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Infinity wars
What does Infinity hold for the Marvel Universe? As the Infinity Stones come to Earth, so too comes the war for control over them. But none who wield the stones truly understand the power they contain...or comprehend what it would take to bring them to their end! The nature of the cosmos itself hangs in the balance as we learn the answer to the question on everyone's lips: Who is Requiem? The ramifications of this story will be felt throughout Infinity for years to come! As cosmic war begins to rage, Gerry Duggan and Mike Deodato Jr. gaze into the Infinite - and bring the truth to light!
Book
The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity
The last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years.
Journal Article
Abiotic and habitat drivers of tick vector abundance, diversity, phenology and human encounter risk in southern California
The distribution, abundance and seasonal activity of vector species, such as ticks and mosquitoes, are key determinants of vector-borne disease risk, and are strongly influenced by abiotic and habitat conditions. Despite the numerous species of tick vectors in the heavily populated North American West Coast, all but Ixodes pacificus, the primary vector of the Lyme disease spirochete, is poorly characterized with regard to seasonal activity patterns and fine scale drivers of distribution and abundance, particularly in heavily populated regions of southern California. This lack of knowledge inhibits both scientific understanding and public health efforts to minimize vector exposure and risk of pathogen transmission to humans. Here we address this gap by characterizing the abiotic and habitat drivers of the distribution, abundance, and diversity of the vector tick community using fine scale temporal surveys over two seasons (2014 and 2015) across coastal and inland regions of Santa Barbara County, CA. We also characterize patterns of seasonal activity of the more common vector species to understand seasonality in risk of vector exposure, and specifically focus on human encounter risk using standardized tick drags as our method of collection. Leveraging plot-level habitat and abiotic variables in partial least squares regression analysis, we find the seven different vector species collected in this study have divergent drivers of activity and abundance. For example, I. pacificus is strongly associated with dense forest habitats and cool and moist microclimates, while Dermacentor occidentalis and Dermacentor variabilis, competent vectors of Rocky Mountain Spotted Fever, were found to be more tolerant of higher average temperatures and more open habitats. These results suggest that I. pacificus may be expected to experience reductions in geographic distribution and seasonal activity under projected land cover and climate change in coastal southern California, while D. occidentalis may experience more limited effects. We discuss implications for changing tick-borne disease risk associated with pathogens transmitted by Ixodes as well as Dermacentor species ticks in the western US, and contrast these predictions with eastern North America.
Journal Article
Amazon deforestation drives malaria transmission, and malaria burden reduces forest clearing
Deforestation and land use change are among the most pressing anthropogenic environmental impacts. In Brazil, a resurgence of malaria in recent decades paralleled rapid deforestation and settlement in the Amazon basin, yet evidence of a deforestation-driven increase in malaria remains equivocal. We hypothesize an underlying cause of this ambiguity is that deforestation and malaria influence each other in bidirectional causal relationships—deforestation increases malaria through ecological mechanisms and malaria reduces deforestation through socioeconomic mechanisms—and that the strength of these relationships depends on the stage of land use transformation. We test these hypotheses with a large geospatial dataset encompassing 795 municipalities across 13 y (2003 to 2015) and show deforestation has a strong positive effect on malaria incidence. Our results suggest a 10% increase in deforestation leads to a 3.3% increase in malaria incidence (∼9,980 additional cases associated with 1,567 additional km² lost in 2008, the study midpoint, Amazon-wide). The effect is larger in the interior and absent in outer Amazonian states where little forest remains. However, this strong effect is only detectable after controlling for a feedback of malaria burden on forest loss, whereby increased malaria burden significantly reduces forest clearing, possibly mediated by human behavior or economic development. We estimate a 1% increase in malaria incidence results in a 1.4% decrease in forest area cleared (∼219 fewer km² cleared associated with 3,024 additional cases in 2008). This bidirectional socioecological feedback between deforestation and malaria, which attenuates as land use intensifies, illustrates the intimate ties between environmental change and human health.
Journal Article
Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1—NFκB—IL-6 signalling axis
Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Although the fundamental link between HPV infection and oncogenesis is established, the specific mechanisms of virus-mediated transformation are not fully understood. We previously demonstrated that the HPV encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 in primary human keratinocytes; however, the molecular basis for STAT3 activation in cervical cancer remains unclear. Here, we show that STAT3 phosphorylation in HPV positive cervical cancer cells is mediated primarily via autocrine activation by the pro-inflammatory cytokine Interleukin 6 (IL-6). Antibody-mediated blockade of IL-6 signalling in HPV positive cells inhibits STAT3 phosphorylation, whereas both recombinant IL-6 and conditioned media from HPV positive cells leads to increased STAT3 phosphorylation within HPV negative cervical cancer cells. Interestingly, we demonstrate that activation of the transcription factor NFκB, involving the small GTPase Rac1, is required for IL-6 production and subsequent STAT3 activation. Our data provides new insights into the molecular re-wiring of cancer cells by HPV E6. We reveal that activation of an IL-6 signalling axis drives the autocrine and paracrine phosphorylation of STAT3 within HPV positive cervical cancers cells and that activation of this pathway is essential for cervical cancer cell proliferation and survival. Greater understanding of this pathway provides a potential opportunity for the use of existing clinically approved drugs for the treatment of HPV-mediated cervical cancer.
Journal Article
The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation
The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.
Neutrophils secrete numerous immune effector molecules including cathelicidin which is associated with antimicrobial properties. Here the authors implicate neutrophil derived cathelicidin in modulation of CD4 T cell homoeostasis and the promotion of Th17 CD4 T cells.
Journal Article
The major secreted protein of the whipworm parasite tethers to matrix and inhibits interleukin-13 function
Infection by soil transmitted parasitic helminths, such as
Trichuris spp
, are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections are poorly understood. Here we show that p43, the single most abundant protein in
T. muris
excretions/secretions, is non-immunogenic during infection and has an unusual sequence and structure containing subdomain homology to thrombospondin type 1 and interleukin (IL)−13 receptor (R) α2. Binding of p43 to IL-13, the key effector cytokine responsible for
T. muris
expulsion, inhibits IL-13 function both in vitro and in vivo. Tethering of p43 to matrix proteoglycans presents a bound source of p43 to facilitate interaction with IL-13, which may underpin chronic intestinal infection. Our results suggest that exploiting the biology of p43 may open up new approaches to modulating IL-13 function and control of
Trichuris
infections.
In the study, the authors identify a protein excreted by the parasite
Trichuris muris
, p43, which can modulate IL-13 function, a key cytokine involved in host protection. These data suggest that p43 may be a novel therapeutic target for both whipworm infections and IL13 mediated pathologies.
Journal Article
Atomic-scale sensing of the magnetic dipolar field from single atoms
The dipole–dipole magnetic interaction between individual atoms on MgO surfaces is quantified by performing electron spin resonance by means of a scanning tunnelling microscope, opening new paths towards structural imaging with sub-nm resolution.
Spin resonance provides the high-energy resolution needed to determine biological and material structures by sensing weak magnetic interactions
1
. In recent years, there have been notable achievements in detecting
2
and coherently controlling
3
,
4
,
5
,
6
,
7
individual atomic-scale spin centres for sensitive local magnetometry
8
,
9
,
10
. However, positioning the spin sensor and characterizing spin–spin interactions with sub-nanometre precision have remained outstanding challenges
11
,
12
. Here, we use individual Fe atoms as an electron spin resonance (ESR) sensor in a scanning tunnelling microscope to measure the magnetic field emanating from nearby spins with atomic-scale precision. On artificially built assemblies of magnetic atoms (Fe and Co) on a magnesium oxide surface, we measure that the interaction energy between the ESR sensor and an adatom shows an inverse-cube distance dependence (
r
−3.01±0.04
). This demonstrates that the atoms are predominantly coupled by the magnetic dipole–dipole interaction, which, according to our observations, dominates for atom separations greater than 1 nm. This dipolar sensor can determine the magnetic moments of individual adatoms with high accuracy. The achieved atomic-scale spatial resolution in remote sensing of spins may ultimately allow the structural imaging of individual magnetic molecules, nanostructures and spin-labelled biomolecules.
Journal Article
Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation
A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (T(H)2)-related pathologies under the control of the archetypal T(H)2 cytokine interleukin-4 (IL-4) and was a fundamental component of T(H)2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
Journal Article
SOX9 plays an essential role in myofibroblast driven hepatic granuloma integrity and parenchymal repair during schistosomiasis-induced liver damage
Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following Schistosoma mansoni infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both naïve and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6c lo monocyte populations in infected SOX9 deficient mice only. Infected SOX9–deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and/or reverse fibrotic disease.
Journal Article