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Linking Marine Biological Activity to Aerosol Chemical Composition and Cloud-Relevant Properties Over the North Atlantic Ocean 期刊论文
JOURNAL OF GEOPHYSICAL RESEARCH-ATMOSPHERES, 2020, 125 (13)
作者:  Mansour, Karam;  39;Dowd, Colin
收藏  |  浏览/下载:34/0  |  提交时间:2020/08/18
aerosol-cloud interactions  CCN  INP  marine aerosol  ocean-atmosphere interactions  oceanic biological activity  
HBO1 is required for the maintenance of leukaemia stem cells 期刊论文
NATURE, 2020, 577 (7789) : 266-+
作者:  MacPherson, Laura;  Anokye, Juliana;  Yeung, Miriam M.;  Lam, Enid Y. N.;  Chan, Yih-Chih;  Weng, Chen-Fang;  Yeh, Paul;  Knezevic, Kathy;  Butler, Miriam S.;  Hoegl, Annabelle;  Chan, Kah-Lok;  Burr, Marian L.;  Gearing, Linden J.;  Willson, Tracy;  Liu, Joy;  Choi, Jarny;  Yang, Yuqing;  Bilardi, Rebecca A.;  Falk, Hendrik;  Nghi Nguyen;  Stupple, Paul A.;  Peat, Thomas S.;  Zhang, Ming;  de Silva, Melanie;  Carrasco-Pozo, Catalina;  Avery, Vicky M.;  Khoo, Poh Sim;  Dolezal, Olan;  Dennis, Matthew L.;  Nuttall, Stewart;  Surjadi, Regina;  Newman, Janet;  Ren, Bin;  Leaver, David J.;  Sun, Yuxin;  Baell, Jonathan B.;  Dovey, Oliver;  Vassiliou, George S.;  Grebien, Florian;  Dawson, Sarah-Jane;  Street, Ian P.;  Monahan, Brendon J.;  Burns, Christopher J.;  Choudhary, Chunaram;  Blewitt, Marnie E.;  Voss, Anne K.;  Thomas, Tim;  Dawson, Mark A.
收藏  |  浏览/下载:60/0  |  提交时间:2020/07/03

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.


  
An acute immune response underlies the benefit of cardiac stem cell therapy 期刊论文
NATURE, 2020, 577 (7790) : 405-+
作者:  Schmacke, Niklas A.;  Hornung, Veit
收藏  |  浏览/下载:40/0  |  提交时间:2020/07/03

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day(1,2), despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect(3). The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury(4,5). Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2(+) and CX3CR1(+) macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2(+) and CX3CR1(+) macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.


  
Sialylation of immunoglobulin E is a determinant of allergic pathogenicity 期刊论文
NATURE, 2020, 582 (7811) : 265-+
作者:  Abdul-Masih, Michael;  Banyard, Gareth;  Bodensteiner, Julia;  Bordier, Emma;  Bowman, Dominic M.;  Dsilva, Karan;  Fabry, Matthias;  Hawcroft, Calum;  Mahy, Laurent;  Marchant, Pablo;  Raskin, Gert;  Reggiani, Maddalena;  Shenar, Tomer;  Tkachenko, Andrew;  Van Winckel, Hans;  Vermeylen, Lore;  Sana, Hugues
收藏  |  浏览/下载:23/0  |  提交时间:2020/07/03

A specific type of glycosylation-sialylation-is more common on immunoglobulin E from individuals with a peanut allergys than from non-atopic people, suggesting that it has a role in regulating anaphylaxis.


Approximately one-third of the world'  s population suffers from allergies(1). Exposure to allergens crosslinks immunoglobulin E (IgE) antibodies that are bound to mast cells and basophils, triggering the release of inflammatory mediators, including histamine(2). Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease(3-5). It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or affect biological activity is completely unknown(6). Here we perform an unbiased examination of glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies. Our analysis reveals an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuates effector-cell degranulation and anaphylaxis in several functional models of allergic disease. Therapeutic interventions-including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor Fc epsilon RI, and administering asialylated IgE-markedly reduce anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease.


  
Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling 期刊论文
NATURE, 2020, 578 (7796) : 582-+
作者:  Faraco, Giuseppe;  Hochrainer, Karin;  Segarra, Steven G.;  Schaeffer, Samantha;  Santisteban, Monica M.;  Menon, Ajay;  Jiang, Hong;  Holtzman, David M.;  Anrather, Josef;  Iadecola, Costantino
收藏  |  浏览/下载:44/0  |  提交时间:2020/07/03

Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections(1). Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family(2). Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter(2). Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics-the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin-that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins-essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.


The glycopeptide antibiotic-related compounds complestatin and corbomycin function by binding to peptidoglycan and blocking the action of autolysins-peptidoglycan hydrolase enzymes that remodel the cell wall during growth.


  
Physical recovery of forest soil after compaction by heavy machines, revealed by penetration resistance over multiple decades 期刊论文
FOREST ECOLOGY AND MANAGEMENT, 2019, 449
作者:  Mohieddinne, Hamza;  Brasseur, Boris;  Spicher, Fabien;  Gallet-Moron, Emilie;  Buridant, Jerome;  Kobaissi, Ahmad;  Horen, Helene
收藏  |  浏览/下载:30/0  |  提交时间:2019/11/27
Forest  Logging operations  Luvisol  Podzol  Penetrometer  Ruts  Biological activity  Resilience