How the intestinal tract develops a tolerance to foreign antigens is still largely unknown. Here we report that extracellular vesicles (EVs) with TGF-β1-dependent immunosuppressive activity are ...produced by intestinal epithelial cells (IECs) under physiological conditions. Transfer of these EVs into inflammatory bowel disease (IBD) mice induced by dextran sulfate sodium salt decreases IBD severity by inducing regulatory T cells and immunosuppressive dendritic cells. In contrast, decreased endogenous EV production promotes IBD development. IECs produce EVs with increased levels of TGF-β1 upon IBD development in an ERK-dependent manner. Furthermore, these EVs tend to localize in the intestinal tract associated with epithelial cell adhesion molecule (EpCAM). Knockdown of EpCAM in vivo increases the severity of murine IBD, and the protective effect of EVs from IECs with decreased EpCAM on murine IBD is blunted. Therefore, our study indicates that EVs from IECs participate in maintaining the intestinal tract immune balance.
Two approaches are adopted to characterize the comprehensive pattern of the copper in-use stocks in China. The top-down results indicate that both the total amount and the per capita quantity of the ...stocks have exhibited a significant and increasing trend for the past 60 years, especially since 2000. The top-down results show that the copper stocks increased from a negligible level of less than 1 kg/capita in 1952 to 44 kg/capita in 2012. The total stocks in 2012 are estimated to be 60 Mt by a top-down approach or 48 Mt by a bottom-up calculation. The bottom-up method determines that the largest reservoir is the infrastructure sector, which accounts for approximately 58% of the total stocks. The spatial pattern indicates that the copper in-use stocks are predominately spatially distributed in the eastern regions of China, a feature that is obviously different from the geographical distribution of the primary resources. Analysis on the prospects of stocks shows both the total magnitude and per capita value will continuously increase in the following decade, and enter a relatively stable stage in around 2030, with a maximum value of 106 kg/capita. The results improve the knowledge about closing copper cycles.
Abstract
Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, ...the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (T
H
9) cell differentiation. CD4 T cells lacking
Atg3
or
Atg5
have increased interleukin-9 (IL-9) expression upon differentiation into T
H
9 cells relative to
Atg3-
or
Atg5
-expressing control cells. In addition, the T
H
9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances T
H
9 cell anticancer functions in vivo, and mice with T cell-specific deletion of
Atg5
have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of T
H
9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of T
H
9 activity for cancer immunotherapy.
This study attempts to speculate on the future of copper metabolism in China based on dynamic substance flow analysis. Based on tremendous growth of copper consumption over the past 63years, China ...will depict a substantially increasing trend of copper in-use stocks for the next 30years. The highest peak will be possibly achieved in 2050, with the maximum ranging between 163Mt and 171Mt. After that, total stocks are expected to slowly decline 147–154Mt by the year 2080. Owing to the increasing demand of in-use stocks, China will continue to have a profound impact on global copper consumption with its high import dependence until around 2020, and the peak demand for imported copper are expected to approach 5.5Mt/year. Thereafter, old scrap generated by domestic society will occupy an increasingly important role in copper supply. In around 2060, approximately 80% of copper resources could come from domestic recycling of old scrap, implying a major shift from primary production to secondary production. With regard to the effect of lifetime distribution uncertainties in different end-use sectors of copper stocks on the predict results, uncertainty evaluation was performed and found the model was relatively robust to these changes.
Display omitted
•The highest peak of copper in-use stocks will be possibly achieved around 2045.•Chinese copper industry will highly depend on imported copper until around 2020.•Since 2060, the net import reliance will descend to 20% or lower.
Improvements of the happiness of the rural population are an essential sign of the effectiveness of relative poverty governance. In the context of today's digital economy, assessing the relationship ...between digital literacy and the subjective happiness of rural low-income groups is of great practicality. Based on data from China Family Panel Studies, the effect of digital literacy on the subjective well-being of rural low-income groups was empirically tested. A significant happiness effect of digital literacy on rural low-income groups was found. Digital literacy promotes the subjective happiness of rural low-income groups through income increase and consumption growth effects. The observed happiness effect is heterogeneous among different characteristic groups, and digital literacy significantly positively impacts the subjective happiness of rural low-income groups. Decomposition of subjective happiness into life satisfaction and job satisfaction shows that digital literacy significantly positively affects the job and life satisfaction of rural low-income groups. This paper demonstrates that digital literacy induces a practical happiness effect. To further strengthen the subjective welfare effect of digital literacy in the construction of digital villages, the government should focus on cultivating digital literacy among low-income groups from the demand side. The construction of digital infrastructure should be actively promoted from the supply side.
TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. ...Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity.
By applying substance flow analysis (SFA), the paper attempts to illustrate how copper utilization pattern has changed in the anthroposphere of China from 1975 to 2010. An analytical framework is ...firstly established and the detailed copper cycles of the specific years 1975, 1985, 1995, 2005 and 2010 are then characterized. Major conclusions include the following: (1) Chinese copper industry has made significant progress driven by large domestic copper demand since 1970s, especially after 1990s. Also the structure of copper industry has shifted from a basic industry to a processing industry. The share of secondary copper production in total refined copper has risen from 20% in 1975 to 38% in 2010; (2) the Chinese society has experienced a rapid copper accumulation since 1990s. The annual input flow to use stage jumped from only 334Gg (that is 0.36kg per capita copper consumption) in 1975 to 7916Gg (5.90kg per capita) in 2010; (3) a large amount of copper has to be imported to meet the huge demand, mainly involving in copper concentrate, refined copper and copper scrap. And the NIR (Net Import Ratio) of the three was 53.0%, 38.7% and 63.0% in 2010, respectively; (4) domestically produced copper scrap increased from 74.5Gg in 1975 to 711.2Gg in 2010. Comparing it with import scrap and domestic new scrap we found that at current stage the in-use stock is still too small to generate high quantities of copper scrap for domestic secondary copper production. (5) Major copper losses occurred through copper Mining, Refining and WM&R, with the Mining exhibited the lowest copper utilization efficiency (CUE) among the three processes, and may have the great potential for increasing copper utilization rate in China.
•An analytical framework is established for characterizing copper cycles in China.•Copper flows of the specific years 1975, 1985, 1995, 2005 and 2010 are quantified.•The utilization pattern of copper resource is illustrated.
Purpose
This study aimed to investigate the deep learning model (DLM) combining computed tomography (CT) images and clinicopathological information for predicting anaplastic lymphoma kinase (ALK) ...fusion status in non-small cell lung cancer (NSCLC) patients.
Materials and methods
Preoperative CT images, clinicopathological information as well as the ALK fusion status from 937 patients in three hospitals were retrospectively collected to train and validate the DLM for the prediction of ALK fusion status in tumors. Another cohort of patients (
n
= 91) received ALK tyrosine kinase inhibitor (TKI) treatment was also included to evaluate the value of the DLM in predicting the clinical outcomes of the patients.
Results
The performances of the DLM trained only by CT images in the primary and validation cohorts were AUC = 0.8046 (95% CI 0.7715–0.8378) and AUC = 0.7754 (95% CI 0.7199–0.8310), respectively, while the DLM trained by both CT images and clinicopathological information exhibited better performance for the prediction of ALK fusion status (AUC = 0.8540, 95% CI 0.8257–0.8823 in the primary cohort,
p
< 0.001; AUC = 0.8481, 95% CI 0.8036–0.8926 in the validation cohort,
p
< 0.001). In addition, the deep learning scores of the DLMs showed significant differences between the wild-type and ALK infusion tumors. In the ALK-target therapy cohort (
n
= 91), the patients predicted as ALK-positive by the DLM showed better performance of progression-free survival than the patients predicted as ALK-negative (16.8 vs. 7.5 months,
p
= 0.010).
Conclusion
Our findings showed that the DLM trained by both CT images and clinicopathological information could effectively predict the ALK fusion status and treatment responses of patients. For the small size of the ALK-target therapy cohort, larger data sets would be collected to further validate the performance of the model for predicting the response to ALK-TKI treatment.
Interleukin 4-induced gene-1 (IL4I1) was initially described as an early IL-4-inducible gene in B cells. IL4I1 protein can inhibit T cell proliferation by releasing its enzymatic catabolite, H2O2, ...and this effect is associated with transient down-regulation of T cell CD3 receptor-zeta (TCRζ) expression. Herein, we show that IL4I1 contributes to the regulation of macrophage programming. We found that expression of IL4I1 increased during bone marrow-derived macrophage (BMDM) differentiation, expression of IL4I1 is much higher in primary macrophages than monocytes, and IL4I1 expression in BMDMs could be induced by Th1 and Th2 cytokines in two different patterns. Gene expression analysis revealed that overexpression of IL4I1 drove the expression of M2 markers (Fizz1, Arg1, YM-1, MR) and inhibited the expression of M1-associated cytokines. Conversely, knockdown of IL4I1 by siRNA resulted in opposite effects, and also attenuated STAT-3 and STAT-6 phosphorylation. Furthermore, IL4I1 produced by macrophages catalyzed L-tryptophan degradation, while levo-1-methyl-tryptophan (L-1-MT), but not dextro-1-methyl-tryptophan, partially rescued IL4I1-dependent inhibition of T cell activation. Other inhibitors, such as diphenylene iodonium (DPI), an anti-IL-10Rα blocking antibody, and a nitric oxide synthase inhibitor, NG-monomethyl-L-arginine, also had this effect. Overall, our findings indicate that IL4I1 promotes an enhanced M2 functional phenotype, which is most likely associated with the phosphorylation of STAT-6 and STAT-3. Moreover, DPI, L-1-MT, NG-monomethyl-L-arginine, and anti-IL-10Rα blocking antibody were all found to be effective IL4I1 inhibitors in vitro.
In this Q&A, Cell Metabolism's Scientific Editor Rosalind Mott talks to Prof. Zhijian Cai about his paper "UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic ...disorders" and his experience with publishing through Cell Press Community Review.
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