Insulin signaling establishes a developmental trajectory of adipose regulatory T cells.

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.

SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells.

Glutaminase regulates glutaminolysis to promote cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here, we demonstrate that kidney-type glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. Upon oxidative stress, the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit ß (SUCLA2) phosphorylated by p38 mitogen-activated protein kinase (MAPK) at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and activity. Activated GLS increases glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, thereby counteracting oxidative stress and promoting tumor cell survival and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutually correlated, were positively associated with advanced stages of PDAC and poor prognosis for patients. Our findings reveal critical regulation of GLS by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development.

Plasma metabolome and cytokine profile reveal glycylproline modulating antibody fading in convalescent COVID-19 patients.

The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the "new normal." The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning-based classification models using 17 features (six cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least six machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2-specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.

Precise Synthesis of Organic Cocrystal Alloys with Full-Spectrum Emission Characteristics for the Stepless Color Changing Display.

Organic luminescent materials are indispensable in optoelectronic displays and solid-state luminescence applications. Compared with single-component, multi-component crystalline materials can improve optoelectronic characteristics. This work forms a series of full-spectrum tunable luminescent charge-transfer (CT) cocrystals ranging from 400 to 800 nm through intermolecular collaborative self-assembly. What is even more interesting is that o-TCP-Cor(x)-Pe(1-x), p-TCP-Cor(x)-Pe(1-x), and o-TCP-AN(x)-TP(1-x) alloys are prepared based on cocrystals by doping strategies, which correspondingly achieve the stepless color change from blue (CIE [0.22, 0.44]) to green (CIE [0.16, 0.14]), from green (CIE [0.27, 0.56]) to orange (CIE [0.58, 0.42]), from yellow (CIE [0.40, 0.57]) to red (CIE [0.65, 0.35]). The work provides an efficient method for precisely synthesizing new luminescent organic semiconductor materials and lays a solid foundation for developing advanced organic solid-state displays.

Quark Mass Dependence of Heavy Quark Diffusion Coefficient from Lattice QCD.

We present the first study of the quark mass dependence of the heavy quark momentum and spatial diffusion coefficients using lattice QCD with light dynamical quarks corresponding to a pion mass of 320 MeV. We find that, for the temperature range 195 MeV

Global Distribution of Mercury in Foliage Predicted by Machine Learning.

Foliar assimilation of elemental mercury (Hg0) from the atmosphere plays a critical role in the global Hg biogeochemical cycle, leading to atmospheric Hg removal and soil Hg insertion. Recent studies have estimated global foliar Hg assimilation; however, large uncertainties remained due to coarse accounting of observed foliar Hg concentrations, posing a substantial challenge in constraining the global Hg budget. Here, we integrated a comprehensive observation database of foliar Hg concentrations and machine learning algorithms to predict the first spatial distribution of foliar Hg concentrations on a global scale, contributing to the first estimate of global Hg pools in foliage. The global average of foliar Hg concentrations was estimated to be 24.0 ng g-1 (7.5-56.5 ng g-1), and the global total in foliar Hg pools reached 4561.3 Mg (1455.2-9062.8 Mg). The spatial distribution showed the hotspots in tropical regions, including the Amazon, Central Africa, and Southeast Asia. A range of 2268.5-2727.0 Mg yr-1 was estimated for annual foliar Hg assimilation accounting for the perennial continuous assimilation by evergreen vegetation foliage. The first spatial maps of foliar Hg concentrations and Hg pools may aid in understanding the global biogeochemical cycling of Hg, especially in the context of climate change and global vegetation greening.

The Safety of Injections in the Infraorbital Region.

BACKGROUND:  Infraorbital filler injection is a commonly used minimally invasive cosmetic procedure on the face, which can cause vascular complications. OBJECTIVE:  In this study, we aimed to explore the anatomical structure of the infraorbital vasculature and to establish an accurate protocol for infraorbital filler injection. METHODS:  The vascular structure of the infraorbital region was evaluated in 84 hemifacial specimens using computed tomography. Four segments (P1-P4) and five sections (C1-C5) were considered. We recorded the number of identified arteries in each slice and at each location and the number of deep arteries. Furthermore, we also measured the infraorbital artery (IOA) distribution. RESULTS:  At P1-P4, the lowest number of arteries was detected in segment P4, with a 317/1727 (18.4%) and 65/338 (2.3%) probability of total and deep arterial identification, respectively. The probabilities of encountering an identified artery at the five designated locations (C1-C5) were 277/1727 (16%), 318/1727 (18.4%), 410/1727 (23.7%), 397/1727 (23%), and 325/1727 (18.8%), respectively. The probability of an IOA being identified at C2 was 68/84 (81%). CONCLUSION:  We described an effective filler injection technique in the infraorbital region to minimize the associated risks. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Heavy Quark Diffusion from 2+1 Flavor Lattice QCD with 320 MeV Pion Mass.

We present the first calculations of the heavy flavor diffusion coefficient using lattice QCD with light dynamical quarks corresponding to a pion mass of around 320 MeV. For temperatures 195 MeV

Nucleon Transversity Distribution in the Continuum and Physical Mass Limit from Lattice QCD.

We report a state-of-the-art lattice QCD calculation of the isovector quark transversity distribution of the proton in the continuum and physical mass limit using large-momentum effective theory. The calculation is done at four lattice spacings a={0.098,0.085,0.064,0.049} fm and various pion masses ranging between 220 and 350 MeV, with proton momenta up to 2.8 GeV. The result is nonperturbatively renormalized in the hybrid scheme with self-renormalization, which treats the infrared physics at large correlation distance properly, and extrapolated to the continuum, physical mass, and infinite momentum limit. We also compare with recent global analyses for the nucleon isovector quark transversity distribution.

Multidimensional Drivers of Mercury Distribution in Global Surface Soils: Insights from a Global Standardized Field Survey.

Soil stores a large amount of mercury (Hg) that has adverse effects on human health and ecosystem safety. Significant uncertainties still exist in revealing environmental drivers of soil Hg accumulation and predicting global Hg distribution owing to the lack of field data from global standardized analyses. Here, we conducted a global standardized field survey and explored a holistic understanding of the multidimensional environmental drivers of Hg accumulation in global surface soils. Hg content in surface soils from our survey ranges from 3.8 to 618.2 µg kg-1 with an average of 74.0 µg kg-1 across the globe. Atmospheric Hg deposition, particularly vegetation-induced elemental Hg0 deposition, is the major source of surface soil Hg. Soil organic carbon serves as the major substrate for sequestering Hg in surface soils and is significantly influenced by agricultural management, litterfall, and elevation. For human activities, changing land-use could be a more important contributor than direct anthropogenic emissions. Our prediction of a new global Hg distribution highlights the hot spots (high Hg content) in East Asia, the Northern Hemispheric temperate/boreal regions, and tropical areas, while the cold spots (low Hg content) are in arid regions. The holistic understanding of multidimensional environmental drivers helps to predict the Hg distribution in global surface soils under a changing global environment.

MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells.

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial respiration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.

Local temperature increases reduce soil microbial residues and carbon stocks.

Warming is known to reduce soil carbon (C) stocks by promoting microbial respiration, which is associated with the decomposition of microbial residue carbon (MRC). However, the relative contribution of MRC to soil organic carbon (SOC) across temperature gradients is poorly understood. Here, we investigated the contribution of MRC to SOC along two independent elevation gradients of our model system (i.e., the Tibetan Plateau and Shennongjia Mountain in China). Our results showed that local temperature increases were negatively correlated with MRC and SOC. Further analyses revealed that rising temperature reduced SOC via decreasing MRC, which helps to explain future reductions in SOC under climate warming. Our findings demonstrate that climate warming has the potential to reduce C sequestration by increasing the decomposition of MRC, exacerbating the positive feedback between rising temperature and CO2 efflux. Our study also considered the influence of multiple environmental factors such as soil pH and moisture, which were more important in controlling SOC than microbial traits such as microbial life-style strategies and metabolic efficiency. Together, our work suggests an important mechanism underlying long-term soil C sequestration, which has important implications for the microbial-mediated C process in the face of global climate change.

Dynamic Timing Control over Multicolor Molecular Emission by Temporal Chemical Locking.

Dynamic control over molecular emission, especially in a time-dependent manner, holds great promise for the development of smart luminescent materials. Here we report a series of dynamic multicolor fluorescent systems based on the time-encoded locking and unlocking of individual vibrational emissive units. The intramolecular cyclization reaction driven by adding chemical fuel acts as a chemical lock to decrease the conformational freedom of the emissive units, thus varying the fluorescence wavelength, while the resulting chemically locked state can be automatically unlocked by the hydrolysis reaction with water molecules. The dynamic molecular system can be driven by adding chemical fuels for multiple times. The emission wavelength and lifetime of the locking states can be readily controlled by elaborating the molecular structures, indicating this strategy as a robust and versatile way to modulate multi-color molecular emission in a time-encoded manner.

Serum Metabolomics Reveals Personalized Metabolic Patterns for Macular Neovascular Disease Patient Stratification.

The macular neovascular disease is a group disorder with complex pathogenesis of neovascularization for vision impairment and irreversible blindness, posing great challenges to precise diagnosis and management. We prospectively recruited participants with age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), and pathological myopia (PM) and compared with cataract patients without fundus diseases as a control group. The serum metabolome was profiled by gas chromatography coupled with time-of-flight mass spectrometry (GC-TOFMS) analysis. Multivariate statistical methods as well as data mining were performed for interpretation of macular neovascularization. A total of 446 participants with macular neovascularization and 138 cataract subjects as the control group were enrolled in this study. By employing GC-TOFMS, 131 metabolites were identified and 33 differentiating metabolites were highlighted in patients with macular neovascularization. For differential diagnosis, three panels of specific metabolomics-based biomarkers provided areas under the curve of 0.967, 0.938, and 0.877 in the discovery phase (n = 328) and predictive values of 87.3%, 79%, and 85.7% in the test phase (n = 256). Personalized pathway dysregulation scores measurement using Lilikoi package in R language revealed the pentose phosphate pathway and mitochondrial electron transport chain as the most important pathways in AMD; purine metabolism and glycolysis were identified as the major disturbed pathways in PCV, while the altered thiamine metabolism and purine metabolism may contribute to PM phenotypes. Serum metabolomics are powerful for characterizing metabolic disturbances of the macular neovascular disease. Differences in metabolic pathways may reflect an underlying macular neovascular disease and serve as therapeutic targets for macular neovascular treatment.

(TS)2WM: Tumor Segmentation and Tract Statistics for Assessing White Matter Integrity with Applications to Glioblastoma Patients.

Glioblastoma (GBM) brain tumor is the most aggressive white matter (WM) invasive cerebral primary neoplasm. Due to its inherently heterogeneous appearance and shape, previous studies pursued either the segmentation precision of the tumors or qualitative analysis of the impact of brain tumors on WM integrity with manual delineation of tumors. This paper aims to develop a comprehensive analytical pipeline, called (TS)2WM, to integrate both the superior performance of brain tumor segmentation and the impact of GBM tumors on the WM integrity via tumor segmentation and tract statistics using the diffusion tensor imaging (DTI) technique. The (TS)2WM consists of three components: (i) A dilated densely connected convolutional network (D2C2N) for automatically segment GBM tumors. (ii) A modified structural connectome processing pipeline to characterize the connectivity pattern of WM bundles. (iii) A multivariate analysis to delineate the local and global associations between different DTI-related measurements and clinical variables on both brain tumors and language-related regions of interest. Among those, the proposed D2C2N model achieves competitive tumor segmentation accuracy compared with many state-of-the-art tumor segmentation methods. Significant differences in various DTI-related measurements at the streamline, weighted network, and binary network levels (e.g., diffusion properties along major fiber bundles) were found in tumor-related, language-related, and hand motor-related brain regions in 62 GBM patients as compared to healthy subjects from the Human Connectome Project.

Transketolase counteracts oxidative stress to drive cancer development.

Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECH-Associated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.

[Toxicity-reducing effect of compatibility of Tripterygium and licorice in animals: systematic review].

The aim of this paper was to systematically evaluate the toxicity-reducing effect of Tripterygium-licorice in animal experiments,and also to provide evidence for basic research on the toxicity reduction of Tripterygium wilfordii. The PubMed,EMbase,Web of Science,CBM,CNKI and Wan Fang Databases from their establishment to August 31 th,2018 were searched. Two independent reviewers screened the papers,extracted the data,assessed the risk of bias using SYRCLE assessment tool and conducted Meta-analysis with Rev Man 5. 3 software. A total of 10 papers involving 31 studies were finally included,15 studies of which were used for Meta-analysis. Four studies were included for chronic hepatotoxicity animal model. In experimental group( 34 animals),Tripterygium was administered at dose of 0. 09-0. 1 mg·kg-1·d-1,and glycyrrhizic acid was administered at dose of 90-100 mg·kg-1,both for 2 weeks; in control group( 34 animals),glycyrrhizic acid was replaced with equal volume of normal saline. Eleven studies were included for acute hepatotoxicity animal model. In experimental group( 66 animals),glycyrrhizic acid was administered at dose of 75-480 mg·kg-1 for 7 days,then glycyrrhizic acid was stopped,and Tripterygium began to be administered at dose of 0. 6-1. 0 mg·kg-1 per 24 h or 48 h for a total of 1-2 times; in control group( 66 animals),glycyrrhizic acid was replaced with equal volume of normal saline or corresponding solvent. The results of Meta-analysis showed that in both chronic hepatotoxicity animal model and acute hepatotoxicity animal model,the transaminase levels in the experimental group were lower than those in the control group( P < 0. 05). Subgroup analysis of acute hepatotoxicity animal model showed that the transaminase levels in the experimental group were lower than those in the control group for every subgroup except " glycyrrhizic acid 75 mg·kg-1" subgroup. However,in terms of the mean difference( MD) and confidence interval( CI),there was no significant difference in transaminase decline between each subgroup. Low dose of glycyrrhizic acid( 90-100 mg·kg-1) has a toxicity-reduction effect on chronic hepatotoxicity induced by tripterygium( 0. 09-0. 10 mg·kg-1). Middle and high doses of glycyrrhizic acid( 120-480 mg·kg-1) have a toxicity-reduction effect on acute hepatotoxicity induced by tripterygium( 0. 6-1. 0 mg·kg-1),but with no significant dose-effect relationship.

Eukaryotic translation initiation factor 5A2 promotes metabolic reprogramming in hepatocellular carcinoma cells.

Reprogramming of intracellular metabolism is common in liver cancer cells. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. In our previous study, we reported that a novel oncogene eukaryotic translation initiation factor 5A2 (EIF5A2) promotes tumorigenesis under hypoxic condition. Here, we aim to investigate the role of EIF5A2 in cell metabolic reprogramming during hepatocellular carcinoma (HCC) development. In this study, we reported that the messenger RNA (mRNA) level of EIF5A2 was upregulated in 59 of 105 (56.2%) HCC clinical samples (P = 0.015), and EIF5A2 overexpression was significantly associated with shorter survival time of patients with HCC (P = 0.021). Ectopic expression of EIF5A2 in HCC cell lines significantly promoted cell growth and accelerated glucose utilization and lipogenesis rates. The high rates of glucose uptake and lactate secretion conferred by EIF5A2 revealed an abnormal activity of aerobic glycolysis in HCC cells. Several key enzymes involved in glycolysis including glucose transporter type 1 and 2, hexokinase 2, phosphofructokinase liver type, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2 isoform, phosphoglycerate mutase 1 and lactate dehydrogenase A were upregulated by overexpression of EIF5A2. Moreover, EIF5A2 showed positive correlations with FASN and ACSS2, two key enzymes involved in the fatty acid de novo biosynthetic pathway, at both protein and mRNA levels in HCC. These results indicated that EIF5A2 may regulate fatty acid de novo biosynthesis by increasing the uptake of acetate. In conclusion, our findings demonstrate that EIF5A2 has a critical role in HCC cell metabolic reprogramming and may serve as a prominent novel therapeutic target for liver cancer treatment.

Mesenchymal stem cells-conditioned medium protects PC12 cells against 2,5-hexanedione-induced apoptosis via inhibiting mitochondria-dependent caspase 3 pathway.

Studies suggested that the conditioned medium of mesenchymal stem cells (MSC-CM) inhibited the increased apoptosis in various cells. However, there are no reports underlying the protection of MSC-CM against 2,5-hexanedione (HD)-induced apoptosis in neural cells. In the present study, the viability was observed in PC12 cells that received HD alone or with MSC-CM by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was estimated by Hoechst 33342 staining and flow cytometry. Mitochondrial transmembrane potential was examined by rhodamine 123. Moreover, we investigated the expression of Bax and Bcl-2, cytochrome c translocation, and caspase 3 activity by real-time polymerase chain reaction, Western blot, and immunochemistry. Nerve growth factor (NGF) was examined in MSCs and MSC-CM. Our results showed that MSC-CM promoted cell survival and reduced apoptosis in HD-exposed PC12 cells. Moreover, MSC-CM significantly reversed disturbance of Bax and Bcl-2, ameliorated disruption of mitochondrial transmembrane potential, and reduced release of cytochrome c and activity of caspase 3 in HD-exposed PC12 cells. In the meantime, NGF was detected in MSCs and MSC-CM. These findings demonstrate that MSC-CM protects against HD-induced apoptosis in PC12 cells via inhibiting mitochondrial pathway. Our results indicate that NGF in MSC-CM may be involved in the protection of MSC-CM against HD-induced apoptosis. Our study clarifies the protection of MSC-CM on HD neurotoxicity and its underlying mechanism.