Ultrasensitive small molecule fluorogenic probe for human heparanase

Heparanase (HPA) is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as various types of cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, no structurally defined probes are available for the detection of heparanase activity. Here we present the development of the first ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity via tuning the electronic effect of the substrate. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.

Heparanase, a critical enzyme involved in the remodeling of the extracellular matrix, activates a disaccharide probe HADP to give a strong fluorescence signal.     

Difference in icosahedral short-range order in early and late transition metal liquids

New short-range order data are presented for equilibrium and undercooled liquids of Ti and Ni. These were obtained from in situ synchrotron x-ray diffraction measurements of electrostatically levitated droplets. While the short-range order of liquid Ni is icosahedral, consistent with Frank's hypothesis, significantly distorted icosahedral order is observed in liquid Ti. This is the first experimental observation of distorted icosahedral short-range order in any liquid, although this has been predicted by theoretical studies on atomic clusters.     

Detecting hidden spatial and spatio-temporal structures in glasses and complex physical systems by multiresolution network clustering

We elaborate on a general method that we recently introduced for characterizing the “natural” structures in complex physical systems via multi-scale network analysis. The method is based on “community detection” wherein interacting particles are partitioned into an “ideal gas” of optimally decoupled groups of particles. Specifically, we construct a set of network representations (“replicas”) of the physical system based on interatomic potentials and apply a multiscale clustering (“multiresolution community detection”) analysis using information-based correlations among the replicas. Replicas may i) be different representations of an identical static system, ii) embody dynamics by considering replicas to be time separated snapshots of the system (with a tunable time separation), or iii) encode general correlations when different replicas correspond to different representations of the entire history of the system as it evolves in space-time. Inputs for our method are the inter-particle potentials or experimentally measured two (or higher order) particle correlations. We apply our method to computer simulations of a binary Kob-Andersen Lennard-Jones system in a mixture ratio of A₈₀B₂₀ , a ternary model system with components “A”, “B”, and “C” in ratios of A₈₈B₇C₅ (as in Al₈₈Y₇Fe₅ , and to atomic coordinates in a Zr₈₀Pt₂₀ system as gleaned by reverse Monte Carlo analysis of experimentally determined structure factors. We identify the dominant structures (disjoint or overlapping) and general length scales by analyzing extrema of the information theory measures. We speculate on possible links between i) physical transitions or crossovers and ii) changes in structures found by this method as well as phase transitions associated with the computational complexity of the community detection problem. We also briefly consider continuum approaches and discuss rigidity and the shear penetration depth in amorphous systems; this latter length scale increases as the system becomes progressively rigid.     

First x-ray scattering studies on electrostatically levitated metallic liquids: demonstrated influence of local icosahedral order on the nucleation barrier

To explain the unusual stability of undercooled liquids against crystallization, Frank hypothesized that the local structures of undercooled liquids contain a significant degree of icosahedral short-range order, which is incompatible with long-range periodicity. We present here the first direct experimental demonstration of Frank's complete hypothesis, showing a correlation between the nucleation barrier and a growing icosahedral short-range order with decreasing temperature in a Ti39.5Zr39.5Ni21 liquid. A new experimental facility, BESL (Beamline Electrostatic Levitation), was developed to enable the synchrotron x-ray structural studies on deeply undercooled, reactive liquids.     

Comparison of hypothesis testing techniques for markov processes estimated from micro versus macro data

We estimate the parameters of a Markov chain model using two types of simulated data: micro, or actual interstate transition counts, and macro aggregate frequency. We compare, by means of Monte Carlo experiments, the validity and power for micro likelihood ratio tests with their macro counterparts, previously developed by the authors to complement standard least-squares point estimates. We consider five specific null hypotheses, including parameter stationarity, entity homogeneity, a zero-order process, a specified probability value, and equal diagonal probabilities. The results from these micro-macro comparisons should help to indicate whether micro panel data collection is justified over the use of simpler state frequency counts.     

Inverse correlation between cohesive energy and thermal expansion coefficient in liquid transition metal alloys

The volume expansion coefficients (α) of twenty-five glass-forming transition metal alloy liquids, measured using the electrostatic levitation technique, are reported. An inverse correlation between α and the cohesive energy is found. The predicted values of α from this relationship agree reasonably well with the published data for thirty other transition metal and alloy liquids; some disagreement was found for a few alloys containing significant amounts of group III and IV elements. A theoretical argument for this empirical relationship is presented.     

First measurements of time-dependent nucleation as a function of composition in Na2O · 2CaO · 3SiO2 glasses

First measurements of the composition dependence of the time-dependent nucleation rate are presented. Nucleation rates of the stoichiometric crystalline phase, Na₂O · 2CaO · 3SiO₂, from quenched glasses made with different SiO₂ concentrations were determined as a function of temperature and glass composition. A strong compositional dependence of the nucleation rates and a weak dependence for the induction times were observed. Using measured values of the liquidus temperatures and growth velocities as a function of glass composition, these data are shown to be consistent with predictions from the classical theory of nucleation, assuming a composition-dependent interfacial energy.