X receptor agonist adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) (10 mM) the glutamate receptor antagonist 6-7-dinitroquinoxaline-2,3-dione (DNQX) (1 mM), and the sodium channel antagonist tetrodotoxin (TTX) (20 microM). Following intravenous furosemide injection (40 mg/kg) reduction and recovery of the ESA correlated with similar changes in the endocochlear potential (EP). Following DNQX and ATPgammaS an additional spectral peak at 200 Hz was often observed. This peak has been postulated to be a correlate of tinnitus in humans but had not previously been observed in a guinea-pig model of tinnitus. These data confirm the spectral characteristics of the ESA in guinea-pigs and show it is dependent on the sensitivity of the auditory nerve and intact auditory neurotransmission. In addition these experiments support the view that the ESA represents summed spontaneous neural activity in the cochlea and provide a platform for studies of the influence of ototoxic compounds on the spontaneous neural outflow of the cochlea as a model of tinnitus.

Acoustic Stimulation↗

Prediction of collective characteristics for ion ensembles in quadrupole ion traps without trajectory simulations.

Fundamental aspects are presented of a two-temperature moment theory for quadrupole ion traps developed via transformation of the Boltzmann equation. Solutions of the moment equations correspond to changes in the ensemble average for any function of ion velocity, because the Boltzmann equation reflects changes to an ion distribution as a whole. The function of primary interest in this paper is the ion effective temperature and its behavior during ion storage and resonance excitation. Calculations suggest that increases in ion effective temperature during resonance excitation are due primarily to power absorption from the main RF trapping field rather than from the dipolar excitation signal. The dipolar excitation signal apparently serves mainly to move ions into regions of the ion trap where the RF electric field, and thus ion RF heating, is greater than near the trap center. Both ideal and non-ideal ion trap configurations are accounted for in the moment equations by incorporating parameterized variables a and q , which are modified versions of the commonly used forms for the DC and AC ring voltages, and b and d , which are new forms that account for the voltages applied to the endcaps. Besides extending the applicability of the moment equations to non-ideal quadrupole ion traps, the modified versions of the parameterized variables can have additional utility. Calculation of the spatial dependence of ion secular oscillation frequencies is demonstrated as an example.

Journal Article↗

Formation of native and non-native interactions in ensembles of denatured ACBP molecules from paramagnetic relaxation enhancement studies.

Paramagnetic relaxation enhancement measurements in the denatured state of ACBP have provided distance restraints that have been used in computer simulations to determine the conformational ensembles representing the denatured states of ACBP under a variety of conditions. A detailed comparison of the residual structure in the denatured state of ACBP under these different conditions has enabled us to infer that regions in the N and C-terminal parts of the protein sequence have a high tendency to interact in the unfolded state under physiological conditions. By comparing the structural features in the denatured states with those in the transition state for folding we also provided new insights into the mechanism of formation of the native state of this protein.

Animals↗

All-atom generalized-ensemble simulations of small proteins.

We give an overview of some generalized-ensemble techniques that have proven successful in all-atom simulations of proteins. We show that these techniques enable efficient investigations of secondary structure formation and folding in peptides and small proteins. Results are presented for various alanine-based artificial peptides and a small protein, the 36-residued villin headpiece subdomain (HP-36). Our results indicate that all-atom simulations of proteins may be more restricted by the accuracy of the present energy functions than by the efficiency of the search algorithms.

Computer Simulation↗

DATA-MEAns: an open source tool for the classification and management of neural ensemble recordings.

The number of laboratories using techniques that allow to acquire simultaneous recordings of as many units as possible is considerably increasing. However, the development of tools used to analyse this multi-neuronal activity is generally lagging behind the development of the tools used to acquire these data. Moreover, the data exchange between research groups using different multielectrode acquisition systems is hindered by commercial constraints such as exclusive file structures, high priced licenses and hard policies on intellectual rights. This paper presents a free open-source software for the classification and management of neural ensemble data. The main goal is to provide a graphical user interface that links the experimental data to a basic set of routines for analysis, visualization and classification in a consistent framework. To facilitate the adaptation and extension as well as the addition of new routines, tools and algorithms for data analysis, the source code and documentation are freely available.

Action Potentials↗

Ensemble dynamics of hippocampal regions CA3 and CA1.

Computational models based on hippocampal connectivity have proposed that CA3 is uniquely positioned as an autoassociative memory network, capable of performing the competing functions of pattern completion and pattern separation. Recently, three independent studies, two using parallel neurophysiological recording methods and one using immediate-early gene imaging, have examined the responses of CA3 and CA1 ensembles to alterations of environmental context in rats. The results provide converging evidence that CA3 is capable of performing nonlinear transformations of sensory input patterns, whereas CA1 may represent changes in input in a more linear fashion.

Animals↗

Applications of the Vitamin D sterol-Vitamin D receptor (VDR) conformational ensemble model.

Over the past 20 years much has been learned about the cellular actions of the steroid hormone 1alpha,25(OH)2-Vitamin D3 (1,25D). Perhaps most importantly structure-function studies led to the discovery that different chemical and physical features of 1,25D are preferred to initiate either exonuclear, non-genomic or endonuclear, genomic cellular signaling. It is well documented that both a 1alpha-OH and 25-OH, and a 6-s-trans, bowl-shaped, sterol conformation are absolutely required for efficient gene transcription, while 6-s-cis locked analogs and 1-deoxy, 25(OH)D3 metabolites activate a variety of non-genomic, rapid responses. These results and the observation that S237 (helix-3; H3) and R274 (H5) are the most static residues in the human 1,25D-Vitamin D receptor (VDR) X-ray construct (see B-values in pdb: 1DB1) and form H-bonds with the 1alpha-OH of 1,25D in the X-ray, genomic pocket (G-pocket), provided the basis for the molecular modeling experiments that led to the discovery of a putative VDR alternative ligand binding pocket (A-pocket). The conformational ensemble model generated from the in silico results provides an explanation for how the VDR can function as a receptor propagating both genomic and non-genomic signaling events. In this report the theoretical gating properties controlling ligand access to the A- and G-pockets will be compared and the model will be used to provide a molecular explanation for the confusing structure-function results pertaining to 1,25D, its side-chain metabolite, 23S,25R-1alpha,25(OH)2-D3-26,23-lactone (BS), and its synthetic two side-chain analog, 21-(3'-hydroxy-3'-methylbutyl)-1alpha,25(OH)2-D3 (KH or Gemini). In addition, evidence that the model is consistent with the pH requirement for Vitamin D sterol-VDR crystallization will be presented.

Arginine↗

Coding and transmission of information by neural ensembles.

The brain processes information about sensory stimuli and motor intentions using a massive ensemble of neurons arrayed in parallel. Individual neurons receive convergent inputs from thousands of other neurons, leading to the possibility that patterns of spikes across the input neurons might be crucial components of the neural code. Recently, advances in multielectrode recording techniques have allowed several laboratories to investigate the nature of the interactions between neurons, and their potential role in information coding. Several recent studies have found that the amount of information coded by correlated activity about sensory and motor variables is small, casting doubt on the hypothesis that correlations between pairs of neurons are important for information coding. However, other studies have documented the appearance of coherent oscillations, during particular task epochs and conditions that require selective processing of sensory information, supporting the hypothesis that coherent oscillations between neurons might reflect the dynamic flow of information in the brain.

Animals↗

Bimolecular reaction simulation using Weighted Ensemble Brownian dynamics and the University of Houston Brownian Dynamics program.

We discuss here the implementation of the Weighted Ensemble Brownian (WEB) dynamics algorithm of Huber and Kim in the University of Houston Brownian Dynamics (UHBD) suite of programs and its application to bimolecular association problems. WEB dynamics is a biased Brownian dynamics (BD) algorithm that is more efficient than the standard Northrup-Allison-McCammon (NAM) method in cases where reaction events are infrequent because of intervening free energy barriers. Test cases reported here include the Smoluchowski rate for association of spheres, the association of the enzyme copper-zinc superoxide dismutase with superoxide anion, and the binding of the superpotent sweetener N-(p-cyanophenyl)-N'-(diphenylmethyl)-guanidinium acetic acid to a monoclonal antibody fragment, NC6.8. Our results show that the WEB dynamics algorithm is a superior simulation method for enzyme-substrate reaction encounters with large free energy barriers.

Acetates↗

Direct molecular dynamics observation of protein folding transition state ensemble.

The concept of the protein transition state ensemble (TSE), a collection of the conformations that have 50% probability to convert rapidly to the folded state and 50% chance to rapidly unfold, constitutes the basis of the modern interpretation of protein engineering experiments. It has been conjectured that conformations constituting the TSE in many proteins are the expanded and distorted forms of the native state built around a specific folding nucleus. This view has been supported by a number of on-lattice and off-lattice simulations. Here we report a direct observation and characterization of the TSE by molecular dynamic folding simulations of the C-Src SH3 domain, a small protein that has been extensively studied experimentally. Our analysis reveals a set of key interactions between residues, conserved by evolution, that must be formed to enter the kinetic basin of attraction of the native state.

Computer Simulation↗

An ESS-analysis for ensembles of prisoner's dilemma strategies.

The ESS (Evolutionary Stable Strategy) concept of Maynard Smith can be applied in its weak form to ensembles of competing PD ("Prisoner's Dilemma") strategies memorizing two to three of one's own and one's opponent's moves. The format of our study is: (1) games have very long duration; (2) Taylor-Jonker dynamics applies; (3) Effects of finite population size can be ignored. It is shown that in the case R greater than (T + S)/2 a set of strategies can be singled out which do not lose against any other strategy while co-operating with themselves. Such a set is uninvadable by other PD strategies if it constitutes more than half of the total population.

Biological Evolution↗

Determination and quantification of pharmacological, physiological, or behavioral manipulations on ensembles of simultaneously recorded neurons in functionally related neural circuits.

The present report describes methods for evaluating the impact of physiological, pharmacological or behavioral manipulations on simultaneously recorded single neurons within a functional sensory network of the awake, freely moving rat. Surgical techniques were developed to implant a subcutaneous electrode at the base of a single facial whisker (mystacial vibrissae) so that uniform electrical stimuli could be routinely delivered to a discrete region of the whisker pad in the awake and freely moving animal. Multi-channel extracellular recording was used to monitor the spike train activity from ensembles of single neurons in whisker-related regions of the thalamus and neocortex. Algorithms were developed to verify the stability of individual cell recordings during extended experimental sessions. Additional analysis procedures and criteria were established for identifying and evaluating the treatment-specific changes in single neuron discharge patterns that are likely to occur under these experimental conditions. Finally, analyses for evaluating the impact of experimental manipulations on sensory representations distributed over populations of neurons are discussed. The development of these techniques has provided us with the means to investigate the influence of systemically administered drugs or broadly projecting monoamine pathways on single neurons and local circuits within primary sensory networks of the awake or anesthetized mammalian brain.

Action Potentials↗

Identification of synaptic connections in neural ensembles by graphical models.

A method for the identification of direct synaptic connections in a larger neural net is presented. It is based on a conditional correlation graph for multivariate point processes. The connections are identified via the partial spectral coherence of two neurons, given all others. It is shown how these coherences can be calculated by inversion of the spectral density matrix. In simulations with GENESIS, we discuss the relevance of the method for identifying different neural ensembles including an excitatory feedback loop and networks with lateral inhibitions.

Computer Graphics↗

Drug release from an ensemble of swellable crosslinked polymer particles.

This paper presents a new model suitable to describe the drug release from drug delivery systems constituted by an ensemble of drug loaded crosslinked polymer particles. The model accounts for the main factors affecting the drug release such as the particle size distribution, the physical state and the concentration profile of the drug inside the polymeric particles, the viscoelastic properties of the polymer-penetrant system and the dissolution-diffusion properties of the loaded drug. In order to check the validity of the model, release experiments were performed by using crosslinked polyvinyl-pyrrolidone (PVP) particles and two different model drugs, MAP (medroxyprogesterone acetate) and TEM (Temazepam). MAP and TEM were chosen because of their completely different dissolution behaviours in water. In particular, TEM undergoes a phase transition to the crystalline state upon dissolution when it is loaded in the polymeric network in the amorphous state. The comparison with the experimental results confirms that the most important factors determining the drug release kinetics can be properly accounted for.

Antineoplastic Agents, Hormonal↗

Forecasting the consequences of accidental releases of radionuclides in the atmosphere from ensemble dispersion modelling.

The RTMOD system is presented as a tool for the intercomparison of long-range dispersion models as well as a system for support of decision making. RTMOD is an internet-based procedure that collects the results of more than 20 models used around the world to predict the transport and deposition of radioactive releases in the atmosphere. It allows the real-time acquisition of model results and their intercomparison. Taking advantage of the availability of several model results, the system can also be used as a tool to support decision making in case of emergency. The new concept of ensemble dispersion modelling is introduced which is the basis for the decision-making application of RTMOD. New statistical parameters are presented that allow gathering the results of several models to produce a single dispersion forecast. The devised parameters are presented and tested on the results of RTMOD exercises.

Air Movements↗

A brain perspective on language mechanisms: from discrete neuronal ensembles to serial order.

Language is constituted by discrete building blocks, sounds and words, which can be concatenated according to serial order principles. The neurobiological organization of these building blocks, in particular words, has been illuminated by recent metabolic and neurophysiological imaging studies. When humans process words of different kinds, various sets of cortical areas have been found to become active differentially. The old concept of two language centers processing all words alike must therefore be replaced by a model according to which words are organized as discrete distributed neuron ensembles that differ in their cortical topographies. The meaning of a word, more precisely, aspects of its reference, may be crucial for determining which set of cortical areas becomes involved in its processing. Whereas the serial order of sounds constituting a word may be established by serially aligned sets of neurons called synfire chains, different mechanisms are necessary for establishing word order in sentences. The serial order of words may be organized by higher-order neuronal sets, called sequence detectors here, which are being activated by sequential excitation of neuronal sets representing words. Sets of sequence detectors are proposed to process aspects of the syntactic information contained in a sentence. Other syntactic rules can be related to general features of the dynamics of cortical activation and deactivation. These postulates about the brain mechanisms of language, which are rooted in principles known from neuroanatomy and neurophysiology, may provide a framework for theory-driven neuroscientific research on language.

Brain↗