Real-space model for activated processes in rejuvenation and memory behavior of glassy systems.

We offer an alternative real-space description, based purely on activated processes, for the understanding of relaxation dynamics in hierarchical landscapes. To this end, we use the cluster model, a coarse-grained lattice model of a jammed system, to analyze rejuvenation and memory effects during aging after a hard quench. In this model, neighboring particles on a lattice aggregate through local interactions into clusters that fragment with a probability based on their size. Despite the simplicity of the cluster model, it has been shown to reproduce salient observables of the aging dynamics in colloidal systems, such as those accounting for particle mobility and displacements. Here, we probe the model for more complex quench protocols and show that it exhibits rejuvenation and memory effects similar to those attributed to the complex hierarchical structure of a glassy energy landscape.

Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat.

Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.

Density fluctuations in granular piles traversing the glass transition: A grain-scale characterization via the internal energy.

The transition into a glassy state of the ensemble of static, mechanically stable configurations of a tapped granular pile is explored using extensive molecular dynamics simulations. We show that different horizontal subregions ("layers") along the height of the pile traverse this transition in a similar manner but at distinct tap intensities. We supplement the conventional approach based purely on properties of the static configurations with investigations of the grain-scale dynamics by which the tap energy is transmitted throughout the pile. We find that the effective energy that particles dissipate is a function of each particle's location in the pile and, moreover, that its value plays a distinctive role in the transformation between configurations. This internal energy provides a "temperature-like" parameter that allows us to align the transition into the glassy state for all layers, as well as different annealing schedules, at a critical value.

Universal features of annealing and aging in compaction of granular piles.

This paper links the nonequilibrium glassy relaxation behavior of otherwise athermal granular materials to those of thermally activated glasses. Thus, it demonstrates a much wider universality among complex glassy materials out of equilibrium. Our three-dimensional molecular dynamics simulations, fully incorporating friction and inelastic collisions, are designed to reproduce experimental behavior of tapped granular piles. A simple theory based on a dynamics of records explains why the typical phenomenology of annealing and aging after a quench should extend to such granular matter, activated by taps, beyond the more familiar realm of polymers, colloids, and magnetic materials that all exhibit thermal fluctuations.

Ground State Properties of the Diluted Sherrington-Kirkpatrick Spin Glass.

We present a numerical study of ground states of the dilute versions of the Sherrington-Kirkpatrick (SK) mean-field spin glass. In contrast to so-called "sparse" mean-field spin glasses that have been studied widely on random networks of finite (average or regular) degree, the networks studied here are randomly bond diluted to an overall density p, such that the average degree diverges as ∼pN with the system size N. Ground state energies are obtained with high accuracy for random instances over a wide range of fixed p. Since this is an NP-hard combinatorial problem, we employ the extremal optimization heuristic to that end. We find that the exponent describing the finite-size corrections ω varies continuously with p, a somewhat surprising result, as one would not expect that gradual bond dilution would change the T=0 universality class of a statistical model. For p→1, the familiar result of ω(p=1)≈2/3 for the SK model is obtained.

Two-time correlations for probing the aging dynamics of glassy colloids.

We present results for the aging dynamics of a dense 2D colloidal system obtained with molecular dynamics simulations. To this end, systems are quenched to densities far above the glass transition with relaxation time scales that used to be prohibitive for such a comprehensive study. We performed extensive simulations to gather detailed statistics about rare rearrangement events. With a simple criterion for identifying irreversible events based on Voronoi tessellations, we find that the rate of those events decelerates hyperbolically. We track the probability density function for particle displacements, the van-Hove function, with sufficient statistics as to reveal its two-time dependence that is indicative of aging. Those displacements, measured from a waiting time tw after the quench up to times t, exhibit a data collapse as a function of t/tw. These findings can be explained comprehensively as manifestations of record dynamics, i.e., a relaxation dynamic driven by record-breaking fluctuations. We show that an on-lattice model of a colloid that was built on record dynamics indeed reproduces the experimental results in great detail.

Aging is a log-Poisson process, not a renewal process.

Aging is a ubiquitous relaxation dynamic in disordered materials. It ensues after a rapid quench from an equilibrium "fluid" state into a nonequilibrium, history-dependent jammed state. We propose a physically motivated description that contrasts sharply with a continuous-time random walk (CTRW) with broadly distributed trapping times commonly used to fit aging data. A renewal process such as CTRW proves irreconcilable with the log-Poisson statistic exhibited, for example, by jammed colloids as well as by disordered magnets. A log-Poisson process is characteristic of the intermittent and decelerating dynamics of jammed matter usually activated by record-breaking fluctuations ("quakes"). We show that such a record dynamics provides a universal model for aging, physically grounded in generic features of free-energy landscapes of disordered systems.

Record dynamics in the parking-lot model.

We present an analytical and numerical study of the parking lot model (PLM) of granular relaxation and make a connection to the aging dynamics of dense colloids. As we argue, the PLM is a Kinetically Constrained Model which features astronomically large equilibration times and displays a characteristic aging behavior on all observable time scales. The density of parked cars displays quasi-equilibrium Gaussian fluctuations interspersed by increasingly rare intermittent events, quakes, which can lead to an increase of the density to new record values. Defining active clusters as the shortest domains of parked cars which must be rearranged to allow further insertions, we find that their typical length grows logarithmically with time for low enough temperatures and show how the number of active clusters on average gradually decreases as the system approaches equilibrium. We further characterize the aging process in terms of the statistics of the record-sized fluctuations in the interstitial free volume which lead to quakes and show that quakes are uncorrelated and that they can be approximately described as a Poisson process in logarithmic time.

From explosive to infinite-order transitions on a hyperbolic network.

We analyze the phase transitions that emerge from the recursive design of certain hyperbolic networks that includes, for instance, a discontinuous ("explosive") transition in ordinary percolation. To this end, we solve the q-state Potts model in the analytic continuation for noninteger q with the real-space renormalization group. We find exact expressions for this one-parameter family of models that describe the dramatic transformation of the transition. In particular, this variation in q shows that the discontinuous transition is generic in the regime q<2 that includes percolation. A continuous ferromagnetic transition is recovered in a singular manner only for the Ising model, q=2. For q>2 the transition immediately transforms into an infinitely smooth order parameter of the Berezinskii-Kosterlitz-Thouless type.

Mesoscopic model of temporal and spatial heterogeneity in aging colloids.

We develop a simple and effective description of the dynamics of dense hard sphere colloids in the aging regime deep in the glassy phase. Our description complements the many efforts to understand the onset of jamming in low density colloids, whose dynamics is still time-homogeneous. Based on a small set of principles, our model provides emergent dynamic heterogeneity, reproduces the known results for dense hard sphere colloids and makes detailed, experimentally-testable predictions for canonical observables in glassy dynamics. In particular, we reproduce the shape of the intermediate scattering function and particle mean-square displacements for jammed colloidal systems, and we predict a growth for the peak of the χ(4) mobility correlation function that is logarithmic in waiting-time. At the same time, our model suggests a novel unified description for the irreversible aging dynamics of structural and quenched glasses based on the dynamical properties of growing clusters of highly correlated degrees of freedom.

Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue.

Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5'-defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development.

Scaling of clusters near discontinuous percolation transitions in hyperbolic networks.

We investigate the onset of the discontinuous percolation transition in small-world hyperbolic networks by studying the systems-size scaling of the typical largest cluster approaching the transition, p ↗ p(c). To this end, we determine the average size of the largest cluster 〈s(max)〉 ∼ N(Ψ(p)) in the thermodynamic limit using real-space renormalization of cluster-generating functions for bond and site percolation in several models of hyperbolic networks that provide exact results. We determine that all our models conform to the recently predicted behavior regarding the growth of the largest cluster, which found diverging, albeit subextensive, clusters spanning the system with finite probability well below p(c) and at most quadratic corrections to unity in Ψ(p) for p ↗ p(c). Our study suggests a large universality in the cluster formation on small-world hyperbolic networks and the potential for an alternative mechanism in the cluster formation dynamics at the onset of discontinuous percolation transitions.

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis.

Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease.

Cooking enhances curcumin anti-cancerogenic activity through pyrolytic formation of "deketene curcumin".

Curcumin is widely used in traditional Asian kitchen as a cooking ingredient. Despite its low bioavailability, epidemiological data, on low cancer incidence in Asia, suggest beneficial health effects of this compound. Therefore, the question arose whether cooking modifies the anti-cancerogenic effects of curcumin. To evaluate this, we pyrolysed curcumin with and without coconut fat or olive oil, and analysed the products by high-performance liquid chromatography (HPLC). A number of more hydrophilic curcumin isoforms and decomposition products, including a compound later identified by nuclear magnetic resonance spectroscopy (NMR) as "deketene curcumin" (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one), formerly described as a synthetic curcumin derivative, were detected. Additionally, we proved that deketene curcumin, compared to curcumin, exhibits higher toxicity on B78H1 melanoma cells resulting in G2 arrest. In conclusion, deketene curcumin is formed as a consequence of pyrolysis during common household cooking, showing stronger anti-cancer effects than curcumin. Moreover, we propose a chemical reaction-pathway for this process.

Peptide-based investigation of the Escherichia coli RNA polymerase σ(70):core interface as target site.

The number of bacterial strains that are resistant against antibiotics increased dramatically during the past decades. This fact stresses the urgent need for the development of new antibacterial agents with novel modes of action targeting essential enzymes such as RNA polymerase (RNAP). Bacterial RNAP is a large multi-subunit complex consisting of a core enzyme (subunits: α(2)ßß'ω) and a dissociable sigma factor (σ(70); holo enzyme: α(2)ßß'ωσ(70)) that is responsible for promoter recognition and transcription initiation. The interface between core RNAP and σ(70) represents a promising binding site. Nevertheless, detailed studies investigating its druggability are rare. Compounds binding to this region could inhibit this protein-protein interaction and thus holo enzyme formation, resulting in inhibition of transcription initiation. Sixteen peptides covering different regions of the Escherichia coli σ(70):core interface were designed; some of them-all derived from σ(70) 2.2 region-led to a strong RNAP inhibition. Indeed, an ELISA-based experiment confirmed the most active peptide P07 to inhibit the σ(70):core interaction. Furthermore, an abortive transcription assay revealed that P07 impedes transcription initiation. In order to study the mechanism of action of P07 in more detail, molecular dynamics simulations and a rational amino acid replacement study were performed, leading to the conclusion that P07 binds to the coiled-coil region in ß' and that its flexible N-terminus inhibits the enzyme by interaction with the ß' lid-rudder-system (LRS). This work revisits the ß' coiled-coil as a hot spot for the protein-protein interaction inhibition and expands it by introduction of the LRS as target site.

2-(3-Oxo-1,3-diphenylpropyl)malonic acids as potent allosteric ligands of the PIF pocket of phosphoinositide-dependent kinase-1: development and prodrug concept.

The protein kinase C-related kinase 2 (PRK2)-interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, we describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3-diphenylpropyl)malonic acids as potent allosteric activators binding to the PIF pocket. Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the PIF pocket. The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1. Employing a prodrug strategy, we were able to corroborate the novel mechanism of action in cells.

Catalytic enzyme activity on a biosensor chip: combination of surface plasmon resonance and mass spectrometry.

Surface plasmon resonance (SPR) as a label-free biosensor technique has become an important tool in drug discovery campaigns during the last couple of years. For good assay performance, it is of high interest to verify the functional activity on the immobilization of the target protein on the chip. This study illustrates the verification of the catalytic activity of the drug target protein PqsD by monitoring substrate conversion as a decrease in SPR signal and product detection by ultra high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS(2)). This assay would be applicable to control surface activity of immobilized ligands.

Ordinary percolation with discontinuous transitions.

Percolation on a one-dimensional lattice and fractals, such as the Sierpinski gasket, is typically considered to be trivial, because they percolate only at full bond density. By dressing up such lattices with small-world bonds, a novel percolation transition with explosive cluster growth can emerge at a non-trivial critical point. There, the usual order parameter, describing the probability of any node to be part of the largest cluster, jumps instantly to a finite value. Here we provide a simple example in the form of a small-world network consisting of a one-dimensional lattice which, when combined with a hierarchy of long-range bonds, reveals many features of this transition in a mathematically rigorous manner.

Optimal vertex cover for the small-world Hanoi networks.

The vertex-cover problem on the Hanoi networks HN3 and HN5 is analyzed with an exact renormalization group and parallel-tempering Monte Carlo simulations. The grand canonical partition function of the equivalent hard-core repulsive lattice-gas problem is recast first as an Ising-like canonical partition function, which allows for a closed set of renormalization-group equations. The flow of these equations is analyzed for the limit of infinite chemical potential, at which the vertex-cover problem is attained. The relevant fixed point and its neighborhood are analyzed and nontrivial results are obtained both for the coverage as well as for the ground-state entropy density, which indicates the complex structure of the solution space. Using special hierarchy-dependent operators in the renormalization group and Monte Carlo simulations, structural details of optimal configurations are revealed. These studies indicate that the optimal coverages (or packings) are not related by a simple symmetry. Using a clustering analysis of the solutions obtained in the Monte Carlo simulations, a complex solution space structure is revealed for each system size. Nevertheless, in the thermodynamic limit, the solution landscape is dominated by one huge set of very similar solutions.