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PDF file - 42K, Quizartinib inhibition of MV4-11 tumor grwoth in vivo

PDF file - 279K, Immunoblots of MV4-11, MOLM14, and SEM-K2 with quizartinib DR

PDF file - 116K, Elevation of pro-apoptotic BimEL mirrors loss of anti-apoptotic Mcl-1

PDF file - 46K, Durability of quizartinib inhibition translates to loss of viability after brief exposure

PDF file - 54K, DMSO and DR to quizartinib, percent apoptotic cells is percent of cells with

PDF file - 74K, CEP-32496 Supplemental Data.

PDF file - 54K, Inhibition of FLT3 phosphorylation and cell viability by FLT3 inhibitors

Benefits of local recovery (restarting only a failed process or task) have been previously demonstrated in parallel solvers. Local recovery has a reduced impact on application performance due to masking of failure delays (for message-passing codes) or dynamic load balancing (for asynchronous many-task codes). In this paper, we implement MPI-process-local checkpointing and recovery of data (as an extension of the Fenix library) in combination with an existing method for local detection of silent errors in partial-differential-equation solvers, to show a path for incorporating lightweight silent-error resilience. In addition, we demonstrate how asynchrony introduced by maximizing computation-communication overlap can halt the propagation of delays. For a prototype stencil solver (including an iterative-solver-like variant) with injected memory bit flips, results show greatly reduced overhead under weak scaling compared to global recovery, and high failure-masking efficiency. The approach is expected to be generalizable to other MPI-based solvers.

Although popular in industry, state-chart notations with ‘run to completion’ semantics lack formal refinement and rigorous verification methods. State-chart models are typically used to design complex control systems that respond to environmental triggers with a sequential process. The model is usually constructed at a concrete level and verified and validated using animation techniques relying on human judgement. Event-B, on the other hand, is based on refinement from an initial abstraction and is designed to make formal verification by automatic theorem provers feasible. We introduce a notion of refinement into a ‘run to completion’ statechart modelling notation, and leverage Event-B ’s tool support for theorem proving. We describe the difficulties in translating ‘run to completion’ semantics into Event-B refinements and suggest a solution. We illustrate our approach and show how critical (e.g. safety) invariant properties can be verified by proof despite the reactive nature of the system. We also show how behavioural aspects of the system can be verified by testing the expected reactions using a temporal logic model checking approach.

We discuss techniques for efficient local detection of silent data corruption in parallel scientific computations, leveraging physical quantities such as momentum and energy that may be conserved by discretized PDEs. The conserved quantities are analogous to “algorithm-based fault tolerance” checksums for linear algebra but, due to their physical foundation, are applicable to both linear and nonlinear equations and have efficient local updates based on fluxes between subdomains. These physics-based checksums enable precise intermittent detection of errors and recovery by rollback to a checkpoint, with very low overhead when errors are rare. We present applications to both explicit hyperbolic and iterative elliptic (unstructured finite-element) solvers with injected memory bit flips.

Colloids with short range attractions self-assemble into sample-spanning structures, whose dynamic nature results in a thermokinematic memory of the deformation history, also referred to as "thixotropy." Here, we study the origins of the thixotropic effect in these time- and rate-dependent materials by investigating hysteresis across different length scales: from particle-level local measurements of coordination number (microscale), to the appearance of density and velocity fluctuations (mesoscale), and up to the shear stress response to an imposed deformation (macroscale). The characteristic time constants at each scale become progressively shorter, and hysteretic effects become more significant as we increase the strength of the interparticle attraction. There are also strong correlations between the thixotropic effects we observe at each scale.

Statechart modelling notations, with so-called ‘run to completion’ semantics and simulation tools for validation, are popular with engineers for designing systems. However, they do not support formal refinement and they lack formal static verification methods and tools. For example, properties concerning the synchronisation between different parts of a system may be difficult to verify for all scenarios, and impossible to verify at an abstract level before the full details of sub-states have been added. Open image in new window , on the other hand, is based on refinement from an initial abstraction and is designed to make formal verification by automatic theorem provers feasible, restricting instantiation and testing to a validation role. In this paper, we introduce a notion of refinement, similar to that of Open image in new window , into a ‘run to completion’ Statechart modelling notation, and leverage Open image in new window ’s tool support for proof. We describe the pitfalls in translating ‘run to completion’ models into Open image in new window refinements and suggest a solution. We illustrate the approach using our prototype translation tools and show by example, how a synchronisation property between parallel Statecharts can be automatically proven at an intermediate refinement level.

We present a general technique to solve Partial Differential Equations, called robust stencils, which make them tolerant to soft faults, i.e. bit flips arising in memory or CPU calculations. We show how it can be applied to a two-dimensional Lax-Wendroff solver. The resulting 2D robust stencils are derived using an orthogonal application of their 1D counterparts. Combinations of 3 to 5 base stencils can then be created. We describe how these are then implemented in a parallel advection solver. Various robust stencil combinations are explored, representing tradeoff between performance and robustness. The results indicate that the 3-stencil robust combinations are slightly faster on large parallel workloads than Triple Modular Redundancy (TMR). They also have one third of the memory footprint. We expect the improvement to be significant if suitable optimizations are performed. Because faults are avoided each time new points are computed, the proposed stencils are also comparably robust to faults as TMR for a large range of error rates. The technique can be generalized to 3D (or higher dimensions) with similar benefits.

This work outlines an equation-based formulation of a digital control program and transducer interacting with a continuous physical process, and an approach using the Coq theorem prover for verifying the performance of the combined hybrid system. Considering thermal dynamics with linear dissipation for simplicity, we focus on a generalizable, physically consistent description of the interaction of the real-valued temperature and the digital program acting as a thermostat. Of interest in this work is the discovery and formal proof of bounds on the temperature, the degree of variation, and other performance characteristics. Our approach explicitly addresses the need to mathematically represent the decision problem inherent in an analog-to-digital converter, which for rare values can take an arbitrarily long time to produce a digital answer (the so-called Buridan's Principle); this constraint ineluctably manifests itself in the verification of thermostat performance. Furthermore, the temporal causality constraints in the thermal physics must be made explicit to obtain a consistent model for analysis. We discuss the significance of these findings toward the verification of digital control for more complex physical variables and fields.

Modern digital hardware and software designs are increasingly complex but are themselves only idealizations of a real system that is instantiated in, and interacts with, an analog physical environment. Insights from physics, formal methods, and complex systems theory can aid in extending reliability and security measures from pure digital computation (itself a challenging problem) to the broader cyber-physical and out-of-nominal arena. Example applications to design and analysis of high-consequence controllers and extreme-scale scientific computing illustrate the interplay of physics and computation. In particular, we discuss the limitations of digital models in an analog world, the modeling and verification of out-of-nominal logic, and the resilience of computational physics simulation. A common theme is that robustness to failures and attacks is fostered by cyber-physical system designs that are constrained to possess inherent stability or smoothness. This chapter contains excerpts from previous publications by the authors.

Verifying that hardware design implementations adhere to specifications is a time intensive and sometimes intractable problem due to the massive size of the system's state space. Formal methods techniques can be used to prove certain tractable specification properties; however, they are expensive, and often require subject matter experts to develop and solve. Nonetheless, hardware verification is a critical process to ensure security and safety properties are met, and encapsulates problems associated with trust and reliability. For complex designs where coverage of the entire state space is unattainable, prioritizing regions most vulnerable to security or reliability threats would allow efficient allocation of valuable verification resources. Stackelberg security games model interactions between a defender, whose goal is to assign resources to protect a set of targets, and an attacker, who aims to inflict maximum damage on the targets after first observing the defender's strategy. In equilibrium, the defender has an optimal security deployment strategy, given the attacker's best response. We apply this Stackelberg security framework to synthesized hardware implementations using the design's network structure and logic to inform defender valuations and verification costs. The defender's strategy in equilibrium is thus interpreted as a prioritization of the allocation of verification resources in the presence of an adversary. We demonstrate this technique on several open-source synthesized hardware designs.

Fms-like tyrosine kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating internal tandem duplication (ITD) mutations are found in approximately 30% of patients with AML and are associated with poor outcome in this patient population. Quizartinib (AC220) has previously been shown to be a potent and selective FLT3 inhibitor. In the current study, we expand on previous observations by showing that quizartinib potently inhibits the phosphorylation of FLT3 and downstream signaling molecules independent of FLT3 genotype, yet induces loss of viability only in cells expressing constitutively activated FLT3. We further show that transient exposure to quizartinib, whether in vitro or in vivo, leads to prolonged inhibition of FLT3 signaling, induction of apoptosis, and drastic reductions in tumor volume and pharmacodynamic endpoints. In vitro experiments suggest that these prolonged effects are mediated by slow binding kinetics that provide for durable inhibition of the kinase following drug removal/clearance. Together these data suggest quizartinib, with its unique combination of selectivity and potent/sustained inhibition of FLT3, may provide a safe and effective treatment against FLT3-driven leukemia. Mol Cancer Ther; 12(4); 438–47. ©2013 AACR.

We identify the sequence of microstructural changes that characterize the evolution of an attractive particulate gel under flow and discuss their implications on macroscopic rheology. Dissipative Particle Dynamics (DPD) is used to monitor shear-driven evolution of a fabric tensor constructed from the ensemble spatial configuration of individual attractive constituents within the gel. By decomposing this tensor into isotropic and non-isotropic components we show that the average coordination number correlates directly with the flow curve of the shear stress vs. shear rate, consistent with theoretical predictions for attractive systems. We show that the evolution in non-isotropic local particle rearrangements are primarily responsible for stress overshoots (strain-hardening) at the inception of steady shear flow and also lead, at larger times and longer scales, to microstructural localization phenomena such as shear banding flow-induced structure formation in the vorticity direction., 15 pages, 4 figures

We present algorithmic techniques for parallel PDE solvers that leverage numerical smoothness properties of physics simulation to detect and correct silent data corruption within local computations. We initially model such silent hardware errors (which are of concern for extreme scale) via injected DRAM bit flips. Our mitigation approach generalizes previously developed "robust stencils" and uses modified linear algebra operations that spatially interpolate to replace large outlier values. Prototype implementations for 1D hyperbolic and 3D elliptic solvers, tested on up to 2048 cores, show that this error mitigation enables tolerating orders of magnitude higher bit-flip rates. The runtime overhead of the approach generally decreases with greater solver scale and complexity, becoming no more than a few percent in some cases. A key advantage is that silent data corruption can be handled transparently with data in cache, reducing the cost of false-positive detections compared to rollback approaches.

We present a methodology to analyze the stationary states and stability of complex fluid flows by using hybrid, discrete, and/or continuum multi-scale simulations. Building on existing theories, our scheme extracts dynamical and equilibrium characteristics from carefully chosen time integrations of these multi-scale evolution equations. Two canonical problems are presented to demonstrate the ability and accuracy of the formalism. The first is an investigation of flow-induced transitions seen in homogeneous, hard- rod liquid crystal suspensions subjected to a linear shear flow. In the second problem, we study the phenomenon of draw resonance, a dynamical instability in an isothermal fiber-spinning process, by using a multi-scale hybrid simulation that incorporates both stochastic and continuum models.

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.

Traditional parallel programming techniques will suffer rapid deterioration of performance scaling with growing platform size, as the work of coping with increasingly frequent failures dominates over useful computation. To address this challenge, we introduce and simulate a novel software architecture that combines a task dependency graph with a substitution graph. The role of the dependency graph is to limit communication and checkpointing and enhance fault tolerance by allowing graph neighbors to exchange data, while the substitution graph promotes fault oblivious computing by allowing a failed task to be substituted on-the-fly by another task, incurring a quantifiable error. We present optimization formulations for trading off substitution errors and other factors such as available system capacity and low-overlap task partitioning among processors, and demonstrate that these can be approximately solved in real time after some simplifications. Simulation studies of our proposed approach indicate that a substitution network adds considerable resilience and simple enhancements can limit the aggregate substitution errors.

SummaryInteractions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.

The dynamics of a solution of rodlike liquid-crystalline molecules are simulated for the related problems of isotropic–nematic spinodal decomposition and the coarsening of misaligned nematic grains. The Doi diffusion equation for the rod distribution function is coupled with the full Onsager intermolecular potential, discretized by the finite-element method, and integrated forward in time by using a parallel, semi-implicit scheme. The Onsager potential models rod interaction on the scale of a single rod length in order to resolve accurately defects and interfaces in structure. Simulation results show the effects of rotational and translational diffusivity ratios on the mechanisms for alignment and phase separation in spinodal decomposition. As rotational motion is restricted, individual grains become more aligned prior to coalescence events. When rods are restricted to diffusive motion along their axis, the spinodal decomposition process is arrested, and the system will reach a pseudo-steady state featuring misaligned nematic grains. These results mark the first dynamic computation of the Doi diffusion equation for spinodal decomposition in nonhomogeneous rigid-rod systems. Nematic coarsening simulations show the effects of misalignment between neighboring ordered domains on the coarsening time and director field around structured interfaces. Results show that the coarsening time is dependent not only on misalignment between grain directors, but also on the tilt angle of the directors into the interface.

The rheological phase diagrams for solutions of rigid rod molecules are computed for planar Couette and Poiseuille flow as a function of Deborah number, initial orientation, and wall separation; this analysis extends the seminal work of Larson and Ottinger [R.G. Larson, H.C. Ottinger, Effect of molecular elasticity on out-of-plane orientations in shearing flows of liquid-crystalline polymers, Macromolecules 24 (1991) 6270–6282] to nonhomogeneous flows. The Doi diffusion equation is solved by using a finite-element discretization of the rod distribution function and Onsager interaction potential. Simulations of planar Couette flow show the familiar logrolling–tumbling–wagging–flow-aligning cascade as Deborah number increases, and the critical Deborah numbers associated with transitions between states vary with wall separation. Defects are caused solely by wall interactions rather than artificial anchoring conditions. Simulations of planar Poiseuille flow show that the system tends toward either logrolling states or composite flow-aligning/logrolling attractors depending on the Deborah number, wall separation, and initial orientation.

Kinetic theory models exhibit dynamics that depend on a few low-order moments of the underlying conformational distribution function. This dependence is exhibited in a compact spectrum of eigenvalues for the Jacobian matrix associated with the dynamical system. We take advantage of this spectrum of eigenvalues through Newton-GMRES iterations to enable dynamic viscoelastic simulators (time-steppers) to obtain stationary states and perform stability/bifurcation analysis. Results are presented for three example problems: (1) the equilibrium behavior of the Doi model with the Onsager excluded volume potential, (2) pressure-driven flow of non-interacting rigid dumbbells in a planar channel, and (3) pressure-driven flow of non-interacting rigid dumbbells through a planar channel with a linear array of equally spaced cylinders.

In high-performance scientific software development, the emphasis is often on short time to first solution. Even when the development of new components mostly reuses existing components or libraries and only small amounts of new code must be created, dealing with the component glue code and software build processes to obtain complete applications is still tedious and error-prone. Component-based software meant to reduce complexity at the application level increases complexity to the extent that the user must learn and remember the interfaces and conventions of the component model itself. To address these needs, we introduce Bocca, the first tool to enable application developers to perform rapid component prototyping while maintaining robust software-engineering practices suitable to HPC environments. Bocca provides project management and a comprehensive build environment for creating and managing applications composed of Common Component Architecture components. Of critical importance for high-performance computing (HPC) applications, Bocca is designed to operate in a language-agnostic way, simultaneously handling components written in any of the languages commonly used in scientific applications: C, C++, Fortran, Python and Java. Bocca automates the tasks related to the component glue code, freeing the user to focus on the scientific aspects of the application. Bocca embraces the philosophy pioneered by Ruby on Rails for web applications: start with something that works, and evolve it to the user's purpose.

Digital systems in an out-of-nominal environment (e.g., one causing hardware bit flips) may not be expected to function correctly in all respects but may be required to fail safely. We present an approach for understanding and verifying a system’s out-of-nominal behavior as an abstraction of nominal behavior that preserves designated critical safety requirements. Because abstraction and refinement are already widely used for improved tractability in formal design and proof techniques, this additional way of viewing an abstraction can potentially verify a system’s out-of-nominal safety with little additional work. We illustrate the approach with a simple model of a turnstile controller with possible logic faults (formalized in the temporal logic of actions and NuSMV), noting how design choices can be guided by the desired out-of-nominal abstraction. Principles of robustness in complex systems (specifically, Boolean networks) are found to be compatible with the formal abstraction approach. This work indicates a direction for broader use of formal methods in safety-critical systems.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Current programming languages and programming models make it easy to create software and hardware systems that fulfill an intended function but also leave such systems open to unintended function and vulnerabilities. Software engineering and code hygiene may make systems incrementally safer, but do not produce the wholesale change necessary for secure systems from the outset. Yet there exists an approach with impressive results: We cite recent examples showing that formal methods, coupled with formally informed digital design, have produced objectively more robust code even beyond the properties directly proven. Though discovery of zero-day vulnerabilities is almost always a surprise and powerful tools like semantic fuzzers can cover a larger search space of vulnerabilities than a developer can conceive of, formal models seem to produce robustness of a higher qualitative order than traditionally developed digital systems. Because the claim is necessarily a qualitative one, we illustrate similar results with an idealized programming language in the form of Boolean networks where we have control of parameters related to stability and adaptability. We argue that verifiability with formal methods is an instance of broader design constraints that promote robustness. We draw analogies to real-world programming models and languages that can be mathematically reasoned about in contrast to ones that are essentially undecidable.

Sharp-interface and thin-interface asymptotic analyses are presented for a generalization of the Beckermann–Karma phase-field model for solidification of a dilute binary alloy when the interface curvature is macroscopic. The ratio of diffusivities, R m ≡ D s ′ / D m ′ , in the solid and melt is arbitrary with 0 ⩽ R m ⩽ 1 . Discrepancies between this diffuse-interface model and the classical, two sided solutal model (TSM) description are quantified up to second order in the small parameter e that controls the interface thickness. We uncover extra terms in the interface species flux balance and in the Gibbs–Thomson equilibrium condition introduced by the finite width of the interface. Asymptotic results in the limit of rapid-interfacial kinetics are presented for both finite phase-field mobility and a quasi-steady state approximation for the phase-field wherein the phase-field responds passively to the concentration field. The possibility of adding additional terms to the phase-field version of the species conservation equation is explored as a means of achieving O ( e 2 ) consistency with the classical model. Our results naturally lead to a generalization of the anti-trapping solutal flux suggested by Karma [Phase-field-formulation for quantitative modeling of alloy solidification, Phys. Rev. Lett. 87(11) (2001) 115701] for the limit R m = 0 . Achieving second order accuracy for arbitrary R m requires judicious choices for the interpolating functions; these are calculated a posteriori using the functional forms of the error terms as a guide.

The Common Component Architecture (CCA) provides a means for software developers to manage the complexity of large-scale scientific simulations and to move toward a plug-and-play environment for high-performance coputing. In the scientific computing context, component models also promote collaboration using independently developed software, thereby allowing particular individals or groups to focus on the aspects of greatest interest to them. The CCA supports parallel and distributed coputing as well as local high-performance connections between components in a language-independent manner. The design places minimal requirements on components and thus facilitates the integration of existing code into the CCA environment. The CCA model imposes minimal ovehead to minimize the impact on application performance. The focus on high performance distinguishes the CCA from most other component models. The CCA is being applied within an increasing range of disciplines, including cobustion research, global climate simulation, and computtional chemistry.

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.

ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance

Recent advances in both computational hardware and multidisciplinary science have given rise to an unprecedented level of complexity in scientific simulation software. This paper describes an ongoing grass roots effort aimed at addressing complexity in high-performance computing through the use of Component-Based Software Engineering (CBSE). Highlights of the benefits and accomplishments of the Common Component Architecture (CCA) Forum and SciDAC ISIC are given, followed by an illustrative example of how the CCA has been applied to drive scientific discovery in quantum chemistry. Thrusts for future research are also described briefly.

This work targets the emerging use of software component technology for high-performance scientific parallel and distributed computing. While component software engineering will benefit the construction of complex science applications, its use presents several challenges to performance measurement, analysis, and optimization. The performance of a component application depends on the interaction (possibly nonlinear) of the composed component set. Furthermore, a component is a ‘binary unit of composition’ and the only information users have is the interface the component provides to the outside world. A performance engineering methodology and development approach is presented to address evaluation and optimization issues in high-performance component environments. We describe a prototype implementation of a performance measurement infrastructure for the Common Component Architecture (CCA) system. A case study demonstrating the use of this technology for integrated measurement, monitoring, and optimization in CCA component-based applications is given. Copyright © 2005 John Wiley & Sons, Ltd.

Regulators of apoptosis are thought to work in concert, but the molecular interactions of this process are not understood. Here, we show that in response to cell death stimulation, survivin, a member of the inhibitor of apoptosis (IAP) gene family, associates with another IAP protein, XIAP, via conserved baculovirus IAP repeats. Formation of a survivin-XIAP complex promotes increased XIAP stability against ubiquitination/proteasomal destruction and synergistic inhibition of apoptosis, which is abolished in XIAP(-/-) cells. Therefore, orchestration of an IAP-IAP complex regulates apoptosis.

This study compares the predictions of several “suspension temperature” models of particle migration to laser Doppler velocimetry measurements in a concentrated suspension of noncolloidal spheres. We compare the shear rate, concentration, and suspension temperature profiles in narrow-gap Couette flow. The models predict the observed macroscopic shear rate and concentration profiles well at moderate bulk particle concentration but diverge from one another and from the data at high concentrations. In addition, the predictions of the models compare poorly with suspension temperature measurements. Most of the models greatly underpredict the magnitude of the scalar temperature, capturing instead only the magnitude of the smaller two diagonal components of the temperature tensor. Also, the models do not predict the observed variation of the suspension temperature with particle concentration. Our investigation shows that both neglect of suspension temperature anisotropy and qualitative choices of model coefficie...

High-resolution laser Doppler velocimetry and flow-induced birefringence measurements were used to determine velocity and stress fields and to calculate a transient planar elongation viscosity profile for viscoelastic flow on the shear-free centerplane of a planar contraction geometry. A novel, two-component Boger fluid was developed that enabled Weissenberg numbers, We, as high as 2.9 to be attained and allowed the stress-optical coefficients of the fluid components to be measured. The experimental apparatus was designed to subject the fluid traveling on the centerplane to Hencky strains, e, as great as 3.5. Despite the high We and e, the flow induced only a weakly nonlinear viscoelastic stress response in the fluid. A spectral decomposition of predictions of linear and nonlinear constitutive equations was used to demonstrate that the weakly nonlinear response was a result of the nonhomogeneous form of the centerplane strain-rate profile in conjunction with the finite response time of the individual relaxation modes. The degree of nonlinear stress response in this experiment cannot be increased by increasing the contraction ratio to increase the total Hencky strain experienced by a fluid element traveling along the centerplane, increasing the flow rate to increase the strain rate at a given point along the centerplane, or introducing a taper to the contraction geometry to change the strain rate profile. Thus, the experimental configuration of flow through a contraction appears to be of limited value in evaluating the accuracy of nonlinear constitutive models in predicting the stress response of a viscoelastic polymer solution to a generalized elongational flow.

A numerical method based on wavelet approximations is developed to solve the diffusion equations that arise from kinetic theory models of polymer dynamics and for coupling with continuum calculations for simulating complex flows of polymer solutions. The dynamics of a liquid crystalline polymer solution in a simple, homogeneous shear flow is computed by using the Doi model with orientational-dependent rotational diffusivity as a function of Deborah number, De, and different initial conditions. Stochastic methods were previously used for computing this flow, and aperiodic behavior was found at high De. Calculations with the wavelet-Galerkin method demonstrate a stable limit cycle in the same parameter regime. The existence of the time-periodic solution is traced to a supercritical Hopf bifurcation at De=De Hopf ; the value of De Hopf scales with ( U − U c ) α , where U is the strength of the intermolecular potential. The exponent in this correlation, α , depends on the form of the mean-field intermolecular potential and can be used to characterize the anisotropic environment experienced by the polymer molecules.

Survivin is an anti-apoptotic protein that is overexpressed in most human cancers. We show that survivin forms complexes with a cellular protein, hepatitis B X-interacting protein (HBXIP), which was originally recognized for its association with the X protein of hepatitis B virus (HBX). Survivin–HBXIP complexes, but neither survivin nor HBXIP individually, bind pro-caspase-9, preventing its recruitment to Apaf1, and thereby selectively suppressing apoptosis initiated via the mitochondria/cytochrome c pathway. Viral HBX protein also interacts with the survivin– HBXIP complex and suppresses caspase activation in a survivin-dependent manner. Thus, HBXIP functions as a cofactor for survivin, and serves as a link between the cellular apoptosis machinery and a viral pathogen involved in hepatocellular carcinogenesis.

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.