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Results for “connectivity mapping”

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PubMed2026

Mapping Allosteric Communication in the Nucleosome with Conditional Activity.

The nucleosome core particle (NCP) regulates genome accessibility through dynamic allosteric communication between histone proteins and DNA. Building on the concept of conditional activity introduced by Lin (2016), we use molecular dynamics simulations and develop an open-source Python library, CONDACT (CONDitional ACTivity), to quantify time-resolved kinetic correlations in nucleosome systems. We analyze long-time simulations of the nucleosome core particle, including two different DNA sequences, the Widom-601 (PDB ID: 3LZ0) and ASP (alpha-satellite palindromic) sequences (PDB ID: 1KX5). By tracking dihedral angle transitions, we identify residues with high dynamical memory and map inter-residue communication pathways across histone subunits and DNA. Our analysis reveals kinetically connected domains involving post-translational modification sites, oncogenic mutation sites, and DNA contact regions, with dynamic coupling observed over distances up to 7.5 nm. These findings offer new insight into the long-range allosteric behavior of the nucleosome and its potential role in regulating chromatin accessibility. Quantifying this allosteric behavior potentially identifies targetable residues and domains for therapeutic intervention.

Nucleosomes↗

PubMed1999

The protein kinase C-mediated MAP kinase pathway involved in the maintenance of cellular integrity in Saccharomyces cerevisiae.

Signal transduction mediated by the single yeast isozyme of protein kinase C (Pkc1p) is essential for the maintenance of cellular integrity in this model eukaryote. The past few years have seen a dramatic increase in our knowledge of the upstream regulatory factors that modulate Pkc1p activity (e.g. Tor2p, Rom1p, Rom2p, Rho1p, Slg1p, Mid2p) and of the downstream targets of the MAP kinase cascade triggered by it (e.g. Rlm1p, SBF complex). The picture that has emerged connects this pathway to a variety of other cellular processes, such as cell cycle progression (Cdc28p, Swi4p), mating (Ste20p), nutrient sensing (Ira1p), calcium homeostasis (calcineurin, Mid2p, Fks2p) and the structural dynamics of the cytoskeleton (Spa1p, Bni1p).

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2003

Connectivity optimization and the positioning of cortical areas.

By examining many alternative arrangements of cortical areas, we have found that the arrangement actually present in the brain minimizes the volume of the axons required for interconnecting the areas. Our observations support the notion that the organization of cortical areas has evolved to optimize interareal connections.

Axons↗

PubMed1973

Origin and direction of replication of bacteriophage 186 DNA.

Intracellular bacteriophage 186 DNA replicates as a single-branched circle during the first round of replication. The free end of the branch is located at a unique position with respect to phage 186 DNA base sequence, and this point should, therefore, correspond to the origin of DNA replication. The position of the growing point has been mapped at various degrees of replication, and found to move unidirectionally from left to right with respect to the denaturation map of phage 186 DNA.A small proportion of the replicating molecules have two linear branches connected to the circle at two different branch points. These structures are consistent with two separate initiations from the same origin, again, with a unidirectional mode of replication. Branch points frequently have a single-stranded connection between the circle and the branch; significant numbers of branch points also possess an extra short single-stranded "whisker" protruding out of the branch point.

Centrifugation, Density Gradient↗

PubMed2005

The structure of bypass of forespore C, an intercompartmental signaling factor during sporulation in Bacillus.

Sporulation in Bacillus subtilis begins with an asymmetric cell division giving rise to smaller forespore and larger mother cell compartments. Different programs of gene expression are subsequently directed by compartment-specific RNA polymerase sigma-factors. In the final stages, spore coat proteins are synthesized in the mother cell under the control of RNA polymerase containing sigma(K), (Esigma(K)). sigma(K) is synthesized as an inactive zymogen, pro-sigma(K), which is activated by proteolytic cleavage. Processing of pro-sigma(K) is performed by SpoIVFB, a metalloprotease that resides in a complex with SpoIVFA and bypass of forespore (Bof)A in the outer forespore membrane. Ensuring coordination of events taking place in the two compartments, pro-sigma(K) processing in the mother cell is delayed until appropriate signals are received from the forespore. Cell-cell signaling is mediated by SpoIVB and BofC, which are expressed in the forespore and secreted to the intercompartmental space where they regulate pro-sigma(K) processing by mechanisms that are not yet fully understood. Here we present the three-dimensional structure of BofC determined by solution state NMR. BofC is a monomer made up of two domains. The N-terminal domain, containing a four-stranded beta-sheet onto one face of which an alpha-helix is packed, closely resembles the third immunoglobulin-binding domain of protein G from Streptococcus. The C-terminal domain contains a three-stranded beta-sheet and three alpha-helices in a novel domain topology. The sequence connecting the domains contains a conserved DISP motif to which mutations that affect BofC activity map. Possible roles for BofC in the sigma(K) checkpoint are discussed in the light of sequence and structure comparisons.

Amino Acid Motifs↗

PubMedDate not supplied

Mapping cognition to the brain through neural interactions.

Brain imaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provide a unique opportunity to study the neurobiology of human memory. As these methods can measure most of the brain, it is possible to examine the operations of large-scale neural systems and their relation to cognition. Two neuroimaging studies, one concerning working memory and the other episodic memory retrieval, serve as examples of application of two analytic methods that are optimised for the quantification of neural systems, structural equation modelling, and partial least squares. Structural equation modelling was used to explore shifting prefrontal and limbic interactions from the right to the left hemisphere in a delayed match-to-sample task for faces. A feature of the functional network for short delays was strong right hemisphere interactions between hippocampus, inferior prefrontal, and anterior cingulate cortices. At longer delays, these same three areas were strongly linked, but in the left hemisphere, which was interpreted as reflecting change in task strategy from perceptual to elaborate encoding with increasing delay. The primary manipulation in the memory retrieval study was different levels of retrieval success. The partial least squares method was used to determine whether the image-wide pattern of covariances of Brodmann areas 10 and 45/47 in right prefrontal cortex (RPFC) and the left hippocampus (LGH) could be mapped on to retrieval levels. Area 10 and LGH showed an opposite pattern of functional connectivity with a large expanse of bilateral limbic cortices that was equivalent for all levels of retrieval as well as the baseline task. However, only during high retrieval was area 45/47 included in this pattern. The results suggest that activity in portions of the RPFC can reflect either memory retrieval mode or retrieval success depending on other brain regions to which it is functionally linked, and imply that regional activity must be evaluated within the neural context in which it occurs. The general hypothesis that learning and memory are emergent properties of large-scale neural network interactions is discussed, emphasising that a region can play a different role across many functions and that role is governed by its interactions with anatomically related regions.

Brain↗

PubMed2000

Evaluation of a noninvasive transcranial Doppler and blood pressure-based method for the assessment of cerebral perfusion pressure in pregnant women.

OBJECTIVE: We have developed a Doppler method for the estimation of cerebral perfusion pressure (CPP) using noninvasive techniques. Our objective was to evaluate our new method in pregnant women. METHODS AND MATERIALS: Laboring women with a lumbar epidural in situ had transcranial Doppler interrogation of the maternal middle cerebral artery (MCA) to measure systolic, diastolic, and mean velocities. A pressure transducer was connected to the epidural catheter and pressure was recorded. Systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure were taken with a Dinamap monitor. Doppler estimated CPP (mm Hg) = [V(mean)/(V(mean) - V(diastolic)](MAP - DBP) and directly measured CPP = MAP - Epidural pressure data were plotted on a Bland-Altman graph with limits of agreement. The mean difference (the mean of the sum of both positive and negative differences) and absolute difference (the mean of the sum of the absolute differences) were calculated. In addition, linear and polynomial regression analyses were performed. RESULTS: Twenty laboring women were studied. All had normal pregnancies. The mean maternal age was 28 +/- 7 years and the mean gestational age was 39 +/- 2 weeks. The mean maternal MAP was 77 +/- 12 mm Hg. The Bland-Altman plot showed a mean difference of 2.2 mm Hg at a mean CPP of 65 +/- 12 mm Hg; with a standard deviation of 4.8 mm Hg, the absolute difference was 3.9 +/- 3.0 mm Hg at a mean CPP of 65 +/- 12 mm Hg. The regression analysis showed an r = 0.92, r(2) = 0.86, and p < 0.0001. CONCLUSIONS: Our formula allows the estimation of CPP using a simple calculation and noninvasively acquired data. This method may be of use for frequent, easy, and accurate CPP and intracranial pressure estimation and may, as such, have significant research and clinical applications.

Adult↗

PubMed2003

Discrete structure of van der Waals domains in globular proteins.

Most globular proteins are divisible by domains, distinct substructures of the globule. The notion of hierarchy of the domains was introduced earlier via van der Waals energy profiles that allow one to subdivide the proteins into domains (subdomains). The question remains open as to what is the possible structural connection of the energy profiles. The recent discovery of the loop-n-lock elements in the globular proteins suggests such a structural connection. A direct comparison of the segmentation by van der Waals energy criteria with the maps of the locked loops of nearly standard size reveals a striking correlation: domains in general appear to consist of one to several such loops. In addition, it was demonstrated that a variety of subdivisions of the same protein into domains is just a regrouping of the loop-n-lock elements.

Protein Conformation↗

PubMed1994

Corticocortical connectivity, autonomous networks, and schizophrenia.

Dr. David hypothesizes that increased, not decreased, corticocortical connectivity causes schizophrenia. He cites studies suggesting excessive semantic priming and cross-hemispheric interference in this disorder to support his hypothesis. These findings, David suggests, reflect excessive transmission of information between neurons or within neural systems. However, considerable caution should be exercised in making neuroanatomic inferences on the basis of cognitive studies alone. There is an increasing consensus that information is represented by the brain as patterns of neural activation, where the same neuron or group of neurons participates in many different representations. Our simulations, which reflect this consensus, suggest that persistent or intrusive activation patterns do not emerge from too many neural connections, but from too few. This condition causes subgroups of neurons to disregard information processing by other neurons and to produce autonomously their own output, which interferes with the functioning of the system as a whole. Direct neuroanatomic or neurochemical studies of the cerebral cortex are needed to fully assess hypotheses regarding abnormal corticocortical connectivity in schizophrenia.

Brain Mapping↗

PubMed2025

Mapping Allosteric Communication in the Nucleosome with Conditional Activity.

The nucleosome core particle (NCP) regulates genome accessibility through dynamic allosteric communication between histone proteins and DNA. Building on the concept of conditional activity introduced by Lin (2016), we use molecular dynamics simulations and develop an open-source Python library, CONDACT (CONDitional ACTivity), to quantify time-resolved kinetic correlations in nucleosome systems. We analyze long-time simulations of the nucleosome core particle, including two different DNA sequences, the Widom-601 and ASP (alpha-satellite palindromic) sequences. By tracking dihedral angle transitions, we identify residues with high dynamical memory and map inter-residue communication pathways across histone subunits and DNA. Our analysis reveals kinetically connected domains involving post-translational modification sites, oncogenic mutation sites, and DNA contact regions, with dynamic coupling observed over distances up to 7.5 nm. These findings offer new insight into the long-range allosteric behavior of the nucleosome and its potential role in regulating chromatin accessibility. Quantifying this allosteric behavior potentially identifies targetable residues and domains for therapeutic intervention.

Journal Article↗

PubMed2000

Path-integral formulation of stochastic processes for exclusive particle systems

We present a systematic formalism to derive a path-integral formulation for hard-core particle systems far from equilibrium. Writing the master equation for a stochastic process of the system in terms of the annihilation and creation operators with mixed commutation relations, we find the Kramers-Moyal coefficients for the corresponding Fokker-Planck equation (FPE), and the stochastic differential equation (SDE) is derived by connecting these coefficients in the FPE to those in the SDE. Finally, the SDE is mapped onto field theory using the path integral, giving the field-theoretic action, which may be analyzed by the renormalization group method. We apply this formalism to a two-species reaction-diffusion system with drift, finding a universal decay exponent for the long-time behavior of the average concentration of particles in arbitrary dimension.

Journal Article↗

PubMed2005

Extended estimator approach for 2 x 2 games and its mapping to the Ising Hamiltonian.

We consider a system of adaptive self-interested agents interacting by playing an iterated pairwise prisoner's dilemma (PD) game. Each player has two options: either cooperate (C) or defect (D). Agents have no (long term) memory to reciprocate nor identifying tags to distinguish C from D. We show how their 16 possible elementary Markovian (one-step memory) strategies can be cast in a simple general formalism in terms of an estimator of expected utilities Delta*. This formalism is helpful to map a subset of these strategies into an Ising Hamiltonian in a straightforward way. This connection in turn serves to shed light on the evolution of the iterated games played by agents, which can represent a broad variety of individuals from firms of a market to species coexisting in an ecosystem. Additionally, this magnetic description may be useful to introduce noise in a natural and simple way. The equilibrium states reached by the system depend strongly on whether the dynamics are synchronous or asynchronous and also on the system connectivity.

Journal Article↗

PubMed2000

Chaotic transition of random dynamical systems and chaos synchronization by common noises

We studied the mechanism behind the connection between the transition to chaos of random dynamical systems and the synchronization of chaotic maps driven by external common noises. Near the chaotic transition, the spatial size of random dynamical systems shows an extreme intermittent behavior. By calculating the scaling exponents, we have found that the origin of this intermittent behavior is on-off intermittency. This led us to conclude that chaotic transitions through on-off intermittency can be regarded as a route for random dynamical systems. To clarify this argument, a two-dimensional random dynamical system and two coupled logistic maps driven by external common noises were analyzed.

Journal Article↗

PubMed1999

Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain.

We describe almost entirely automated procedures for estimation of global, voxel, and cluster-level statistics to test the null hypothesis of zero neuroanatomical difference between two groups of structural magnetic resonance imaging (MRI) data. Theoretical distributions under the null hypothesis are available for 1) global tissue class volumes; 2) standardized linear model [analysis of variance (ANOVA and ANCOVA)] coefficients estimated at each voxel; and 3) an area of spatially connected clusters generated by applying an arbitrary threshold to a two-dimensional (2-D) map of normal statistics at voxel level. We describe novel methods for economically ascertaining probability distributions under the null hypothesis, with fewer assumptions, by permutation of the observed data. Nominal Type I error control by permutation testing is generally excellent; whereas theoretical distributions may be over conservative. Permutation has the additional advantage that it can be used to test any statistic of interest, such as the sum of suprathreshold voxel statistics in a cluster (or cluster mass), regardless of its theoretical tractability under the null hypothesis. These issues are illustrated by application to MRI data acquired from 18 adolescents with hyperkinetic disorder and 16 control subjects matched for age and gender.

Adolescent↗

PubMed2000

Conformational flexibility in the apolipoprotein E amino-terminal domain structure determined from three new crystal forms: implications for lipid binding.

An amino-terminal fragment of human apolipoprotein E3 (residues 1-165) has been expressed and crystallized in three different crystal forms under similar crystallization conditions. One crystal form has nearly identical cell dimensions to the previously reported orthorhombic (P2(1)2(1)2(1)) crystal form of the amino-terminal 22 kDa fragment of apolipoprotein E (residues 1-191). A second orthorhombic crystal form (P2(1)2(1)2(1) with cell dimensions differing from the first form) and a trigonal (P3(1)21) crystal form were also characterized. The structures of the first orthorhombic and the trigonal form were determined by seleno-methionine multiwavelength anomalous dispersion, and the structure of the second orthorhombic form was determined by molecular replacement using the structure from the trigonal form as a search model. A combination of modern experimental and computational techniques provided high-quality electron-density maps, which revealed new features of the apolipoprotein E structure, including an unambiguously traced loop connecting helices 2 and 3 in the four-helix bundle and a number of multiconformation side chains. The three crystal forms contain a common intermolecular, antiparallel packing arrangement. The electrostatic complimentarity observed in this antiparallel packing resembles the interaction of apolipoprotein E with the monoclonal antibody 2E8 and the low density lipoprotein receptor. Superposition of the model structures from all three crystal forms reveals flexibility and pronounced kinks in helices near one end of the four-helix bundle. This mobility at one end of the molecule provides new insights into the structural changes in apolipoprotein E that occur with lipid association.

Animals↗

PubMed2004

Olfactory receptors and odor coding in mammals.

Humans and other mammals perceive a vast number of volatile chemicals as having distinct odors. This ability derives from the existence of a large family of olfactory receptors that number about 350 in man and 1000 in mice. Individual odorants activate distinct combinations of olfactory receptors, generating an immense array of combinatorial receptor codes that define odorant identities. Sensory neurons in the nose express only one receptor type each and connect to the olfactory bulb in a spatially organized manner that yields a stereotyped sensory map. A secondary projection from the bulb to the cortex transforms receptor inputs, generating another, different stereotyped map that may permit the integration of inputs from combinations of receptors. Another olfactory structure in the nasal septum of animals, the vomeronasal organ, has two additional receptor families that detect pheromones and induce hormonal and behavioral responses through a different projection to the brain.

Animals↗

PubMed2005

Metabolic network analysis of Streptomyces tenebrarius, a Streptomyces species with an active entner-doudoroff pathway.

Streptomyces tenebrarius is an industrially important microorganism, producing an antibiotic complex that mainly consists of the aminoglycosides apramycin, tobramycin carbamate, and kanamycin B carbamate. When S. tenebrarius is used for industrial tobramycin production, kanamycin B carbamate is an unwanted by-product. The two compounds differ only by one hydroxyl group, which is present in kanamycin carbamate but is reduced during biosynthesis of tobramycin. (13)C metabolic flux analysis was used for elucidating connections between the primary carbon metabolism and the composition of the antibiotic complex. Metabolic flux maps were constructed for the cells grown on minimal medium with glucose or with a glucose-glycerol mixture as the carbon source. The addition of glycerol, which is more reduced than glucose, led to a three-times-greater reduction of the kanamycin portion of the antibiotic complex. The labeling indicated an active Entner-Doudoroff (ED) pathway, which was previously considered to be nonfunctional in Streptomyces. The activity of the pentose phosphate (PP) pathway was low (10 to 20% of the glucose uptake rate). The fluxes through Embden-Meyerhof-Parnas (EMP) and ED pathways were almost evenly distributed during the exponential growth on glucose. During the transition from growth phase to production phase, a metabolic shift was observed, characterized by a decreased flux through the ED pathway and increased fluxes through the EMP and PP pathways. Higher specific NADH and NADPH production rates were calculated in the cultivation on glucose-glycerol, which was associated with a lower percentage of nonreduced antibiotic kanamycin B carbamate.

Aminoglycosides↗

PubMed1990

Linkage analysis of five fibrillar collagen loci in a large French Marfan syndrome family.

Marfan syndrome consists of a group of dominantly inherited disorders of connective tissue with wide clinical variability. Using the candidate gene approach, we have attempted to map the gene defect in a large French Marfan syndrome family with no ocular manifestations. We performed linkage studies with polymorphic probes for five structural procollagen genes. The data obtained exclude linkage of Marfan syndrome to the two major fibrillar collagen (COL1A1, COL1A2, and COL2A1) genes. These results confirm previously published data obtained from smaller pedigrees. A small positive lod score (Z = 0.99, theta = 0.00) was obtained for the COL3A1-COL5A2 gene cluster located on chromosome 2.

Chromosome Mapping↗