Macrophages (MΦ) play an essential role in innate immune responses and can either display a pro-inflammatory, classically activated phenotype (M1) or undergo an alternative activation program (M2) ...promoting immune regulation. M-CSF is used to differentiate monocytes into MΦ and IFN-γ or IL-4+IL-13 to further polarize these cells towards M1 or M2, respectively. Recently, differentiation using only GM-CSF or M-CSF has been described to induce a M1- or M2-like phenotype, respectively. In this study, we combined both approaches by differentiating human MΦ in GM-CSF or M-CSF followed by polarization with either IFN-γ or IL-4+IL-13. We describe the phenotypic differences between CD14(hi) CD163(hi) CD206(int) FOLR2-expressing M-CSF MΦ and CD14(lo) CD163(lo) CD206(hi) GM-CSF MΦ but show that both macrophage populations reacted similarly to further polarization with IFN-γ or IL-4+IL-13 with up- and down-regulation of common M1 and M2 marker genes. We also show that high expression of the mannose receptor (CD206), a marker of alternative activation, is a distinct feature of GM-CSF MΦ. Changes of the chromatin structure carried out by chromatin modification enzymes (CME) have been shown to regulate myeloid differentiation. We analyzed the expression patterns of CME during MΦ polarization and show that M1 up-regulate the histone methyltransferase MLL and demethylase KDM6B, while resting and M2 MΦ were characterized by DNA methyltransferases and histone deacetylases. We demonstrate that MLL regulates CXCL10 expression and that this effect could be abrogated using a MLL-Menin inhibitor. Taken together we describe the distinct phenotypic differences of GM-CSF or M-CSF MΦ and demonstrate that MΦ polarization is regulated by specific epigenetic mechanisms. In addition, we describe a novel role for MLL as marker for classical activation. Our findings provide new insights into MΦ polarization that could be helpful to distinguish MΦ activation states.
A sufficient condition for the infinite dimensionality of the Bergman space of a pseudoconvex domain is given. This condition holds on any pseudoconvex domain that has at least one smooth boundary ...point of finite type in the sense of D’Angelo.
Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism ...responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL-12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds.
Let
Ω
⊂
C
be an open set. We show that
∂
¯
has closed range in
L
2
(
Ω
)
if and only if the Poincaré–Dirichlet inequality holds. Moreover, we give necessary and sufficient potential-theoretic ...conditions for the
∂
¯
-operator to have closed range in
L
2
(
Ω
)
. We also give a new necessary and sufficient potential-theoretic condition for the Bergman space of
Ω
to be infinite dimensional.
Context. The most metal-poor stars are the relics of the early chemical evolution of the Galaxy. Their chemical composition is an important tool to constrain the nucleosynthesis in the first ...generation of stars. The aim is to observe a sample of extremely metal-poor star (EMP stars) candidates selected from the Sloan Digital Sky Survey Data Release 12 (SDSS DR12) and determine their chemical composition. Aims. We obtain medium resolution spectra of a sample of six stars using the X-shooter spectrograph at the Very Large Telescope (VLT) and we used ATLAS models to compute the abundances. Methods. Five stars of the sample have a metallicity Fe/H between −2.5 dex and −3.2 dex. We confirm the recent discovery of SDSS J002314.00+030758.0 as a star with an extremely low Fe/H ratio. Assuming the α-enhancement Ca/Fe = +0.4 dex, we obtain Fe/H = −6.1 dex. Results. We could also determine its magnesium abundance and found that this star exhibits a very high ratio Mg/Fe≤ +3.60 dex assuming Fe/H = −6.13 dex. We determined the carbon abundance and found A(C) = 6.4 dex. From this carbon abundance, this stars belongs to the lower band of the A(C)–Fe/H diagram.
Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is ...driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
Climate change, fuel security and economics are creating a requirement for alternative, renewable fuels. Bioethanol is currently produced from land-based crops but in future marine biomass could be ...used as an alternative biomass source for bioethanol production. Macroalgae such as
Laminaria
spp. grow in abundance around the United Kingdom, reaching >4 m in length and containing up to 55% dry weight of the carbohydrates laminarin and mannitol. Using enzymes, these can be hydrolysed and converted to glucose and fructose, which in turn can be utilised by yeasts to produce ethanol. In previous studies on ethanol production from macroalgae, pre-treatment was at 65°C, pH 2 for 1 h prior to fermentation. This paper shows that these pre-treatments are not required for the fermentations conducted, with higher ethanol yields being achieved in untreated fermentations than in those with altered pH or temperature pre-treatments. This result was seen in fresh and defrosted macroalgae samples using
Saccharomyces cerevisiae
and 1 U kg
−1
laminarinase.
The genus Burkholderia includes pathogenic gram-negative bacteria that cause melioidosis, glanders, and pulmonary infections of patients with cancer and cystic fibrosis. Drug resistance has made ...development of new antimicrobials critical. Many approaches to discovering new antimicrobials, such as structure-based drug design and whole cell phenotypic screens followed by lead refinement, require high-resolution structures of proteins essential to the parasite.
We experimentally identified 406 putative essential genes in B. thailandensis, a low-virulence species phylogenetically similar to B. pseudomallei, the causative agent of melioidosis, using saturation-level transposon mutagenesis and next-generation sequencing (Tn-seq). We selected 315 protein products of these genes based on structure-determination criteria, such as excluding very large and/or integral membrane proteins, and entered them into the Seattle Structural Genomics Center for Infection Disease (SSGCID) structure determination pipeline. To maximize structural coverage of these targets, we applied an "ortholog rescue" strategy for those producing insoluble or difficult to crystallize proteins, resulting in the addition of 387 orthologs (or paralogs) from seven other Burkholderia species into the SSGCID pipeline. This structural genomics approach yielded structures from 31 putative essential targets from B. thailandensis, and 25 orthologs from other Burkholderia species, yielding an overall structural coverage for 49 of the 406 essential gene families, with a total of 88 depositions into the Protein Data Bank. Of these, 25 proteins have properties of a potential antimicrobial drug target i.e., no close human homolog, part of an essential metabolic pathway, and a deep binding pocket. We describe the structures of several potential drug targets in detail.
This collection of structures, solubility and experimental essentiality data provides a resource for development of drugs against infections and diseases caused by Burkholderia. All expression clones and proteins created in this study are freely available by request.
Summary
Grasses represent an abundant and widespread source of lignocellulosic biomass, which has yet to fulfil its potential as a feedstock for biorefining into renewable and sustainable biofuels ...and commodity chemicals. The inherent recalcitrance of lignocellulosic materials to deconstruction is the most crucial limitation for the commercial viability and economic feasibility of biomass biorefining. Over the last decade, the targeted genetic engineering of grasses has become more proficient, enabling rational approaches to modify lignocellulose with the aim of making it more amenable to bioconversion. In this review, we provide an overview of transgenic strategies and targets to tailor grass cell wall polysaccharides for biorefining applications. The bioengineering efforts and opportunities summarized here rely primarily on (A) reprogramming gene regulatory networks responsible for the biosynthesis of lignocellulose, (B) remodelling the chemical structure and substitution patterns of cell wall polysaccharides and (C) expressing lignocellulose degrading and/or modifying enzymes in planta. It is anticipated that outputs from the rational engineering of grass cell wall polysaccharides by such strategies could help in realizing an economically sustainable, grass‐derived lignocellulose processing industry.
Neutrophils are the first line of defense against pathogens and abnormal cells. They regulate many biological processes such as infections and inflammation. Increasing evidence demonstrated a role ...for neutrophils in cancer, where different subpopulations have been found to possess both pro- or anti-tumorigenic functions in the tumor microenvironment. In this review, we discuss the phenotypic and functional diversity of neutrophils in cancer, their prognostic significance, and therapeutic relevance in human and preclinical models. Molecular imaging methods are increasingly used to probe neutrophil biology
in vivo
, as well as the cellular changes that occur during tumor progression and over the course of treatment. This review will discuss the role of neutrophil imaging in oncology and the lessons that can be drawn from imaging in infectious diseases and inflammatory disorders. The major factors to be considered when developing imaging techniques and biomarkers for neutrophils in cancer are reviewed. Finally, the potential clinical applications and the limitations of each method are discussed, as well as the challenges for future clinical translation.
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