N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still ...unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.
Data-independent acquisition (DIA) is an emerging technology for quantitative proteomic analysis of large cohorts of samples. However, sample-specific spectral libraries built by data-dependent ...acquisition (DDA) experiments are required prior to DIA analysis, which is time-consuming and limits the identification/quantification by DIA to the peptides identified by DDA. Herein, we propose DeepDIA, a deep learning-based approach to generate in silico spectral libraries for DIA analysis. We demonstrate that the quality of in silico libraries predicted by instrument-specific models using DeepDIA is comparable to that of experimental libraries, and outperforms libraries generated by global models. With peptide detectability prediction, in silico libraries can be built directly from protein sequence databases. We further illustrate that DeepDIA can break through the limitation of DDA on peptide/protein detection, and enhance DIA analysis on human serum samples compared to the state-of-the-art protocol using a DDA library. We expect this work expanding the toolbox for DIA proteomics.
Lanthanide upconversion nanophosphors (UCNPs) show unique upconversion luminescence where lower-energy photons (such as near-infrared (NIR) excitation) are converted into higher-energy photons ...covering the NIR to the UV region, and are considered to have a bright future in clinical translation. As UCNPs are used in a significant number of potential bio-applications, their biosafety is important and has attracted significant attention. In this critical review, recent reports regarding the cellular internalization, biodistribution, excretion, cytotoxicity and
in vivo
toxic effects of UCNPs are reviewed. In particular, the studies which evaluated the association between the chemical and physical properties of UCNPs and their biodistribution, excretion, and toxic effects are presented in detail. Finally, we also discuss the challenges of ensuring the biosafety of UCNPs
in vivo
.
The association between the chemo-physical properties of UCNPs and their biodistribution, excretion, and toxic effects is presented in this review.
Large-scale profiling of intact glycopeptides is critical but challenging in glycoproteomics. Data independent acquisition (DIA) is an emerging technology with deep proteome coverage and accurate ...quantitative capability in proteomics studies, but is still in the early stage of development in the field of glycoproteomics. We propose GproDIA, a framework for the proteome-wide characterization of intact glycopeptides from DIA data with comprehensive statistical control by a 2-dimentional false discovery rate approach and a glycoform inference algorithm, enabling accurate identification of intact glycopeptides using wide isolation windows. We further utilize a semi-empirical spectrum prediction strategy to expand the coverage of spectral libraries of glycopeptides. We benchmark our method for N-glycopeptide profiling on DIA data of yeast and human serum samples, demonstrating that DIA with GproDIA outperforms the data-dependent acquisition-based methods for glycoproteomics in terms of capacity and data completeness of identification, as well as accuracy and precision of quantification. We expect that this work can provide a powerful tool for glycoproteomic studies.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes severe complications and even death. However, asymptomatic infection has also been reported, highlighting the ...difference in immune responses among individuals. Here we performed single-cell chromatin accessibility and T cell-receptor analyses of peripheral blood mononuclear cells collected from individuals convalescing from COVID-19 and healthy donors. Chromatin remodelling was observed in both innate and adaptive immune cells in the individuals convalescing from COVID-19. Compared with healthy donors, recovered individuals contained abundant TBET-enriched CD16
and IRF1-enriched CD14
monocytes with sequential trained and activated epigenomic states. The B-cell lineage in recovered individuals exhibited an accelerated developmental programme from immature B cells to antibody-producing plasma cells. Finally, an integrated analysis of single-cell T cell-receptor clonality with the chromatin accessibility landscape revealed the expansion of putative SARS-CoV-2-specific CD8
T cells with epigenomic profiles that promote the differentiation of effector or memory cells. Overall, our data suggest that immune cells of individuals convalescing from COVID-19 exhibit global remodelling of the chromatin accessibility landscape, indicative of the establishment of immunological memory.
There are thousands of lipid species existing in cells, which belong to eight different categories. Lipids are the essential building blocks of cells. Recent studies have started to unveil the ...important functions of lipids in regulating cell metabolism. However, we are still at a very early stage in fully understanding the physiological and pathological functions of lipids. The application of lipidomics for studying lipid metabolism can provide a direct readout of the cellular status and broadens our understanding of the mechanisms that underpin metabolic disease states. This review provides an introduction to lipid metabolism and its role in modulating homeostasis and immunity. We also describe representative applications of lipidomics for studying lipid metabolism in inflammation-related diseases.
In this work, we synthesized highly water-dispersible multiwalled carbon nanotubes@polydopamine (MWCNTs@PDA) core–shell composites by a facile in situ oxidative polymerization. The composites were ...successfully applied as a novel matrix for the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF–MS) analysis of various water-soluble small molecule compounds. It was found that MWCNTs@PDA composites have a higher sensitivity and peak intensities for small molecules detection.
Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications
. Epidemiological studies have ...suggested that diabetes is also linked to an increased risk of cancer
. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in ...its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose‐6‐phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation.
Synopsis
This study shows that SIRT5 desuccinylates and deglutarylates IDH2 and G6PD, respectively, and activates both enzymes to maintain cellular NADPH homeostasis and to enhance cellular antioxidant defense.
SIRT5 protects cells from oxidative damage by controlling NADPH homeostasis.
SIRT5 catalyzes IDH2 desuccinylation and G6PD deglutarylation to stimulate their enzyme activity.
SIRT5 desuccinylase activity is triggered by oxidative stimuli.
This study shows that SIRT5 desuccinylates and deglutarylates IDH2 and G6PD, respectively, and activates both enzymes to maintain cellular NADPH homeostasis and to enhance cellular antioxidant defense.
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