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The ideas and the conceptual steps leading from the ergodic hypothesis for equilibrium statistical mechanics to the chaotic hypothesis for equilibrium and nonequilibrium statistical mechanics are illustrated. The fluctuation theorem linear law and universal slope prediction for reversible systems is briefly derived. Applications to fluids are briefly alluded to. (c) 1998 American Institute of Physics.
We consider a dynamical system with state space M, a smooth, compact subset of some R(n), and evolution given by T(t), x(t)=T(t)x, x in M; T(t) is invertible and the time t may be discrete, t in Z, T(t)=T(t), or continuous, t in R. Here we show that starting with a continuous positive initial probability density rho(x,0)>0, with respect to dx, the smooth volume measure induced on M by Lebesgue measure on R(n), the expectation value of logrho(x,t), with respect to any stationary (i.e., time invariant) measure nu(dx), is linear in t, nu(logrho(x,t))=nu(logrho(x,0))+Kt. K depends only on nu and vanishes when nu is absolutely continuous with respect to dx.(c) 1998 American Institute of Physics.
By quenching into the metastable region of the three-dimensional Ising model, we investigate the paths that the magnetization (energy) takes as a function of time. We accumulate the magnetization (energy) paths into time-dependent distributions from which we reconstruct the free energy as a function of the magnetic field, temperature, and system size. From the reconstructed free energy, we obtain the free-energy barrier that is associated with the transition from a metastable state to the stable equilibrium state. Although mean-field theory predicts a sharp transition between the metastable and the unstable region where the free-energy barrier is zero, the results for the nearest-neighbor Ising model show that the free-energy barrier does not go to zero.
Conformational properties of polymers, such as average dihedral angles or molecular alpha-helicity, display a rather weak dependence on the detailed arrangement of the elementary constituents (atoms). We propose a computer simulation method to explore the polymer phase space using a variant of the standard multicanonical method, in which the density of states associated to suitably chosen configurational variables is considered in place of the standard energy density of states. This configurational density of states is used in the Metropolis acceptance/rejection test when configurations are generated with the help of a hybrid Monte Carlo algorithm. The resulting configurational probability distribution is then modulated by exponential factors derived from the general principle of the maximal constrained entropy by requiring that certain average configurational quantities take preassigned (possibly temperature dependent) values. Thermal averages of other configurational quantities can be computed by using the probability distributions obtained in this way. Moments of the energy distribution require an extra canonical sampling of the system phase space at the desired temperature, in order to locally thermalize the configurational degrees of freedom. As an application of these ideas we present the study of the structural properties of two simple models: a bead-and-spring model of polyethylene with independent hindered torsions and an all-atom model of alanine and glycine oligomers with 12 amino acids in vacuum.
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Hamilton paths, or Hamiltonian paths, are walks on a lattice which visit each site exactly once. They have been proposed as models of globular proteins and of compact polymers. A previously published algorithm [Mansfield, Macromolecules 27, 5924 (1994)] for sampling Hamilton paths on simple square and simple cubic lattices is tested for bias and for efficiency. Because the algorithm is a Metropolis Monte Carlo technique obviously satisfying detailed balance, we need only demonstrate ergodicity to ensure unbiased sampling. Two different tests for ergodicity (exact enumeration on small lattices, nonexhaustive enumeration on larger lattices) demonstrate ergodicity unequivocally for small lattices and provide strong support for ergodicity on larger lattices. Two other sampling algorithms [Ramakrishnan et al., J. Chem. Phys. 103, 7592 (1995); Lua et al., Polymer 45, 717 (2004)] are both known to produce biases on both 2x2x2 and 3x3x3 lattices, but it is shown here that the current algorithm gives unbiased sampling on these same lattices. Successive Hamilton paths are strongly correlated, so that many iterations are required between statistically independent samples. Rules for estimating the number of iterations needed to dissipate these correlations are given. However, the iteration time is so fast that the efficiency is still very good except on extremely large lattices. For example, even on lattices of total size 10x10x10 we are able to generate tens of thousands of uncorrelated Hamilton paths per hour of CPU time.
Moving random-pixel arrays (RPAs) were used to study the movement aftereffect (MAE) for translational texture motion and to quantify the contribution of RPA-sensitive motion sensors to the MAE as a function of eccentricity. Size-scaled patterns were used to make a fair comparison across eccentricities. At the upper end of the velocity range it was found, for all eccentricities, that motion sensors tuned to velocities exceeding about 10-20 deg s-1 do not contribute to the translational MAE, even though they do contribute to motion perception. As a consequence the subpopulation of local motion sensors that contributes to the MAE shrinks with eccentricity, because there are fewer low-velocity-tuned and more high-velocity-tuned motion sensors for increasing eccentricity. Thus there is a quantitative, but not a qualitative, difference between the MAEs generated at different eccentricities.
The present work develops and implements a biomathematical statement of how reciprocal connectivity drives stress-adaptive homeostasis in the corticotropic (hypothalamo-pituitary-adrenal) axis. In initial analyses with this interactive construct, we test six specific a priori hypotheses of mechanisms linking circadian (24-h) rhythmicity to pulsatile secretory output. This formulation offers a dynamic framework for later statistical estimation of unobserved in vivo neurohormone secretion and within-axis, dose-responsive interfaces in health and disease. Explication of the core dynamics of the stress-responsive corticotropic axis based on secure physiological precepts should help to unveil new biomedical hypotheses of stressor-specific system failure.
Lipid membrane fusion is critical to cellular transport and signaling processes such as constitutive secretion, neurotransmitter release, and infection by enveloped viruses. Here, we introduce a powerful computational methodology for simulating membrane fusion from a starting configuration designed to approximate activated prefusion assemblies from neuronal and viral fusion, producing results on a time scale and degree of mechanistic detail not previously possible to our knowledge. We use an approach to the long time scale simulation of fusion by constructing a Markovian state model with large-scale distributed computing, yielding an understanding of fusion mechanisms on time scales previously impossible to simulate to our knowledge. Our simulation data suggest a branched pathway for fusion, in which a common stalk-like intermediate can either rapidly form a fusion pore or remain in a metastable hemifused state that slowly forms fully fused vesicles. This branched reaction pathway provides a mechanistic explanation both for the biphasic fusion kinetics and the stable hemifused intermediates previously observed experimentally. Our distributed computing and Markovian state model approaches provide sufficient sampling to detect rare transitions, a systematic process for analyzing reaction pathways, and the ability to develop quantitative approximations of reaction kinetics for fusion.
Single-molecule fluorescence experiments have shown that the conformation of the complex between Escherichia coli general NAD(P)H:flavin oxidoreductase (FRE) and flavin adenine dinucleotide (FAD) fluctuates over a range of timescales between 10(-4) and 1 s. Here we use (15)N and (13)C relaxation dispersion NMR methods to study millisecond-timescale dynamics in the complex. In this time regime, the protein is extremely flexible, with residues that undergo conformational exchange located throughout the molecule. Three distinct regions of dynamics are quantified, with two of them involving residues making contact to the donor (Tyr-35) and acceptor (FAD) sites that participate in the electron transfer reaction monitored in single-molecule experiments. Modulation of the donor-acceptor distance through these conformational exchange processes, occurring with rates of approximately 400 and 1,200 s(-1) (22 degrees C), affects the rate of electron transfer and partially accounts for the range of the observed dynamics monitored in the fluorescence experiments.
At the end of each developmental stage, insects perform the ecdysis sequence, an innate behavior necessary for shedding the old cuticle. Ecdysis triggering hormones (ETHs) initiate these behaviors through direct actions on the CNS. Here, we identify the ETH receptor (ETHR) gene in the moth Manduca sexta, which encodes two subtypes of GPCR (ETHR-A and ETHR-B). Expression of ETHRs in the CNS coincides precisely with acquisition of CNS sensitivity to ETHs and behavioral competence. ETHR-A occurs in diverse networks of neurons, producing both excitatory and inhibitory neuropeptides, which appear to be downstream signals for behavior regulation. These peptides include allatostatins, crustacean cardioactive peptide (CCAP), calcitonin-like diuretic hormone, CRF-like diuretic hormones (DHs) 41 and 30, eclosion hormone, kinins, myoinhibitory peptides (MIPs), neuropeptide F, and short neuropeptide F. In particular, cells L(3,4) in abdominal ganglia coexpress kinins, DH41, and DH30, which together elicit the fictive preecdysis rhythm. Neurons IN704 in abdominal ganglia coexpress CCAP and MIPs, whose joint actions initiate the ecdysis motor program. ETHR-A also is expressed in brain ventromedial cells, whose release of EH increases excitability in CCAP/MIP neurons. These findings provide insights into how innate, centrally patterned behaviors can be orchestrated via recruitment of peptide cotransmitter neurons.
The traditional view that the map of the face in the ventral posterior medial thalamus (VPM) is static and highly discrete was derived largely from qualitative studies that reported only small, robust, and nonoverlapping receptive fields (RFs). Here, by using more quantitative techniques, we have provided evidence for an alternative hypothesis: the RFs in the VPM are large and overlapping and tend to shift as a function of post-stimulus time. These results were obtained through simultaneous recordings of up to 23 single neurons across the whisker representation in the VPM of rats. Under both awake and anesthetized conditions, these neurons responded robustly at short (4-6 ms) and/or long (15-25 ms) latencies to discrete vibromechanical stimulation of single facial whiskers. Computer graphics were used to construct three-dimensional plots depicting the magnitudes of neuronal responses to stimulation of each of several whiskers as a function of post-stimulus time. These "spatiotemporal RFs" demonstrated that (i) the RFs of VPM neurons are quite large, covering up to 20 whiskers and (ii) the spatial locations of these RFs may shift dramatically over the first 35 ms of post-stimulus time, especially from the caudal-most to the rostral-most whiskers on the face. These results suggest that the VPM contains a dynamic and distributed representation of the face, in which stimulus information is coded in both spatial and temporal domains.
Cooperative interactions link the behavior of different amino acid residues within a protein molecule. As a result, the effects of chemical or physical perturbations to any given residue are propagated to other residues by an intricate network of interactions. Very often, amino acids "sense" the effects of perturbations occurring at very distant locations in the protein molecule. In these studies, we have investigated by computer simulation the structural distribution of those interactions. We show here that cooperative interactions are not intrinsically bi-directional and that different residues play different roles within the intricate network of interactions existing in a protein. The effect of a perturbation to residue j on residue k is not necessarily equal to the effect of the same perturbation to residue k on residue j. In this paper, we introduce a computer algorithm aimed at mapping the network of cooperative interactions within a protein. This algorithm exhaustively performs single site thermodynamic mutations to each residue in the protein and examines the effects of those mutations on the distribution of conformational states. The algorithm has been applied to three different proteins (lambda repressor fragment 6-85, chymotrypsin inhibitor 2, and barnase). This algorithm accounts well for the observed behavior of these proteins.
Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of erbB receptors. The peptides effectively inhibited growth of two types of transformed cells overexpressing different erbB receptors, T6-17 and 32D, in standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell viability assays. The study identifies distinct loops within the membrane-proximal part of the subdomain IV as potential receptor-receptor interaction sites for the erbB receptors and demonstrates the possibility of disabling receptor activity by structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1.EGF complex, consistent with the involvement of subdomain IV in inter-receptor interactions, are proposed. Small dimerization inhibitors described herein can be useful as probes to elucidate different erbB signaling pathways and may be developed as therapeutic agents.
Drebrin, an actin-binding 70-kDa protein with an unusually slow SDS-PAGE mobility corresponding to approximately 120 kDa, containing a proline-rich, profilin-binding motif, had originally been reported from neuronal cells, but recently has also been found in diverse other kinds of tissues and cell lines. In biochemical analyses of various cells and tissues, employing gel filtration, sucrose gradient centrifugation, immunoprecipitation and -blotting, we have identified distinct states of soluble drebrin: a approximately 4S monomer, an 8S, ca. 217-kDa putative trimer, a 13S and a > 20S oligomer. In the 8S particles only [35S]methionine-labelled drebrin but no other actin-binding protein has been detected in stoichiometric amounts. By immunofluorescence and immunoelectron microscopy, drebrin-positive material often appeared as "granules" up to 400 nm in diameter, in some cell types clustered near the Golgi apparatus or in lamellipodia, particularly at leading edges, or in dense-packed submembranous masses at tips (acropodia) or ruffles of leading edges, in filopodia and at plaques of adhering junctions. We conclude that these drebrin complexes and drebrin-rich structures allow the build-up and maintenance of high local drebrin concentrations in strategic positions for the regulation of actin filament assembly, thereby contributing to cell motility and morphology, in particular local changes of plasticity and the formation of protrusions.
Chemical protective clothing (PC) use while working results in elevated rectal temperatures (Tre) that limit work time. Particle barrier, vapor permeable (PBVP) PCs allow workers to cool themselves by evaporating some sweat. The purpose of this study was to compare the effects on worker productivity of two types of PBVP suits, a Kleenguard (PPPC) (Kimberly Clark), and a Tyvek (PEPC) (DuPont) suit. Fifteen males in a repeated measures design performed four work tests consisting of a walk/arm curl combination at a time-weighted work rate of 1.0 L/min (300 kcal/hr), two in a wet bulb globe temperature (WBGT) of 26 degrees C and two in a WBGT of 18 degrees C, with subjects wearing each suit once in each environment. No significant difference (p > 0.05) was observed between the suits at 18 degrees C WBGT, but a significant difference was found (p < 0.05) between the suits, with the PPPC having a lower Tre in the WBGT = 26 degrees C at the 80th, 100th, and 120th min. A significant difference (p < .05) was also seen in the 26 degrees C WBGT with the PPPC resulting in a lower heart rate (HR) at the 40th, 60th, 80th, 100th, and 120th min and rate of perceived exertion (RPE) at the 75th, 90th, and 120th min. Additionally, a significant difference (p < .05) was seen between PEPC and PPPC for Tre, delta Tre, mean skin temp (mTsk), delta mTsk, and HR, each regressed against time in the 26 degrees C WBGT. Twelve of the 15 subjects also reported feeling cooler in the PPPC versus the PEPC in either WBGT environment.
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