Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death

Dense circumnuclear molecular gas in starburst galaxies

We present results from a study of the dense circumnuclear molecular gas of starburst galaxies. The study aims to investigate the interplay between starbursts, active galactic nuclei and molecular gas.We characterize the dense gas traced by HCN, HCO and HNC and examine its kinematics in the circumnuclear regions of nine starburst galaxies observed with the Australia Telescope Compact Array. We detect HCN (1-0) and HCO (1-0) in seven of the nine galaxies and HNC (1-0) in four. Approximately 7 arcsec resolution maps of the circumnuclear molecular gas are presented. The velocity-integrated intensity ratios, HCO (1-0)/HCN (1-0) and HNC (1-0)/HCN (1-0), are calculated. Using these integrated intensity ratios and spatial intensity ratio maps, we identify photon-dominated regions (PDRs) in NGC 1097, NGC 1365 and NGC 1808. We find no galaxy which shows the PDR signature in only one part of the observed nuclear region.We also observe unusually strong HNC emission in NGC 5236, but it is not strong enough to be consistent with X-ray-dominated region chemistry. Rotation curves are derived for five of the galaxies and dynamical mass estimates of the inner regions of three of the galaxies are made. © 2016 The Authors.This project was supported by the Brother Vincent Cotter Award for Physics (UNSW). LVM has been supported by Grant AYA2011-30491-C02-01 co-financed by MICINN and FEDER funds, and the Junta de Andalucia (Spain) grants P08-FQM-4205 and TIC-114. WAB acknowledges the support as a Visiting Professor of the Chinese Academy of Sciences (KJZD-EW-T01). The research leading to these results has received funding from the European Community's Seventh Framework Programme (/FP7/2007-2013/) under grant agreement No 229517.Peer Reviewe

Quantized charge transport through a static quantum dot using a surface acoustic wave

We present a detailed study of the surface acoustic wave mediated quantized transport of electrons through a split gate device containing an impurity potential defined quantum dot within the split gate channel. A new regime of quantized transport is observed at low RF powers where the surface acoustic wave amplitude is comparable to the quantum dot charging energy. In this regime resonant transport through the single-electron dot state occurs which we interpret as turnstile-like operation in which the traveling wave amplitude modulates the entrance and exit barriers of the quantum dot in a cyclic fashion at GHz frequencies. For high RF powers, where the amplitude of the surface acoustic wave is much larger than the quantum dot energies, the quantized acoustoelectric current transport shows behavior consistent with previously reported results. However, in this regime, the number of quantized current plateaus observed and the plateau widths are determined by the properties of the quantum dot, demonstrating that the microscopic detail of the potential landscape in the split gate channel has a profound influence on the quantized acoustoelectric current transport.Comment: 9 page

The HO Southern Galactic Plane Survey (HOPS) - I. Techniques and HO maser data

The definitive version can be found at: http://onlinelibrary.wiley.com/ Copyright Royal Astronomical SocietyWe present first results of the HO Southern Galactic Plane Survey (HOPS), using the Mopra Radio Telescope with a broad-band backend and a beam size of about 2 arcmin. We have observed 100 deg of the southern Galactic plane at 12mm (19.5-27.5GHz), including spectral line emission from HO masers, multiple metastable transitions of ammonia, cyanoacetylene, methanol and radio recombination lines. In this paper, we report on the characteristics of the survey and HO maser emission. We find 540 HO masers, of which 334 are new detections. The strongest maser is 3933Jy and the weakest is 0.7Jy, with 62 masers over 100Jy. In 14 maser sites, the spread in the velocity of the HO maser emission exceeds 100kms. In one region, the HO maser velocities are separated by 351.3kms. The rms noise levels are typically between 1 and 2Jy, with 95 per cent of the survey under 2Jy. We estimate completeness limits of 98 per cent at around 8.4Jy and 50 per cent at around 5.5Jy. We estimate that there are between 800 and 1500 HO masers in the Galaxy that are detectable in a survey with similar completeness limits to HOPS. We report possible masers in NH (11,9) and (8,6) emission towards G19.61-0.23 and in the NH (3,3) line towards G23.33-0.30.Peer reviewe

Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases

Spoken word recognition of novel words, either produced or only heard during learning

This document is the Accepted Manuscript Version of the following article: Tania S. Zamuner, Elizabeth Morin-Lessard, Stephanie Strahm, and Michael P. A. Page, 'Soke word recognition of novel words, either produced or only heard during learning', Journal of Memory and Language, Vol. 89, August 2016, pp. 55-67, doi: 10.1016/j.jml.2015.10.003. Under embargo. Embargo end date: 1 December 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Psycholinguistic models of spoken word production differ in how they conceptualize the relationship between lexical, phonological and output representations, making different predictions for the role of production in language acquisition and language processing. This work examines the impact of production on spoken word recognition of newly learned non-words. In Experiment 1, adults were trained on non-words with visual referents; during training, they produced half of the non-words, with the other half being heard-only. Using a visual world paradigm at test, eye tracking results indicated faster recognition of non-words that were produced compared with heard-only during training. In Experiment 2, non-words were correctly pronounced or mispronounced at test. Participants showed a different pattern of recognition for mispronunciation on non-words that were produced compared with heard-only during training. Together these results indicate that production affects the representations of newly learned words.Peer reviewedFinal Accepted Versio

Laboratory adapted Escherichia coli K-12 becomes a pathogen of Caenorhabditis elegans upon restoration of O antigen biosynthesis

Escherichia coli has been the leading model organism for many decades. It is a fundamental player in modern biology, facilitating the molecular biology revolution of the last century. The acceptance of E.?coli as model organism is predicated primarily on the study of one E. coli lineage; E. coli K-12. However, the antecedents of today's laboratory strains have undergone extensive mutagenesis to create genetically tractable offspring but which resulted in loss of several genetic traits such as O antigen expression. Here we have repaired the wbbL locus, restoring the ability of E. coli K-12 strain MG1655 to express the O antigen. We demonstrate that O antigen production results in drastic alterations of many phenotypes and the density of the O antigen is critical for the observed phenotypes. Importantly, O antigen production enables laboratory strains of E. coli to enter the gut of the Caenorhabditis elegans worm and to kill C. elegans at rates similar to pathogenic bacterial species. We demonstrate C. elegans killing is a feature of other commensal E.?coli. We show killing is associated with bacterial resistance to mechanical shear and persistence in the C. elegans gut. These results suggest C. elegans is not an effective model of human-pathogenic E. coli infectious disease