Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.

BACKGROUND: Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. METHODS: Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. RESULTS: A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. CONCLUSIONS: Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.

From collective periodic running states to completely chaotic synchronised states in coupled particle dynamics.

We consider the damped and driven dynamics of two interacting particles evolving in a symmetric and spatially periodic potential. The latter is exerted to a time-periodic modulation of its inclination. Our interest is twofold: First, we deal with the issue of chaotic motion in the higher-dimensional phase space. To this end, a homoclinic Melnikov analysis is utilised assuring the presence of transverse homoclinic orbits and homoclinic bifurcations for weak coupling allowing also for the emergence of hyperchaos. In contrast, we also prove that the time evolution of the two coupled particles attains a completely synchronised (chaotic) state for strong enough coupling between them. The resulting "freezing of dimensionality" rules out the occurrence of hyperchaos. Second, we address coherent collective particle transport provided by regular periodic motion. A subharmonic Melnikov analysis is utilised to investigate persistence of periodic orbits. For directed particle transport mediated by rotating periodic motion, we present exact results regarding the collective character of the running solutions entailing the emergence of a current. We show that coordinated energy exchange between the particles takes place in such a manner that they are enabled to overcome--one particle followed by the other--consecutive barriers of the periodic potential resulting in collective directed motion.

Current control in a tilted washboard potential via time-delayed feedback.

We consider the motion of an overdamped Brownian particle in a washboard potential exerted to a static tilting force. The bias yields directed net particle motion, i.e., a current. It is demonstrated that with an additional time-delayed feedback term, the particle current can be reversed against the direction of the bias. The control function induces a ratchetlike effect that hinders further current reversals and thus the particle moves against the direction of the static bias. Furthermore, varying the delay time allows also to continuously depreciate and even stop the transport in the washboard potential. We identify and characterize the underlying mechanism which applies to the current control in a wide temperature range.

Directed transport of an inertial particle in a washboard potential induced by delayed feedback.

We consider motion of an underdamped Brownian particle in a washboard potential that is subjected to an unbiased time-periodic external field. While in the limiting deterministic system in dependence of the strength and phase of the external field directed net motion can exist; for a finite temperature the net motion averages to zero. Strikingly, with the application of an additional time-delayed feedback term directed particle motion can be accomplished persisting up to fairly high levels of the thermal noise. In detail, there exist values of the feedback strength and delay time for which the feedback term performs oscillations that are phase locked to the time-periodic external field. This yields an effective biasing rocking force promoting periods of forward and backward motion of distinct duration, and thus directed motion. In terms of phase space dynamics we demonstrate that with applied feedback desymmetrization of coexisting attractors takes place leaving the ones supporting either positive or negative velocities as the only surviving ones. Moreover, we found parameter ranges for which in the presence of thermal noise the directed transport is enhanced compared to the noiseless case.

Transition between locked and running states for dimer motion induced by periodic external driving.

We study the motion of a dimer in a one-dimensional spatially periodic washboard potential. The tilt of the latter is time-periodically modulated by an ac field. We focus interest on the detrapping of the (static) ground state solution of the dimer caused by the ac field. Moreover, we demonstrate that slow tilt modulations not only induce a trapping-detrapping transition but drive the dimer dynamics into a regime of transient long-range running states. Most strikingly, the motion proceeds then unidirectionally, so that the dimer covers huge distances regardless of the fact that the bias force in the driven system vanishes on the average. We elucidate the underlying dynamics in phase space and associate long-lasting running states with the motion in ballistic channels occurring due to stickiness to invariant tori.

Compounds of paired electrons and lattice solitons moving with supersonic velocity.

We study the time evolution of two correlated electrons of opposite spin in an anharmonic lattice chain. The electrons are described quantum mechanically by the Hubbard model while the lattice is treated classically. The lattice units are coupled via Morse-Toda potentials. Interaction between the lattice and the electrons arises due to the dependence of the electron transfer-matrix element on the distance between neighboring lattice units. Localized configurations comprising a paired electron and a pair of lattice deformation solitons are constructed such that an associated energy functional is minimized. We investigate long-lived, stable pairing features. It is demonstrated that traveling pairs of lattice solitons serve as carriers for the paired electrons realizing coherent transport of the two correlated electrons. We also observe dynamical narrowing of the states, that is, starting from an initial double-peak profile of the electron probability distribution, a single-peak profile is adopted going along with enhancement of localization of the paired electrons. Interestingly, a parameter regime is identified for which supersonic transport of paired electrons is achieved.

Deterministic escape dynamics of two-dimensional coupled nonlinear oscillator chains.

We consider the deterministic escape dynamics of a chain of coupled oscillators under microcanonical conditions from a metastable state over a cubic potential barrier. The underlying dynamics is conservative and noise free. We introduce a two-dimensional chain model and assume that neighboring units are coupled by Morse springs. It is found that, starting from a homogeneous lattice state, due to the nonlinearity of the external potential the system self-promotes an instability of its initial preparation and initiates complex lattice dynamics leading to the formation of localized large amplitude breathers, evolving in the direction of barrier crossing, accompanied by global oscillations of the chain transverse to the barrier. A few chain units accumulate locally sufficient energy to cross the barrier. Eventually the metastable state is left and either these particles dissociate or pull the remaining chain over the barrier. We show this escape for both linear rodlike and coil-like configurations of the chain in two dimensions.

Resonancelike phenomena in the mobility of a chain of nonlinear coupled oscillators in a two-dimensional periodic potential.

We study the Langevin dynamics of a two-dimensional discrete oscillator chain absorbed on a periodic substrate and subjected to an external localized point force. Going beyond the commonly used harmonic bead-spring model, we consider a nonlinear Morse interaction between the next-nearest neighbors. We focus interest on the activation of directed motion instigated by thermal fluctuations and the localized point force. In this context the local transition states are identified and the corresponding activation energies are calculated. It is found that the transport of the chain in point force direction is determined by stepwise escapes of a single unit or segments of the chain due to the existence of multiple locally stable attractors. The nonvanishing net current of the chain is quantitatively assessed by the value of the mobility of the center of mass. It turns out that the latter as a function of the ratio of the competing length scales of the system, that is the period of the substrate potential and the equilibrium distance between two chain units, shows a resonance behavior. More precisely there exists a set of optimal parameter values maximizing the mobility. Interestingly, the phenomenon of negative resistance is found, i.e., the mobility possesses a minimum at a finite value of the strength of the thermal fluctuations for a given overcritical external driving force.

Synchronization and firing death in the dynamics of two interacting excitable units with heterogeneous signals.

We study the response of two coupled FitzHugh-Nagumo systems to heterogeneous external inputs. The latter, modeled by periodic parametric stimuli, force the uncoupled excitable systems into a regime of chaotic firing. Due to parameter dispersion involved in randomly distributed amplitudes and/or phases of the external forces the units are nonidentical and their firing events will be asynchronous. Interest is focused on mutually synchronized spikings arising through the coupling. It is demonstrated that the phase difference of the two external forces crucially affects the onset of spike synchronization as well as the resulting degree of synchrony. For large phase differences the degree of spike synchrony is constricted to a maximal possible value and cannot be enhanced upon increasing the coupling strength. We even found that overcritically strong couplings lead to suppression of firing so that the units perform synchronous subthreshold oscillations. This effect, which we call "firing death," is due to a coupling-induced modification of the excitation threshold impeding spiking of the units. In clear contrast, when only the amplitudes of the forces are distributed perfect spike synchrony is achieved for sufficiently strong coupling.

Self-organized escape of oscillator chains in nonlinear potentials.

We present the noise-free escape of a chain of linearly interacting units from a metastable state over a cubic on-site potential barrier. The underlying dynamics is conservative and purely deterministic. The mutual interplay between nonlinearity and harmonic interactions causes an initially uniform lattice state to become unstable, leading to an energy redistribution with strong localization. As a result, a spontaneously emerging localized mode grows into a critical nucleus. By surpassing this transition state, the nonlinear chain manages a self-organized, deterministic barrier crossing. Most strikingly, these noise-free, collective nonlinear escape events proceed generally by far faster than transitions assisted by thermal noise when the ratio between the average energy supplied per unit in the chain and the potential barrier energy assumes small values.

Electron capture and transport mediated by lattice solitons.

We study electron transport in a one-dimensional molecular lattice chain. The molecules are linked by Morse interaction potentials. The electronic degree of freedom, expressed in terms of a tight binding system, is coupled to the longitudinal displacements of the molecules from their equilibrium positions along the axis of the lattice. More specifically, the distance between two sites influences in an exponential fashion the corresponding electronic transfer matrix element. We demonstrate that when an electron is injected in the undistorted lattice it causes a local deformation such that a compression results leading to a lowering of the electron's energy below the lower edge of the band of linear states. This corresponds to self-localization of the electron due to a polaronlike effect. Then, if a traveling soliton lattice deformation is launched a distance apart from the electron's position, upon encountering the polaronlike state it captures the latter dragging it afterwards along its path. Strikingly, even when the electron is initially uniformly distributed over the lattice sites a traveling soliton lattice deformation gathers the electronic amplitudes during its traversing of the lattice. Eventually, the electron state is strongly localized and moves coherently in unison with the soliton lattice deformation. This shows that for the achievement of coherent electron transport we need not start with the polaronic effect.

Regular patterns in dichotomically driven activator-inhibitor dynamics.

We investigate Turing pattern formation in the presence of additive dichotomous fluctuations in the context of an extended system with diffusive coupling and FitzHugh-Nagumo kinetics. The fluctuations vary in space and/or time. Depending on the realization of the dichotomous switching the system is, at a given time (for spatial disorder at a given position) in one of two possible excitable dynamical regimes. Each of the two excitable dynamics for itself does not support pattern formation. With proper dichotomous fluctuations, however, the homogeneous steady state is destabilized via a Turing instability. We investigate the influence of different switching rates (different correlation length of the spatial disorder) on pattern formation. We find three distinct mechanisms: For slow switching existing boundaries become unstable, for high rates the system exhibits "effective bistability" which allows for a Turing instability. For medium rates the fluctuations create spatial structures via a new mechanism where the influence of the fluctuations is twofold. First they produce local inhomogeneities, which then grow (again caused by fluctuations) until the whole space is covered. Utilizing a nonlinear map approach we show bistability of a period-one and a period-two orbit being associated with the steady homogeneous and the Turing pattern state, respectively. Finally, for purely static dichotomous disorder we find destabilization of homogeneous steady states for finite nonzero correlation length of the disorder resulting again in Turing patterns.

Modelling the thermal evolution of enzyme-created bubbles in DNA.

The formation of bubbles in nucleic acids (NAs) is fundamental in many biological processes such as DNA replication, recombination, telomere formation and nucleotide excision repair, as well as RNA transcription and splicing. These processes are carried out by assembled complexes with enzymes that separate selected regions of NAs. Within the frame of a nonlinear dynamics approach, we model the structure of the DNA duplex by a nonlinear network of coupled oscillators. We show that, in fact, from certain local structural distortions, there originate oscillating localized patterns, that is, radial and torsional breathers, which are associated with localized H-bond deformations, reminiscent of the replication bubble. We further study the temperature dependence of these oscillating bubbles. To this aim, the underlying nonlinear oscillator network of the DNA duplex is brought into contact with a heat bath using the Nosé-Hoover method. Special attention is paid to the stability of the oscillating bubbles under the imposed thermal perturbations. It is demonstrated that the radial and torsional breathers sustain the impact of thermal perturbations even at temperatures as high as room temperature. Generally, for non-zero temperature, the H-bond breathers move coherently along the double chain, whereas at T=0 standing radial and torsional breathers result.

Mobile polaron solutions and nonlinear electron transfer in helical protein models.

We consider the electron transfer along helical forms of proteins. The spatial structure of the protein helices is modeled by three-dimensional oscillator networks whose constituents represent peptide groups. Covalent and hydrogen bonds between the peptide units are modeled by point-point interaction potentials. The electronic degree of freedom is described by a tight-binding system including besides the nearest-neighbor exchange interactions between covalently connected units also third- or fourth-nearest neighbor interactions between hydrogen-bonded sites. In addition each peptide unit possesses an internal vibrational degree of freedom. The various dynamical degrees of freedom are coupled to each other making the exchange of electronic, intramolecular, and bond-vibrational energy possible. In the first part of the paper we investigate the static polaron formation resulting from strong interactions between the electron and the intramolecular vibrations. The 3-10 helix and the alpha helix are investigated. Polaron states are constructed analytically on the basis of a variational approach. Compared to the alpha helix the 3-10 helix supports stronger localized polarons. In the second part of the paper we take the coupling of the polaron with the vibrations of the three-dimensional protein matrix into account focusing interest on the bond-assisted initiation of polaron motion. In detail it is demonstrated that the interplay of the protein matrix and the polaron dynamics conspire to activate not only the polaron motion but also to maintain a long-lived coherently traveling localized pattern along the lattice of peptide units. Starting from a nonequilibrium state it is shown that coexisting electron and bond-vibration breathers assist the relaxation dynamics towards energy equilibration and the attainment of a stationary regime.

[The effect of selected disintegrants on the properties of three hydrochlorothiazide tablet formulations]. / Einfluss ausgewählter Sprengmittel auf die Eigenschaften von drei Hydrochlorothiazid-Tablettenrezepturen.

The admixture of disintegrants was investigated in three different hydrochlorothiazide formulations with respect to tablet properties. Sodiumcarboxymethyl starchs, Na-CMS (Explotab, Primojel, Na-CMS AB-G.D.R.), cross-linked polyvinylpyrrolidone, CL PVP (Polyplasdone) and potato starch were applied. The investigations were especially aimed at the alteration of tablet properties in dependence on compressive force. Considering the values of decomposition and compressive strength Polyplasdone XL has been proved to be the most effective disintegrant for the hydrochlorothiazide formulations investigated. Potato starch shows the worst results. There are only slight differences between the three Na-CMS.

[Application of polyethylene glycol (PEG) to the control of permeability of poly(meth)acrylate coatings]. / Einsatz von Polyethylenglycol (PEG) zur Steuerung der Permeabilität von Poly(meth)acrylatüberzügen.

Pellets with pholedrine sulphate are coated by means of a fluid-bed process with poly(meth)acrylate materials (Eudragit RS, Eudragit E 30 D, Scopacryl D 340) and varying portions of PEG 6000. In addition to influencing drug release by change of the thickness it was studied the admixture of PEG to the films. Figure logarithm permeability coefficient vs. the portion of PEG can be used to select a coating composition with wished permeability. By application of aqueous latex dispersions (Eudragit E 30 D, Scopacryl D 340) PEG dissolves completely very fast from the coatings. On the other hand if organic lac solution (Eudragit RS) is used a stagnation of the dissolution process after some min is observed. By leaching out the PEG the structure of the resulting films is loosened and therefore its permeability is increased.

[Use of poly(meth)acrylates for the control and release of pholedrine sulfate from microdragees]. / Einsatz von Poly(meth)acrylaten zur Steuerung der Freisetzung von Pholedrinsulfat aus Mikrodragees.

Pellets with pholedrine sulphate are coated by means of a fluid-bed process with six different poly(meth)acrylate coating materials. The coatings showed drug release widely different. A wide pH-independent release showed film-coated pellets with Eudragit RS, RL and E 30D as coating material. By application of Scopacryl D 336, D 339 and D 340 the acceleration of liberation by the pH-value of 7,4 is related to the increasing amount of acrylic acid in polymer. The rate of release can be controlled by mixing coatings with different permeability in wide range. Diagram of logarithm permeability coefficient against the mixing proportion can be used for selection a coating composition with wished permeability.

[The influence of plasticizers on the permeability of polymethacrylate films (Eudragit RS)]. / Einfluss von Weichmachern auf die Permeabilität von Polymethacrylatüberzügen (Eudragit RS).

Pellets with pholedrine sulphate are coated by means of a fluid-bed process with polymethacrylates and increasing portions of plasticizers. The addition of PEG 6000 increased the film permeability. On the other hand triacetin effected no change and dibuthyl phthalate decreased the permeability in relation to films without plasticizers. When the films were contacted 8 h with phosphate buffer (pH = 7,4) PEG could not be detected and triacetin film contents was reduced to about 30%. Unlike that the portion of dibuthyl phthalate decreased insignificantly.

[The in vitro liberation behavior of quinidine from drug forms with prolonged release by various liberation methods]. / Untersuchungen zum in-vitro-Freisetzungsverhalten von Chinidin aus Arzneiformen mit verlängerter Wirksamkeit anhand verschiedener Liberationsmodelle.

The liberation behaviour of the following preparations were tested using two models: Chinidin-Duriles (Astra, Sweden), Chinidin-longo (VEB Isis-Chemie Zwickau, GDR), Chinidin-retard-Isis (VEB Isis-Chemie Zwickau, GDR). The received data were estimated by multivariate statistical methods. It was found, that the three tested preparations are different in their liberation behaviour. Moreover it was shown, that there are differences between the two apparatus. Nevertheless both methods are able to characterize the liberation behaviour of the three preparations.

[The stability of hydrochlorothiazide and cyclopenthiazide in various drug forms. 2. The stability of Disalunil tablets]. / Untersuchungen zur Stabilität von Hydrochlorothiazid und Cyclopenthiazid in unterschiedlichen Arzneiformen. 2. Mitteilung: Stabilität von Disalunil-Tabletten.

Checking-up the stability of hydrochlorothiazid tablets (Disalunil), chemical and especially pharmaceutical-technological analyses were forming part of the adequate test programme. The pharmaceutical and chemical properties of the Disalunil tablets will be regarded as sufficient ones at normal conditions of their storage. In case the tablets will be stored, however, in their original packing under conditions of an increased humidity or with additional water, the water sorption will result in prolonged disintegration rates as well as in a reduced radial breaking strength and dissolution rate. This significant depreciation of the drug cannot be recognized by chemical-analytical methods.