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Steered molecular dynamics (SMD) simulation has been applied to molecular dissociation events by adding harmonic forces to molecules, and within most SMDs, molecules are pulled at a constant velocity. Instead of the constant-velocity pulling, a constant force can also be utilized in SMD, which we call constant-force SMD (CF-SMD) simulation. CF-SMD employs a constant force that reduces activation barriers, enhancing a dissociation event. Here, we present the capability of CF- SMD simulation to estimate a dissociation rate in equilibrium. We performed all-atom CF-SMD simulations for an NaCl system and protein-ligand systems, producing dissociation rates under various forces. We extrapolated them to the dissociation rate in the absence of a constant force, using Dudko-Hummer-Szabo model. We demonstrated that CF-SMD simulations combined with the model predicted a dissociation rate in equilibrium. CF-SMD simulation would be a powerful tool to estimate dissociation rate in a direct and computationally efficient manner.

Cryptic sites are binding pockets that are transiently formed in an apo form or that are induced by ligand binding. The investigation of cryptic sites is crucial for drug discovery, since these sites are ubiquitous in disease-related human proteins, and targeting them expands the number of drug targets greatly. However, although many computational studies have attempted to identify cryptic sites, the detection remains challenging. Here, we aimed to characterize and detect cryptic sites in terms of structural fluctuations in an apo form, investigating proteins each of which possesses a cryptic site. From their X-ray structures, we saw that aromatic residues tended to be found in cryptic sites. To examine structural fluctuations of the apo forms, we performed molecular dynamics (MD) simulations, producing probability distributions of the solvent-accessible surface area per aromatic residue. To detect aromatic residues in cryptic sites, we have proposed a "cryptic-site index" based on the distribution, demonstrating the performance via several measures, such as recall and specificity. Besides, we found that high-ranking aromatic residues were likely to probe concaves in a cryptic site. This implies that such fluctuations provide a profile of scaffolds of compounds with the potential to bind to a particular cryptic site.

To elucidate computationally a binding mechanism of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB), a GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was performed. This method is one of generalized ensemble methods and produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stably keeping the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model, and sampling was carried out from conformations where bosentan was distant from the binding site in the hETB’s binding pocket. The deepest basin in the resultant free-energy landscape was assigned to the native-like complex conformation. The obtained binding mechanism is as follows. First, bosentan fluctuating randomly in solution is captured by a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly-casting). Bosentan then occasionally slides from the tip to root of the N-terminal tail (ligand–sliding). In this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with accompanying a quick reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed, and eventually the native-like complex is completed. The bosentan-captured conformations by the tip- and root-regions of the N-terminal tail correspond to two basins in the free-energy landscape, and the ligand–sliding corresponds to overcoming a free-energy barrier between the basins.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world. It is necessary to examine the viral proteins that play a notorious role in the invasion of our body. The main protease (3CLpro) facilitates the maturation of the coronavirus. It is thought that the dimerization of 3CLpro leads to its catalytic activity; the detailed mechanism has, however, not been suggested. Furthermore, the structural differences between the predecessor SARS-CoV 3CLpro and SARS-CoV-2 3CLpro have not been fully understood. Here, we show the structural and dynamical differences between the two main proteases, and demonstrate the relationship between the dimerization and the activity via atomistic molecular dynamics simulations. Simulating monomeric and dimeric 3CLpro systems for each protease, we show that (i) global dynamics between the two different proteases are not conserved, (ii) the dimerization stabilizes the catalytic dyad and hydration water molecules behind the dyad, and (iii) the substrate-binding site (active site) and hydration water molecules in each protomer fluctuate asymmetrically. We then speculate the roles of hydration water molecules in their catalytic activity.

Shinji Iida, Tadaaki Mashimo, Takashi Kurosawa, Hironobu Hojo, Hiroya Muta, Yuji Goto, Yoshifumi Fukunishi, Haruki Nakamura, and Junichi Higo, "Variation of free‐energy landscape of the p53 C‐terminal domain induced by acetylation: Enhanced conformational sampling", Journal of Computational Chemistry, 37, 2687-2700, Wiley, 2016, The C‐terminal domain (CTD) of tumor suppressor protein p53 is an intrinsically disordered region that binds to various partner proteins, where lysine of CTD is acetylated/nonacetylated and histidine neutralized/non‐neutralized. Because of the flexibility of the unbound CTD, a free‐energy landscape (FEL) is a useful quantity for determining its statistical properties. We conducted enhanced conformational sampling of CTD in the unbound state via virtual system coupled multicanonical molecular dynamics, in which the lysine was acetylated or nonacetylated and histidine was charged or neutralized. The fragments were expressed by an all‐atom model and were immersed in an explicit solvent. The acetylation and charge‐neutralization varied FEL greatly, which might be convenient to exert a hub property. The acetylation slightly enhanced alpha‐helix structures that are more compact than sheet/loop conformations. The charge‐neutralization produced hairpins. Additionally, circular dichroism experiments confirmed the computational results. We propose possible binding mechanisms of CTD to partners by investigating FEL.

Cytoplasmic dynein is responsible for intra-cellular transport in eukaryotic cells. Using Fluctuating Finite Element Analysis (FFEA), a novel algorithm that represents proteins as continuum viscoelastic solids subject to thermal noise, we are building computational tools to study the mechanics of these molecular machines. Here we present a methodology for obtaining the material parameters required to represent the flexibility of cytoplasmic dynein within FFEA from atomistic molecular dynamics (MD) simulations, and show that this continuum representation is sufficient to capture the principal dynamic properties of the motor.

Intrinsically disordered regions (IDRs) of a protein employ a flexible binding manner when recognizing a partner molecule. Moreover, it is recognized that binding of IDRs to a partner molecule is accompanied by folding, with a variety of bound conformations often being allowed in formation of the complex. In this study, we investigated a fragment of the disordered p53 C-terminal domain (CTDf) that interacts with one of its partner molecules, S100B, as a representative IDR. Although the 3D structure of CTDf in complex with S100B has been previously reported, the specific interactions remained controversial. To clarify these interactions, we performed generalized ensemble molecular dynamics (MD) simulations (virtual-system coupled multicanonical MD, termed V-McMD), which enable effective conformational sampling beyond that provided by conventional MD. These simulations generated a multimodal structural distribution for our system including CTDf and S100B, indicating that CTDf forms a variety of complex structures upon binding to S100B. We confirmed that our results are consistent with chemical shift perturbations and nuclear Overhauser effects that were observed in previous studies. Furthermore, we calculated the conformational entropy of CTDf in bound and isolated (free) states. Comparison of these CTDf entropies indicated that the disordered CTDf shows further increase in conformational diversity upon binding to S100B. Such entropy gain by binding may comprise an important feature of complex formation for IDRs.

This paper shows that WKB wave function can be expressed in the form of an adiabatic expansion. To build a bridge between two widely invoked approximation schemes seems pedagogically instructive. Further, “cubic-WKB” method that has been devised in order to overcome the divergence problem of WKB can be also presented in the form of an adiabatic approximation: The adiabatic expansion of a wave function contains a certain parameter. When this parameter is adjusted so as to make the next order correction vanish approximately, the adiabatic wave function becomes equivalent to that of the “cubic-WKB”.

We introduce various, recently developed, generalized ensemble methods, which are useful to sample various molecular configurations emerging in the process of protein–protein or protein–ligand binding. The methods introduced here are those that have been or will be applied to biomolecular binding, where the biomolecules are treated as flexible molecules expressed by an all-atom model in an explicit solvent. Sampling produces an ensemble of conformations (snapshots) that are thermodynamically probable at room temperature. Then, projection of those conformations to an abstract low-dimensional space generates a free-energy landscape. As an example, we show a landscape of homo-dimer formation of an endothelin-1-like molecule computed using a generalized ensemble method. The lowest free-energy cluster at room temperature coincided precisely with the experimentally determined complex structure. Two minor clusters were also found in the landscape, which were largely different from the native complex form. Although those clusters were isolated at room temperature, with rising temperature a pathway emerged linking the lowest and second-lowest free-energy clusters, and a further temperature increment connected all the clusters. This exemplifies that the generalized ensemble method is a powerful tool for computing the free-energy landscape, by which one can discuss the thermodynamic stability of clusters and the temperature dependence of the cluster networks.

La culture de masse emploie abondamment le stereotype pour se structurer quitte a le mieux critiquer ou a prendre son contre-pied. En effet, repandu dans toutes les couches sociales, il presente un des moyens les plus efficaces pour etablir un espace de complicite avec le public. En meme temps, malgre sa puissance representative, le stereotype se revele souvent fragile, car il change de nature selon la societe a laquelle il s’adresse ou selon les medias qui le vehiculent. C’est ce changement que nous tenterons d’eclaircir a travers le cas du Sazae-san, un manga de quatre cases qui a connu une immense popularite et une etonnante longevite dans le Japon de l’apres-guerre. Le manga presente en effet deux particularites fort interessantes pour notre propos. D’abord sa notoriete : publie au depart dans un journal local juste un an apres la defaite a la deuxieme guerre mondiale, il deviendra une icone du journal le plus influant du pays durant la periode qui a connu le redressement impressionnant de l’industrie et la transformation profonde de la societe. Ensuite sa complicite avec les medias : diffuse a l’echelle locale ensuite nationale par des journaux, le manga sera adapte au petit ecran a partir de 1969 et il continue a etre diffuse meme aujourd’hui malgre la disparition de son auteure. Ces deux facteurs jouent un role determinant dans le traitement du stereotype, qu’opere l’un des plus celebres manga japonais.

We serially determined serum erythropoietin (Epo) and the reticulocyte count in patients with various types of leukemia during chemotherapy. Serum Epo increased soon after the initiation of chemotherapy and decreased after the termination of therapy irrespective of the types of leukemia or treatment regimen. However, it did not stay at low level but fluctuated. The reticulocyte count, on the other hand, showed a transient rise while serum Epo level descended. The value of serum Epo when increased was higher than the value expected from hemoglobin concentration; this finding was similar to that in aplastic anemia. These results suggest that myelosuppression is a major factor for the increase in serum Epo level during leukemia chemotherapy.

— The etiology of idiopathic portal hypertension (IPH) is not known. To obtain clues to the pathogenesis, an attempt was made to produce a hepatic lesion similar to that in IPH by repeated injections of aggregated killed non-pathogenic E. coli directly into the portal vein. In the treated dogs, histology of the liver showed dense fibrosis in the portal tract and an aberrant vasculature around the portal area after 1 month. Portal pressure was elevated and middle-to-small-sized portal branches were decreased in number as studied by portography. These changes closely mimic those seen in human IPH. The possibility is discussed that chronic entrance of an antigen such as bacteria from the intestine to the portal venous system plays an etiologic role in IPH.

The electric power industry has undergone considerable changes in the past decade throughout the world. The essential feature of these changes is to promote competition among utilities and to form active power market with reliable and less expensive electricity. Under these circumstances, stabilization and voltage stability problems of power systems are very important. Power systems engineers are examining the effect of the resistance value of braking resistors and the timing of their insertion on the improvement of the stability level. In this paper, we report on experiments carried out on the optimal size and switching of braking resistors, shunt capacitors, and other auxiliary devices. The experimental system model consists of a single synchronous generator connected through two parallel transmission lines to an infinite bus. © 2008 Wiley Periodicals, Inc. Electron Comm Jpn, 91(8): 11–19, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecj.10130

The correlations of the QCD Dirac eigenvalues are studied with use of an extended chiral random matrix model. The inclusion of spatial dependence which the orginal model lacks enables us to investigate the effects of diffusion modes. We get analytical expressions of level correlation functions with non-universal behavior caused by diffusion modes which is characterized by Thouless energy. Pion mode is shown to be responsible for these diffusion effects when QCD vacuum is considered a disorderd medium.

The correlations of the QCD Dirac eigenvalues are studied with use of an extended chiral random matrix model. The inclusion of spatial dependence which the original model lacks enables us to investigate the effects of diffusion modes. We get analytical expressions of level correlation functions with non-universal behavior caused by diffusion modes which is characterized by Thouless energy. Pion mode is shown to be responsible for these diffusion effects when QCD vacuum is considered a disordered medium., Comment: 17 pages, section 4.3 removed, minor changes

Applications of wheeled mobile robots have been widely expanded in the field of flexible automation. However for the purpose of smooth motion and simple planning, development of holonomic omnidirectional vehicles has been expected. To meet the requirements of holonomic omnidirectional motion, we propose a new vehicle mechanism using three balls instead of wheels, in which each driving unit consists of a servomotor and a ball. This study focuses on the analysis of dynamics and control of the vehicle. After presenting the mechanism of the vehicle, a nonlinear model which expresses the dynamics of the vehicle is derived. The analysis of the dynamics based on a linearized model clarifies the characteristics of the vehicle such as controllability and observability of the model. Thus, a simple independent ball rotational speed controller for each ball is used to realize the omnidirectional motion control of the vehicle. Validity of the model and effectiveness of the controller are evaluated based on simulations and experiments.

We present a complete analytical theory of conductance fluctuations in quantum dots in the regime of chaotic dynamics. Using the supersymmetry method we calculate for the first time exactly the conductance distribution function for a system of noninteracting electrons. Knowledge of this quantity enables us to obtain information about statistical properties of wave functions of a closed dot. The far tail of the distribution function describes fluctuations of resonance conductance in the Coulomb blockade regime

The authors consider the spectral statistics of independent electrons moving at zero temperature in a weakly disordered metallic ring threaded by a magnetic flux. The analysis is based on the supersymmetry method involving both commuting and anticommuting variables. Besides, they consider an ensemble of Gaussian distributed symmetric random matrices (Gaussian orthogonal ensemble) which are perturbed by a small time reversal symmetry breaking contribution. For energies smaller than the inverse diffusion time around the ring Ec, the spectral correlation functions of both models can be represented in terms of supermatrix integrals of identical structure. In conformity with recent numerical results, this implies that the spectral properties of the two models coincide. These matrix integrals are to a large extent universal, i.e. they depend only on two physical parameters: the mean level spacing and a symmetry breaking parameter which is identified as the typical sensitivity of levels to the time reversal symmetry breaking perturbation. The authors parametrize the relevant matrix coset space of the nonlinear sigma -model in a novel way which is particularly convenient for treating models in the crossover between the two symmetry classes. As an example, they present a detailed calculation of the level-level correlation function. The basic formalism, however, applies quite generally and can be used for the investigation of different types of correlation functions and system geometries as well.

The persistent current of a system of isolated mesoscopic rings is calculated. In such a system one has to average over impurities, keeping the number of particles in each ring constant. We show that, although a standard thermodynamic formula for the persistent current gives different results depending on whether the calculation is done with a fixed number of particles or with a fixed chemical potential, a dynamic response is not sensitive to the averaging procedure. This allows us to do a calculation with a fixed chemical potential, which is a simpler tank because well-developed methods of statistical physics baned on Green functions exist. This is true also for interacting systems

Since interferons are reported to inhibit collagen synthesis in vivo and in vitro, they are possible anti-fibrogenic drugs. However, little is known about the effect of interferons on connective tissue metabolism in liver disease. To investigate the effect, serum concentrations of the aminoterminal domain of procollagen type III and type IV (7-S collagen) were measured in 16 patients with chronic hepatitis B during alpha interferon treatment. The levels were also determined during prednisolone withdrawal treatment to investigate the effect on hepatic collagen turnover. In patients with chronic hepatitis B, the serum levels of both markers were significantly elevated before any treatment (procollagen type III: 1.10 +/- 0.39 U/ml, 7-S collagen: 6.69 +/- 3.71 ng/ml) compared with levels in 41 healthy volunteers (pro-collagen type III: 0.53 +/- 0.13 U/ml, P0.001; 7-S collagen: 4.72 +/- 0.57 ng/ml, P0.001). Both levels were even more elevated during interferon therapy (procollagen type III: 1.36 +/- 0.58 U/ml, P0.05; 7-S collagen: 8.77 +/- 4.68 ng/ml, P0.01). On the other hand, serum procollagen type III and 7-S collagen levels were both decreased during prednisolone treatment (procollagen type III: 0.62 +/- 0.13 U/ml, P0.001; 7-S collagen: 4.66 +/- 1.69 ng/ml, P0.01). These preliminary data suggest that interferon alpha enhanced, but prednisolone inhibited the turnover of procollagen type III and IV in the liver. Further study is required to interpret this observation in relation to anti-fibrotic therapy.

We calculate the persistent current induced at zero temperature by an external, constant, and homogeneous magnetic field in an ensemble of isolated mesoscopic rings. In each ring, the electrons are assumed to move independently under the influence of a Gaussian white noise random impurity potential. We account for the magnetic field only in terms of the flux threading each ring, without considering the field present in the body of the ring. We pay particular attention to the constraint of integer particle number on each ring. We evaluate the persistent current non-perturbatively, using a generating functional involving Grassmann integration. The magnetic flux threading each ring breaks the orthogonal symmetry of the formalism; forcing us to calculate explicitly the orthogonal-unitary crossover. The resulting expression for the average persistent current is paramagnetic, periodic in the flux with a period of half the elementary flux quantum φ0, odd when the sign of the flux is reversed, and has a maximum value of about 0.3 E c d φ 0 , where d is the mean level spacing and Ec the Thouless energy. This is about two orders of magnitude below experiment.

Using the supersymmetry method we present a nonperturbative calculation of the ensemble-averaged persistent current at zero temperature. Special care is taken to exactly restrict the particle number on each ring to an integer value. Our result is obtained by integrating exactly over a Goldstone mode of zero momentum in a domain of flux values where perturbation theory fails. Thus we extend previous perturbative calculations to the vicinity of half-integer multiples of the magnetic-flux quantum, a regime inaccessible up to now at zero temperature.

This paper describes a novel analytical approach to the problem of conductance fluctuations in mesoscopic systems which, in particular, gives account of the influence of the coupling to external leads. We consider the case of a linear disordered sample in the metallic regime, which is coupled to two ideally conducting external leads. Using the many-channel approximation to Landauer's formula, we relate the conductance to the total transmission probability through the sample. The microscopic Hamiltonian of the quasi-one-dimensional disordered sample is formulated in terms of a random matrix, and the elements of the associated scattering matrix which determine the transmission are constructed from statistical scattering theory. We show that in addition to the Thouless energy, Ec, and the mean level spacing, d, there exists in the theory, a third energy scale, Γ, determined by the number of channels in the leads and the strength of the coupling between disordered sample and leads. Related to Γ, is a new length scale, L0. We find that for sample lengths L >L0, the properties of the conductance depend only weakly on the coupling to the external leads and, for very large L, become identical with those of quasi-one-dimensional conductors in the weak localization limit. On the other hand, for L

A general stochastic traffic cellular automaton (CA) model, which includes slow-to-start effect and driver's perspective, is proposed in this paper. It is shown that this model includes well known traffic CA models such as Nagel-Schreckenberg model, Quick-Start model, and Slow-to-Start model as specific cases. Fundamental diagrams of this new model clearly show metastable states around the critical density even when stochastic effect is present. We also obtain analytic expressions of the phase transition curve in phase diagrams by using approximate flow-density relations at boundaries. These phase transition curves are in excellent agreement with numerical results., 16 pages, 13 figures

We calculate two-point energy level correlation function in weakly disorderd metallic grain with taking account of localization corrections to the universal random matrix result. Using supersymmetric nonlinear sigma model and exactly integrating out spatially homogeneous modes, we derive the expression valid for arbitrary energy differences from quantum to diffusive regime for the system with broken time reversal symmetry. Our result coincides with the one obtained by Andreev and Altshuler [Phys. Rev. Lett. 72, 902 (1995)] where homogeneous modes are perturbatively treated., Comment: 12 pages, no figure, REVTeX 3.1 with pLaTeX 2e; v2: minor grammatical changes

We study S-matrix correlations for random matrix ensembles with a Hamiltonian which is the sum of a given deterministic part and of a random matrix with a Gaussian probability distribution. Using Efetov's supersymmetry formalism, we show that, in the limit of infinite matrix size of the Hamiltonian, correlation functions of S-matrix elements are universal on the scale of the local mean level spacing: the dependence of the deterministic part enters into these correlation functions only through the average S-matrix and the average level density. This statement applies to each of the three symmetry classes (orthogonal, unitary, and symplectic)., 5 pages, no figure, REVTeX 3.1 with pLaTeX 2e. Minor corrections, references added. Accepted for publication in Phys. Rev. E

We investigate the deviation of the level-correlation functions from the universal form for the chiral symmetric classes. Using the supersymmetric nonlinear sigma model we formulate the perturbation theory. The large energy behavior is compared with the result of the diagrammatic perturbation theory. We have the diffuson and cooperon contributions even in the average density of states. For the unitary and orthogonal classes we get the small energy behavior that suggests a weakening of the level repulsion. For the symplectic case we get a result with opposite tendency., Comment: 7 pages, revtex, 2 eps figures, references added, some minor changes

Background: Theserum erythropoietin level increases markedly during chemotherapy for leukemia. A number of hypotheses have been built for the mechanism, none of them satisfactory. Difficulty in evaluating bone marrow activity hampers the elucidation. Therefore, we focused on patients who had non-hematological cancer and no evidence of bone marrow suppression. Methods: Twelve patients, who had lung cancer (fourwith small cellcancer andeight with non-small cell cancer) and who had not undergone any chemotherapy, were studied. During chemotherapy, we measured serum erythropoietin, serum iron, unsaturated iron binding capacity and hemoglobin concentration in these patients. Results: Theserum erythropoietin level before chemotherapy (10.8 ± 7.4mU/ml) waswithin the normal range butthepeakvalues afterthe first treatment (73.4 ± 90.4mU/ml) increased in all patients. In the patients with small cell cancer, a transient but marked increase in erythropoietin value (204.6 ± 167.3 mU/ml) was observed after each session of chemotherapy while hemoglobin concentration decreased gradually. Throughout treatments, elevation of the serum iron concentration and concomitant reduction of unsaturated iron binding capacity were observed after each session of chemotherapy. They regained their original values whilst the serum erythropoietin level decreased after each chemotherapy session was completed. Conclusions: It is suggested that the suppression of erythroid marrow by chemo­ therapeutic agents causes the changes in serum erythropoietin level during chemotherapy in patients with lung cancer.

By extending the supersymmetry formalism we develop a statistical description for the conductance through a quantum dot coupled to external leads with point contacts. The electronic states inside the dot are formed by both the random and regular parts of confinement potential and have a finite lifetime due to the presence of the external contacts. The explicit form of the distribution function for the one-channel conductance is obtained. This function depends in a universal way on the transmission coefficients between the dot and the leads. The generalization of the results for the low-frequency impedance of the dot is suggested.

We characterized six self-indicating substrates, synthesized as the derivative compounds of acetylphenyl phosphate, for serum prostatic acid phosphatase (PAP) activity. One of the substrates, 2,6-dichloro-4-acetylphenyl phosphate (DCAPP), is superior to others in terms of stability, affinity, and low Km for PAP. The hydrolyzed product, 2,6-dichloro-4-acetylphenol (DCAP), has a maximum absorption at 334.2 nm, a pKa of 4.15, and a molar absorptivity at 340 nm of 21,490 L.mol-1.cm-1 in citrate-HCl buffer, pH 5.4. PAP activity was assessed by subtracting tartaric acid-inhibited acid phosphatase activity from total acid phosphatase activity. Our assay system involving DCAPP is a unique kinetic method that shows good reproducibility, wide analytical dynamic range, and high specificity for PAP. Moreover, it is easily adaptable to automated analyzers because the product, DCAP, can be monitored at 340 nm.

We describe a new precipitation method for high-density-lipoprotein cholesterol quantitation. The new method uses magnetic force instead of centrifugal force to separate highdensity-lipoprotein from other lipoproteins that are fractioned with a precipitating reagent. The reagents used for the new method are the same as those for the conventional method except that magnetizable particles are included in the former. The magnetizable particles are used without any modifications. The correlation between the new and the centrifuge methods with dextran sulfate-magnesium chloride, sodium phosphotungstate-magnesium chloride and polyethylene glycol 6,000 were satisfactory ( r = 0.990, 0.997 and 0.997, respectively). The new method, which can be combined with any precipitating reagents used in conventional methods, is very simple to perform and does not need any special equipment.

The time evolution of a wave packet within a disordered quantum dot is investigated. It is shown that although the disorder-averaged electron density is nearly homogeneous at times of the order of the diffusive time across the dot, at larger times there is a remarkable evolution towards a state with incrasing correlation with the original state i.e., an echo appears). At long times compared to the inverse mean level spacing the density distirubiton becomes time independent and preserves a memory of the original state. These effects are shown to reveal themselves in the relaxation of current through a quantum dot weakly coupled to reservoirs.

Calcul de la moyenne et de la variance des coefficients de la conductance a la temperature nulle pour un fil metallique desordonne compose de trois branches, en utilisant la theorie statistique de la diffusion. Chaque branche est couplee a son extremite a une branche parfaitement conductrice. Le desordre est modelise par un Hamiltonien aleatoire microscopique appartenant a l'ensemble orthogonal Gaussien. L'augmentation de la force de couplage du troisieme bras (sonde de tension) entraine la modification de la variance du coefficient de la conductance de la trace principale de la valeur universelle de la geometrie a deux bras vers celle de la geometrie a trois bras. La variance du coefficient de la resistance est fortement affectee par la force de couplage du bras dont on mesure la resistance

Calcul analytique, en utilisant l'approximation a plusieurs canaux de la formule de Landauer et une theorie statistique de diffusion, de la moyenne et de la variance de la conductance d'un echantillon desordonne decrit par un hamiltonien aleatoire et couple a chaque bout a un conducteur parfait. Ce couplage affecte fortement le comportement de la conductivite pur les echantillons L≤L 0 ou L 0 est une longueur caracteristique dix fois superieure au libre parcours moyen elastique. Pour L≥L 0 , ce couplage n'est pas significatif

A complete analytical theory of conductance fluctuations in quantum dots is developed. For the first time the conductance distribution function is calculated exactly. The calculations are performed using the supersymmetry method.

It is shown that the ordinary framework of (adiabatic) time-dependent Hartree-Fock method can uniquely speCify the collective submanifold and its canonical coordinate system, with the aid of the RP A and the canonicity condition. Some criticism is given to the pesimistic viewpoint concerning the unique specification of collective submanifold within the adiabatic time-dependent Hartree-Fock method. A decisive foundation of the approach developed by Marumori, Maskawa, Sakata and one of the present authors (A. K.) is given.