Computing Time-Optimal Clearing Strategies for Pursuit-Evasion Problems with Linear Programming

This paper addresses and solves the problem of finding optimal clearing strategies for a team of robots in an environment given as a graph. The graph-clear model is used in which sweeping of locations, and their recontamination by intruders, is modelled over a surveillance graph. Optimization of strategies is carried out for shortest total travel distance and time taken by the robot team and under constraints of clearing costs of locations. The physical constraints of access and timely movements by the robots are also accounted for, as well as the ability of the robots to prevent recontamination of already cleared areas. The main result of the paper is that this complex problem can be reduced to a computable LP problem. To further reduce complexity, an algorithm is presented for the case when graph clear strategies are a priori available by using other methods, for instance by model checking

Neurofilament light chain in the vitreous humor of the eye

Background: Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. This study investigated the presence of NfL in the vitreous humor and its associations with amyloid beta, tau, inflammatory cytokines and vascular proteins, apolipoprotein E (APOE) genotypes, Mini-Mental State Examination (MMSE) scores, systemic disease, and ophthalmic diseases. / Methods: This is a single-site, prospective, cross-sectional cohort study. Undiluted vitreous fluid (0.5–1.0 mL) was aspirated during vitrectomy, and whole blood was drawn for APOE genotyping. NfL, amyloid beta (Aβ), total Tau (t-Tau), phosphorylated Tau (p-Tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous were quantitatively measured by immunoassay. The main outcome measures were the detection of NfL levels in the vitreous humor and its associations with the aforementioned proteins. Linear regression was used to test the associations of NfL with other proteins, APOE genotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases. / Results: NfL was detected in all 77 vitreous samples. NfL was not found to be associated with ophthalmic conditions, APOE genotypes, MMSE scores, or systemic disease (p > 0.05). NfL levels were positively associated with increased vitreous levels of Aβ40 (p = 7.7 × 10−5), Aβ42 (p = 2.8 × 10−4), and t-tau (p = 5.5 × 10−7), but not with p-tau181 (p = 0.53). NfL also had significant associations with inflammatory cytokines such as interleukin-15 (IL-15, p = 5.3 × 10−4), IL-16 (p = 2.2 × 10−4), monocyte chemoattractant protein-1 (MCP1, p = 4.1 × 10−4), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1, p = 2.9 × 10−6), Vegf-C (p = 8.6 × 10−6), vascular cell adhesion molecule-1 (VCAM-1, p = 5.0 × 10−4), Tie-2 (p = 6.3 × 10−4), and intracellular adhesion molecular-1 (ICAM-1, p = 1.6 × 10−4). / Conclusion: NfL is detectable in the vitreous humor of the eye and significantly associated with amyloid beta, t-tau, and select inflammatory and vascular proteins in the vitreous. Additionally, NfL was not associated with patients’ clinical eye condition. Our results serve as a foundation for further investigation of NfL in the ocular fluids to inform us about the potential utility of its presence in the eye

Variability in bioreactivity linked to changes in size and zeta potential of diesel exhaust particles in human immune cells

Acting as fuel combustion catalysts to increase fuel economy, cerium dioxide (ceria, CeO(2)) nanoparticles have been used in Europe as diesel fuel additives (Envirox™). We attempted to examine the effects of particles emitted from a diesel engine burning either diesel (diesel exhaust particles, DEP) or diesel doped with various concentrations of CeO(2) (DEP-Env) on innate immune responses in THP-1 and primary human peripheral blood mononuclear cells (PBMC). Batches of DEP and DEP-Env were obtained on three separate occasions using identical collection and extraction protocols with the aim of determining the reproducibility of particles generated at different times. However, we observed significant differences in size and surface charge (zeta potential) of the DEP and DEP-Env across the three batches. We also observed that exposure of THP-1 cells and PBMC to identical concentrations of DEP and DEP-Env from the three batches resulted in statistically significant differences in bioreactivity as determined by IL-1β, TNF-α, IL-6, IFN-γ, and IL-12p40 mRNA (by qRT-PCR) and protein expression (by ELISPOT assays). Importantly, bioreactivity was noted in very tight ranges of DEP size (60 to 120 nm) and zeta potential (−37 to −41 mV). Thus, these physical properties of DEP and DEP-Env were found to be the primary determinants of the bioreactivity measured in this study. Our findings also point to the potential risk of over- or under- estimation of expected bioreactivity effects (and by inference of public health risks) from bulk DEP use without taking into account potential batch-to-batch variations in physical (and possibly chemical) properties

Modulation of human macrophage responses to mycobacterium tuberculosis by silver nanoparticles of different size and surface modification

Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications

MR thermometry characterization of a hyperthermia ultrasound array designed using the k-space computational method

BACKGROUND: Ultrasound induced hyperthermia is a useful adjuvant to radiation therapy in the treatment of prostate cancer. A uniform thermal dose (43°C for 30 minutes) is required within the targeted cancerous volume for effective therapy. This requires specific ultrasound phased array design and appropriate thermometry method. Inhomogeneous, acoustical, three-dimensional (3D) prostate models and economical computational methods provide necessary tools to predict the appropriate shape of hyperthermia phased arrays for better focusing. This research utilizes the k-space computational method and a 3D human prostate model to design an intracavitary ultrasound probe for hyperthermia treatment of prostate cancer. Evaluation of the probe includes ex vivo and in vivo controlled hyperthermia experiments using the noninvasive magnetic resonance imaging (MRI) thermometry. METHODS: A 3D acoustical prostate model was created using photographic data from the Visible Human Project(®). The k-space computational method was used on this coarse grid and inhomogeneous tissue model to simulate the steady state pressure wavefield of the designed phased array using the linear acoustic wave equation. To ensure the uniformity and spread of the pressure in the length of the array, and the focusing capability in the width of the array, the equally-sized elements of the 4 × 20 elements phased array were 1 × 14 mm. A probe was constructed according to the design in simulation using lead zerconate titanate (PZT-8) ceramic and a Delrin(® )plastic housing. Noninvasive MRI thermometry and a switching feedback controller were used to accomplish ex vivo and in vivo hyperthermia evaluations of the probe. RESULTS: Both exposimetry and k-space simulation results demonstrated acceptable agreement within 9%. With a desired temperature plateau of 43.0°C, ex vivo and in vivo controlled hyperthermia experiments showed that the MRI temperature at the steady state was 42.9 ± 0.38°C and 43.1 ± 0.80°C, respectively, for 20 minutes of heating. CONCLUSION: Unlike conventional computational methods, the k-space method provides a powerful tool to predict pressure wavefield in large scale, 3D, inhomogeneous and coarse grid tissue models. Noninvasive MRI thermometry supports the efficacy of this probe and the feedback controller in an in vivo hyperthermia treatment of canine prostate

Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Functional alpha-1B adrenergic receptors on human epicardial coronary artery endothelial cells

Alpha-1-adrenergic receptors (α1-ARs) regulate coronary arterial blood flow by binding catecholamines, norepinephrine (NE), and epinephrine (EPI), causing vasoconstriction when the endothelium is disrupted. Among the three α1-AR subtypes (α1A, α1B, and α1D), the α1D subtype predominates in human epicardial coronary arteries and is functional in human coronary smooth muscle cells (SMCs). However, the presence or function of α1-ARs on human coronary endothelial cells (ECs) is unknown. Here we tested the hypothesis that human epicardial coronary ECs express functional α1-ARs. Cultured human epicardial coronary artery ECs were studied using quantitative real-time reverse transcription polymerase chain reaction, radioligand binding, immunoblot, and 3H-thymidine incorporation. The α1B-subtype messenger ribonucleic acid (mRNA) was predominant in cultured human epicardial coronary ECs (90–95% of total α1-AR mRNA), and total α1-AR binding density in ECs was twice that in coronary SMCs. Functionally, NE and EPI through the α1B subtype activated extracellular signal-regulated kinase (ERK) in ECs, stimulated phosphorylation of EC endothelial nitric oxide synthase (eNOS), and increased deoxyribonucleic acid (DNA) synthesis. These results are the first to demonstrate α1-ARs on human coronary ECs and indicate that the α1B subtype is predominant. Our findings provide another potential mechanism for adverse cardiac effects of drug antagonists that nonselectively inhibit all three α1-AR subtypes

The Ordered Extension of Pseudopodia by Amoeboid Cells in the Absence of External Cues

Eukaryotic cells extend pseudopodia for movement. In the absence of external cues, cells move in random directions, but with a strong element of persistence that keeps them moving in the same direction Persistence allows cells to disperse over larger areas and is instrumental to enter new environments where spatial cues can lead the cell. Here we explore cell movement by analyzing the direction, size and timing of ∼2000 pseudopodia that are extended by Dictyostelium cells. The results show that pseudpopod are extended perpendicular to the surface curvature at the place where they emerge. The location of new pseudopods is not random but highly ordered. Two types of pseudopodia may be formed: frequent splitting of an existing pseudopod, or the occasional extension of a de novo pseudopod at regions devoid of recent pseudopod activity. Split-pseudopodia are extended at ∼60 degrees relative to the previous pseudopod, mostly as alternating Right/Left/Right steps leading to relatively straight zigzag runs. De novo pseudopodia are extended in nearly random directions thereby interrupting the zigzag runs. Persistence of cell movement is based on the ratio of split versus de novo pseudopodia. We identify PLA2 and cGMP signaling pathways that modulate this ratio of splitting and de novo pseudopodia, and thereby regulate the dispersal of cells. The observed ordered extension of pseudopodia in the absence of external cues provides a fundamental insight into the coordinated movement of cells, and might form the basis for movement that is directed by internal or external cues