Discrete time optimal control with frequency constraints for non-smooth systems

We present a Pontryagin maximum principle for discrete time optimal control problems with (a) pointwise constraints on the control actions and the states, (b) frequency constraints on the control and the state trajectories, and (c) nonsmooth dynamical systems. Pointwise constraints on the states and the control actions represent desired and/or physical limitations on the states and the control values; such constraints are important and are widely present in the optimal control literature. Constraints of the type (b), while less standard in the literature, effectively serve the purpose of describing important spectral properties of inertial actuators and systems. The conjunction of constraints of the type (a) and (b) is a relatively new phenomenon in optimal control but are important for the synthesis control trajectories with a high degree of fidelity. The maximum principle established here provides first order necessary conditions for optimality that serve as a starting point for the synthesis of control trajectories corresponding to a large class of constrained motion planning problems that have high accuracy in a computationally tractable fashion. Moreover, the ability to handle a reasonably large class of nonsmooth dynamical systems that arise in practice ensures broad applicability our theory, and we include several illustrations of our results on standard problems

TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation

Endothelial cell proliferation is a critical event during angiogenesis, regulated by both soluble factors and mechanical forces. Although the proliferation of tumor cells is studied extensively, little is known about the proliferation of tumor endothelial cells (TEC) and its contribution to tumor angiogenesis. We have recently shown that reduced expression of the mechanosensitive ion channel TRPV4 in TEC causes aberrant mechanosensitivity that result in abnormal angiogenesis. Here, we show that TEC display increased proliferation compared to normal endothelial cells (NEC). Further, we found that TEC exhibit high basal ERK1/2 phosphorylation and increased expression of proliferative genes important in the G1/S phase of the cell cycle. Importantly, pharmacological activation of TRPV4, with a small molecular activator GSK1016790A (GSK), significantly inhibited TEC proliferation, but had no effect on the proliferation of NEC or the tumor cells (epithelial) themselves. This reduction in TEC proliferation by TRPV4 activation was correlated with a decrease in high basal ERK1/2 phosphorylation. Finally, using a syngeneic tumor model revealed that TRPV4 activation, with GSK, significantly reduced endothelial cell proliferation in vivo. Our findings suggest that TRPV4 channels regulate tumor angiogenesis by selectively inhibiting tumor endothelial cell proliferation

TRPV4 Mechanotransduction in Fibrosis

Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis

Distributed and collaborative visualization of large data sets using high-speed

network

LARGE SCALE PROBLEM SOLVING USING AUTOMATIC CODE GENERATION AND DISTRIBUTED VISUALIZATION

Abstract. Scientific computation faces multiple scalability challenges in trying to take advantage of the latest generation compute, network and graphics hardware. We present a comprehensive approach to solving four important scalability challenges: programming productivity, scalability to large numbers of processors, I/O bandwidth, and interactive visualization of large data. We describe a scenario where our integrated system is applied in the field of numerical relativity. A solver for the governing Einstein equations is generated and executed on a large computational cluster; the simulation output is distributed onto a distributed data server, and finally visualized using distributed visualization methods and high-speed networks. A demonstration of this system was awarded first place in the IEEE SCALE 2009 Challenge

Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here, we show that the mechanosensitive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 KO mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies

Oral Nutritional Supplementation Improves Growth in Children at Malnutrition Risk and with Picky Eating Behaviors

The problem of poor nutrition with impaired growth persists in young children worldwide, including in India, where wasting occurs in 20% of urban children (<5 years). Exacerbating this problem, some children are described by their parent as a picky eater with behaviors such as eating limited food and unwillingness to try new foods. Timely intervention can help prevent nutritional decline and promote growth recovery; oral nutritional supplements (ONS) and dietary counseling (DC) are commonly used. The present study aimed to determine the effects of ONS along with DC on growth in comparison with the effects of DC only. Enrolled children (N = 321) were >24 to ≤48 months old, at malnutrition risk (weight-for-height percentile 3rd to 15th), and described as a picky eater by their parent. Enrollees were randomized to one of the three groups (N = 107 per group): ONS1 + DC; ONS2 + DC; and DC only. From day 1 to day 90, study findings showed significant increases in weight-for-height percentile for ONS1 + DC and for ONS2 + DC interventions, as compared to DC only (p = 0.0086 for both). There was no significant difference between the two ONS groups. Anthropometric measurements (weight and body mass index) also increased significantly over time for the two ONS groups (versus DC only, p < 0.05), while ONS1 + DC significantly improved mid-upper-arm circumference (p < 0.05 versus DC only), as well. ONS groups showed a trend toward greater height gain when compared to DC only group, but the differences were not significant within the study interval. For young Indian children with nutritional risk and picky eating behaviors, our findings showed that a 90-day nutritional intervention with either ONS1 or ONS2, along with DC, promoted catch-up growth more effectively than did DC alone