Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications

Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.     

A state-dependent linear recurrent formula with application to time series with structural breaks

An underlying assumption in Multivariate Singular Spectrum Analysis (MSSA) is that the time series are governed by a linear recurrent continuation. However, in the presence of a structural break, multiple series can be transferred from one homogeneous state to another over a comparatively short time breaking this assumption. As a consequence, forecasting performance can degrade significantly. In this paper, we propose a state-dependent model to incorporate the movement of states in the linear recurrent formula called a State-Dependent Multivariate SSA (SD-MSSA) model. The proposed model is examined for its reliability in the presence of a structural break by conducting an empirical analysis covering both synthetic and real data. Comparison with standard MSSA, BVAR, VAR and VECM models shows the proposed model outperforms all three models significantly.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Driving the cell cycle with a minimal CDK control network

Control of eukaryotic cell proliferation involves an extended regulatory network, the complexity of which has made it difficult to understand the basic principles of the cell cycle. To investigate the core engine of the mitotic cycle we have generated a minimal control network in fission yeast that efficiently sustains cellular reproduction. Here we demonstrate that orderly progression through the major events of the cell cycle can be driven by oscillation of an engineered monomolecular cyclin-dependent protein kinase (CDK) module lacking much of the canonical regulation. We show further that the CDK oscillator acts as the primary organizer of the cell cycle, imposing timing and directionality to a system of two CDK activity thresholds that define independent cell cycle phases. We propose that this simple core architecture forms the basic control of the eukaryotic cell cycle.     

Sex ratio adjustment and kin discrimination in malaria parasites

Malaria parasites and related Apicomplexans are the causative agents of the some of the most serious infectious diseases of humans, companion animals, livestock and wildlife. These parasites must undergo sexual reproduction to transmit from vertebrate hosts to vectors, and their sex ratios are consistently female-biased. Sex allocation theory, a cornerstone of evolutionary biology, is remarkably successful at explaining female-biased sex ratios in multicellular taxa, but has proved controversial when applied to malaria parasites. Here we show that, as predicted by theory, sex ratio is an important fitness-determining trait and Plasmodium chabaudi parasites adjust their sex allocation in response to the presence of unrelated conspecifics. This suggests that P. chabaudi parasites use kin discrimination to evaluate the genetic diversity of their infections, and they adjust their behaviour in response to environmental cues. Malaria parasites provide a novel way to test evolutionary theory, and support the generality and power of a darwinian approach.     

Superoxide activates mitochondrial uncoupling proteins.

Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.     

Iterative Reconstruction for Transmission Tomography on GPU Using Nvidia CUDA

The iterative reconstruction algorithms for X-ray CT image reconstruction suffer from their high computational cost.Recently Nvidia releases common unified device architecture(CUDA),allowing developers to access to the processing power of Nvidia graphical processing units(GPUs),in order to perform general purpose computations.The use of the GPU,as an alternative computation platform,allows decreasing processing times,for parallel algorithms.This paper aims to demonstrate the feasibility of such an implement...     

Calcium-dependent enhancement of calcium current in smooth muscle by calmodulin-dependent protein kinase II.

Calcium entry through voltage-activated Ca2+ channels is important in regulating many cellular functions. Activation of these channels in many cell types results in feedback regulation of channel activity. Mechanisms linking Ca2+ channel activity with its downregulation have been described, but little is known of the events responsible for the enhancement of Ca2+ current that in many cells follows Ca2+ channel activation and an increase in cytoplasmic Ca2+ concentration. Here we investigate how this positive feedback is achieved in single smooth muscle cells. We find that in these cells voltage-activated calcium current is persistently but reversibly enhanced after periods of activation. This persistent enhancement of the Ca2+ current is mediated by activation of calmodulin-dependent protein kinase II because it is blocked when either the rise in cytoplasmic Ca2+ is inhibited or activation of calmodulin-dependent protein kinase II is prevented by specific peptide inhibitors of calcium-calmodulin or calmodulin-dependent protein kinase II itself. This mechanism may be important in different forms of Ca2+ current potentiation, such as those that depend on prior Ca2+ channel activation or are a result of agonist-induced release of Ca2+ from internal stores.     

Calcium gradients in single smooth muscle cells revealed by the digital imaging microscope using Fura-2

Calcium is believed to control a variety of cellular processes, often with a high degree of spatial and temporal precision. For a cell to use Ca2+ in this manner, mechanisms must exist for controlling the ion in a localized fashion. We have now gained insight into such mechanisms from studies which measured Ca2+ in single living cells with high resolution using a digital imaging microscope and the highly fluorescent Ca2+-sensitive dye, Fura-2. Levels of Ca2+ in the cytoplasm, nucleus and sarcoplasmic reticulum (SR) are clearly different. Free [Ca2+] in the nucleus and SR was greater than in the cytoplasm and these gradients were abolished by Ca2+ ionophores. When external Ca2+ was raised above normal in the absence of ionophores, free cytoplasmic Ca2+ increased but nuclear Ca2+ did not. Thus, nuclear [Ca2+] appears to be regulated independently of cytoplasmic [Ca2+] by gating mechanisms in the nuclear envelope. The observed regulation of intranuclear Ca2+ in these contractile cells may thus be seen as a way to prevent fluctuation in Ca2+-linked nuclear processes during the rise in cytoplasmic [Ca2+] which triggers contraction. The approach described here offers the opportunity of following changes in Ca2+ in cellular compartments in response to a wide range of stimuli, allowing new insights into the role of local changes in Ca2+ in the regulation of cell function.