Computationally efficient boundary element methods for high-frequency Helmholtz problems in unbounded domains

This chapter presents the application of the boundary element method to high-frequency Helmholtz problems in unbounded domains. Based on a standard combined integral equation approach for sound-hard scattering problems we discuss the discretization, preconditioning and fast evaluation of the involved operators. As engineering problem, the propagation of high-intensity focused ultrasound fields into the human rib cage will be considered. Throughout this chapter we present code snippets using the open-source Python boundary element software BEM++ to demonstrate the implementation

A fast boundary element method for the scattering analysis of high-intensity focused ultrasound

High-intensity focused ultrasound (HIFU) techniques are promising modalities for the non-invasive treatment of cancer. For HIFU therapies of, e.g., liver cancer, one of the main challenges is the accurate focusing of the acoustic field inside a ribcage. Computational methods can play an important role in the patient-specific planning of these transcostal HIFU treatments. This requires the accurate modeling of acoustic scattering at ribcages. The use of a boundary element method (BEM) is an effective approach for this purpose because only the boundaries of the ribs have to be discretized instead of the standard approach to model the entire volume around the ribcage. This paper combines fast algorithms that improve the efficiency of BEM specifically for the high-frequency range necessary for transcostal HIFU applications. That is, a Galerkin discretized Burton-Miller formulation is used in combination with preconditioning and matrix compression techniques. In particular, quick convergence is achieved with the operator preconditioner that has been designed with on-surface radiation conditions for the high-frequency approximation of the Neumann-to-Dirichlet map. Realistic computations of acoustic scattering at 1 MHz on a human ribcage model demonstrate the effectiveness of this dedicated BEM algorithm for HIFU scattering analysis

Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells.

Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to "ER stress" and activation of the "unfolded protein response" (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host

p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress.

Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and consequently trigger ER stress signaling. Following ER stress, many cell types arrest within the G(1) phase, although recent studies have identified a novel ER stress G(2) checkpoint. Here, we report that ER stress affects cell cycle progression via two classes of signal: an early inhibition of protein synthesis leading to G(2) delay involving CHK1 and a later induction of G(1) arrest associated both with the induction of p53 target genes and loss of cyclin D(1). We show that substitution of p53/47 for p53 impairs the ER stress G(1) checkpoint, attenuates the recovery of protein translation, and impairs induction of NOXA, a mediator of cell death. We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G(2) progression prior to ultimate G(1) arrest

Culture Wars, Revanchism, Moral Panics and the Creative City. A Reconstruction of a Decline of Tolerant Public Policy: The Case of Dutch Anti-squatting Legislation

Squatting became illegal in the Netherlands on 1 October 2010. The paper examines the dynamics involved. Theoretically drawing on debates about culture wars, revanchism, moral panics and the creative city, it is based on participant observation in squatter meetings, debates with politicians, a parliament hearing, lobbying meetings and various informal encounters, on a survey and on a collection of documents. A key mechanism that the paper explores is the following. Strategies of resistance that seem more or less manageable in the local context of a creative city can, when they backfire, cause a moral panic on the national level. This provides ammunition for revanchist politicians

Transcranial direct current stimulation impairs updating of avoidance-based associative learning

IntroductionExposure-based psychotherapies for the treatment of anxiety- and fear-based disorders rely on “corrective” associative learning. Namely the repeated confrontation with feared stimuli in the absence of negative outcomes allows the formation of new, corrected associations of safety, indicating that such stimuli no longer need to be avoided. Unfortunately, exposure-facilitated corrective learning tends to be bound by context and often poorly generalizes. One brain structure, the prefrontal cortex, is implicated in context-guided behavior and may be a relevant target for improving generalization of safety learning. Here, we tested whether inhibition of the left prefrontal cortex causally impaired updating of context-bound associations specifically or, alternatively, impaired updating of learned associations irrespective of contextual changes. Additionally, we tested whether prefrontal inhibition during corrective learning influenced subsequent generalization of associations to a novel context.MethodsIn two separate experiments, participants received either 10 min of 2 mA cathodal transcranial direct current stimulation (tDCS) over EEG coordinate F3 (Experiment 1 n = 9, Experiment 2 n = 22) or sham stimulation (Experiment 1 n = 10, Experiment 2 n = 22) while previously learned associations were reversed in the same or a different context from initial learning. Next, to assess generalization of learning, participants were asked to indicate which of the previously seen images they preferred in a novel, never seen before context.ResultsResults indicate that tDCS significantly impaired reversal irrespective of context in Experiment 2 only. When taking learning rate across trials into account, both experiments suggest that participants who received sham had the greatest learning rate when reversal occurred in a different context, as expected, whereas participants who received active tDCS in this condition had the lowest learning rate. However, active tDCS was associated with preferring the originally disadvantageous, but then neural stimulus after stimulus after reversal occurred in a different context in Experiment 1 only.DiscussionThese results support a causal role for the left prefrontal cortex in the updating of avoidance-based associations and encourage further inquiry investigating the use of non-invasive brain stimulation on flexible updating of learned associations

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Pathogenesis and treatment of chronic pulmonary disease

Generation of representative primary virus isolates from blood plasma after isolation of HIV-1 with CD44 MicroBeads

Infection of cell cultures with cell-free virus isolated from HIV-infected patients is notoriously difficult and results in a loss of viral variation. Here, we describe viral sequences from PBMC, U87.CD4.CCR5 and U87.CD4.CXCR4 cell cultures and compare them to those from blood plasma from 12 patients from whom virus particles were isolated using CD44 MicroBeads. In both PBMC and U87.CD4.CCR5 cultures, 66% of the plasma viral strains were retrieved after culturing. In addition, coreceptor use was predicted based on the env-V3 sequence and tested in U87.CD4 cells expressing either CCR5 or CXCR4. Recovery was lower for the CXCR4-using viruses. Only 50% of the virus clusters predicted to use CXCR4 could be retrieved from cell cultures, while 71% of CCR5-using strains were found in U87.CCR5 cultures. Therefore, isolation of primary viruses with CD44 MicroBeads results in a good representation in cell culture of the in vivo divergence