Zero Temperature Dynamics of 2D and 3D Ising Ferromagnets

We consider zero-temperature, stochastic Ising models with nearest-neighbor interactions in two and three dimensions. Using both symmetric and asymmetric initial configurations, we study the evolution of the system with time. We examine the issue of convergence of the dynamics and discuss the nature of the final state of the system. By determining a relation between the median number of spin flips per site, the probability p that a spin in the initial spin configuration takes the value +1, and lattice size, we conclude that in two and three dimensions, the system converges to a frozen (but not necessarily uniform) state when p is not equal to 1/2. Results for p=1/2 in three dimensions are consistent with the conjecture that the system does not evolve towards a fully frozen limiting state. Our simulations also uncover `striped' and `blinker' states first discussed by Spirin et al., and their statistical properties are investigated.Comment: 17 pages, 12 figure

The Interplay of Host Autophagy and Eukaryotic Pathogens

For intracellular pathogens, host cells provide a replicative niche, but are also armed with innate defense mechanisms to combat the intruder. Co-evolution of host and pathogens has produced a complex interplay of host-pathogen interactions during infection, with autophagy emerging as a key player in the recent years. Host autophagy as a degradative process is a significant hindrance to intracellular growth of the pathogens, but also can be subverted by the pathogens to provide support such as nutrients. While the role of host cell autophagy in the pathogenesis mechanisms of several bacterial and viral pathogens have been extensively studied, less is known for eukaryotic pathogens. In this review, we focus on the interplay of host autophagy with the eukaryotic pathogens Plasmodium spp, Toxoplasma, Leishmania spp and the fungal pathogens Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. The differences between these eukaryotic pathogens in terms of the host cell types they infect, infective strategies and the host responses required to defend against them provide an interesting insight into how they respond to and interact with host cell autophagy. Due to the ability to infect multiple host species and cell types during the course of their usually complex lifestyles, autophagy plays divergent roles even for the same pathogen. The scenario is further compounded since many of the eukaryotic pathogens have their own sets of either complete or partial autophagy machinery. Eukaryotic pathogen-autophagy interplay is thus a complex relationship with many novel insights for the basic understanding of autophagy, and potential for clinical relevance

Metastability in zero-temperature dynamics: Statistics of attractors

The zero-temperature dynamics of simple models such as Ising ferromagnets provides, as an alternative to the mean-field situation, interesting examples of dynamical systems with many attractors (absorbing configurations, blocked configurations, zero-temperature metastable states). After a brief review of metastability in the mean-field ferromagnet and of the droplet picture, we focus our attention onto zero-temperature single-spin-flip dynamics of ferromagnetic Ising models. The situations leading to metastability are characterized. The statistics and the spatial structure of the attractors thus obtained are investigated, and put in perspective with uniform a priori ensembles. We review the vast amount of exact results available in one dimension, and present original results on the square and honeycomb lattices.Comment: 21 pages, 6 figures. To appear in special issue of JPCM on Granular Matter edited by M. Nicodem

Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3–LC3 interaction, thus inhibiting the parasite’s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host–parasite interaction without affecting the host’s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.This work was supported by grants from Institut Mérieux (MRG_20052016 to M.M.M). S.S. and A.F.C. were recipients of Fundação para a Ciência e Tecnologia fellowships SFRH/BPD/116451/2016 and SFRH/BPD/112009/2015, respectively. H.R. and V.S. were supported by core funds from NCBS-TIFR. A.L. was supported by Sanofi-Institut Pasteur 2018 Prize to M.M.M.info:eu-repo/semantics/publishedVersio

Directional emission of light from a nano-optical Yagi-Uda antenna

The plasmon resonance of metal nanoparticles can enhance and direct light from optical emitters in much the same way that radio frequency (RF) antennas enhance and direct the emission from electrical circuits. In the RF regime, a typical antenna design for high directivity is the Yagi-Uda antenna, which basically consists of a one-dimensional array of antenna elements driven by a single feed element. Here, we present the experimental demonstration of directional light emission from a nano-optical Yagi-Uda antenna composed of an array of appropriately tuned gold nanorods. Our results indicate that nano-optical antenna arrays are a simple but efficient tool for the spatial control of light emission.Comment: 4 pages, including 4 figure

Diverging and Converging: Integrative Insights on a Paradox Meta-perspective

Paradox theory stands at an exciting moment in organization and management theory. Scholars increasingly seek out insights about the nature and management of contradictory demands to explain a wide array of organizational phenomena across multiple levels of analysis. Our two reviews in the 2016 Academy of Management Annals attest to this growing breadth and depth, each integrating and expanding related, yet different bodies of research. Schad, Lewis, Raisch, and Smith (2016) emphasize the depth of scholarship by analyzing an increasing number of paradox studies within management science. Putnam, Fairhurst, and Banghart (2016) highlight the breadth of scholarship by comparing paradoxes that emerge from multiple theories and paradigms that embrace an interdisciplinary orientation. By drawing on distinct literatures, these two manuscripts reveal diverse insights and reflections about paradoxical demands in organizations. In this integrative reflection, we juxtapose our two review articles, surface distinct assumptions and emphases, highlight complementarities, and raise questions for future scholarship. In doing so, we hope to fuel insights toward a meta-perspective on paradox

Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease

Lumbar hernia diagnosed after laparoscopic hiatal hernia surgery

The presence of a new lumbar swelling or pain in the postoperative period following laparoscopic surgery should raise the suspicion of a lumbar hernia. Cross‐sectional imaging can be used to establish an early diagnosis to enable successful management

Identification of Mechanosensitive Genes during Embryonic Bone Formation

Although it is known that mechanical forces are needed for normal bone development, the current understanding of how biophysical stimuli are interpreted by and integrated with genetic regulatory mechanisms is limited. Mechanical forces are thought to be mediated in cells by “mechanosensitive” genes, but it is a challenge to demonstrate that the genetic regulation of the biological system is dependant on particular mechanical forces in vivo. We propose a new means of selecting candidate mechanosensitive genes by comparing in vivo gene expression patterns with patterns of biophysical stimuli, computed using finite element analysis. In this study, finite element analyses of the avian embryonic limb were performed using anatomically realistic rudiment and muscle morphologies, and patterns of biophysical stimuli were compared with the expression patterns of four candidate mechanosensitive genes integral to bone development. The expression patterns of two genes, Collagen X (ColX) and Indian hedgehog (Ihh), were shown to colocalise with biophysical stimuli induced by embryonic muscle contractions, identifying them as potentially being involved in the mechanoregulation of bone formation. An altered mechanical environment was induced in the embryonic chick, where a neuromuscular blocking agent was administered in ovo to modify skeletal muscle contractions. Finite element analyses predicted dramatic changes in levels and patterns of biophysical stimuli, and a number of immobilised specimens exhibited differences in ColX and Ihh expression. The results obtained indicate that computationally derived patterns of biophysical stimuli can be used to inform a directed search for genes that may play a mechanoregulatory role in particular in vivo events or processes. Furthermore, the experimental data demonstrate that ColX and Ihh are involved in mechanoregulatory pathways and may be key mediators in translating information from the mechanical environment to the molecular regulation of bone formation in the embryo