Random walk loop soups and conformal loop ensembles

The random walk loop soup is a Poissonian ensemble of lattice loops; it has been extensively studied because of its connections to the discrete Gaussian free field, but was originally introduced by Lawler and Trujillo Ferreras as a discrete version of the Brownian loop soup of Lawler and Werner, a conformally invariant Poissonian ensemble of planar loops with deep connections to conformal loop ensembles (CLEs) and the Schramm-Loewner evolution (SLE). Lawler and Trujillo Ferreras showed that, roughly speaking, in the continuum scaling limit, ``large'' lattice loops from the random walk loop soup converge to ``large'' loops from the Brownian loop soup. Their results, however, do not extend to clusters of loops, which are interesting because the connection between Brownian loop soup and CLE goes via cluster boundaries. In this paper, we study the scaling limit of clusters of ``large'' lattice loops, showing that they converge to Brownian loop soup clusters. In particular, our results imply that the collection of outer boundaries of outermost clusters composed of ``large'' lattice loops converges to CLE.Comment: 30 pages, 7 figures, to appear in Probab. Theory Related Field

Correlation-based entanglement criterion in bipartite multiboson systems

We describe a criterion for the detection of entanglement between two multi-boson systems. The criterion is based on calculating correlations of Gell-Mann matrices with a fixed boson number on each subsystem. This applies naturally to systems such as two entangled spinor Bose-Einstein condensates. We apply our criterion to several experimentally motivated examples, such as an $S^z S^z$ entangled BECs, ac Stark shift induced two-mode squeezed BECs, and photons under parametric down conversion. We find that entanglement can be detected for all parameter regions for the most general criterion. Alternative criteria based on a similar formalism are also discussed together with their merits.Comment: 8 pages, 4 figures, journal versio

Structural basis for the disaggregase activity and regulation of Hsp104

The Hsp104 disaggregase is a two-ring ATPase machine that rescues various forms of non-native proteins including the highly resistant amyloid fibers. The structural-mechanistic underpinnings of how the recovery of toxic protein aggregates is promoted and how this potent unfolding activity is prevented from doing collateral damage to cellular proteins are not well understood. Here, we present structural and biochemical data revealing the organization of Hsp104 from Chaetomium thermophilum at 3.7 angstrom resolution. We show that the coiled-coil domains encircling the disaggregase constitute a 'restraint mask' that sterically controls the mobility and thus the unfolding activity of the ATPase modules. In addition, we identify a mechanical linkage that coordinates the activity of the two ATPase rings and accounts for the high unfolding potential of Hsp104. Based on these findings, we propose a general model for how Hsp104 and related chaperones operate and are kept under control until recruited to appropriate substrates

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL

A Radical New Interdisciplinary Space for Sonification

RADICAL is a new three-year project with the ambitious goal of developing a fundamental understanding of the relationship between sonification design and the listener and to stimulate a revitalised agenda for sonification research and practice. Understanding of the role of embodied perception, spatial considerations, and aesthetics in our listening to, and perception of, sonification remains limited. This interdisciplinary project draws together experts in computer science, sonification, listening and perception, ethnography, music composition, and aesthetics to derive a fundamentally new understanding from which to derive concrete guidelines for better and more successful sonification design. The act of listening involves embodied perception, that is, making sense of and responding to sound involves not just our ears but is shaped by aspects of our entire physical body as well as our interactions with the space in which listening takes place. We are conducting a comprehensive study of sonification making and listening to better understand the relationships between sonifications, their designers, and their listeners. From this we will develop a new theory of sonification listening and derive an aesthetics of sonification which, up till now, has no accepted definition. These outcomes will be important in formulating a new framework for successful sonification design.https://projectRadical.github.i

Dual input stream transformer for vertical drift correction in eye-tracking reading data.

We introduce a novel Dual Input Stream Transformer (DIST) for the challenging problem of assigning fixation points from eye-tracking data collected during passage reading to the line of text that the reader was actually focused on. This post-processing step is crucial for analysis of the reading data due to the presence of noise in the form of vertical drift. We evaluate DIST against eleven classical approaches on a comprehensive suite of nine diverse datasets. We demonstrate that combining multiple instances of the DIST model in an ensemble achieves high accuracy across all datasets. Further combining the DIST ensemble with the best classical approach yields an average accuracy of 98.17 %. Our approach presents a significant step towards addressing the bottleneck of manual line assignment in reading research. Through extensive analysis and ablation studies, we identify key factors that contribute to DIST's success, including the incorporation of line overlap features and the use of a second input stream. Via rigorous evaluation, we demonstrate that DIST is robust to various experimental setups, making it a safe first choice for practitioners in the field

Listener-centred Sonification Practice as Transdisciplinary Experimental Artistic Engagement

Project RADICAL presents sonification research and practice as a listener-centred, transdisciplinary activity. In this chapter, authors discuss sonification from perspectives of artistic and musical practice. Particular emphasis is placed on spatial listening, embodied experience, environmental interaction, and communication, resulting in an interroga- tion of methodology, objects and foundations often assumed for sonifica- tion. The reader is invited to apply an ethnographic ear to a roundtable presentation investigating new sonic and musical practices that converge upon a reframing of sonification as engaged aesthetic activity productive of and carrying new technical and epistemic knowledge

Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.Medical Research CouncilThis is the final version of the article. It first appeared from the British Medical Journal via https://doi.org/10.1136/thoraxjnl-2015-20740

Heritability and intrafamilial aggregation of arterial characteristics

BACKGROUND: We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components. METHODS: Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively. RESULTS: We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P </= 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r >/= 0.12; P </= 0.02) with the exception of PPc (r = -0.007; P = 0.90) in parent-offspring pairs. The sib-sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (rhoG >/= 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (rhoE = 0.10, P = 0.03). CONCLUSION: The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits