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Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2–4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein–protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance. CRISPR screening and protein–protein interaction networks identify components and mechanisms of nutrient-dependent mTORC1 signalling in regulatory T cells and reveal how mTORC1 integrates immunological cues and nutrient signals for adaptive immunity.

Electrocatalytic synthesis for aldehydes from alcohols exhibits unique superiorities as a promising technology. However, such cascade reactions are severely limited by the low selectivity resulting from the peroxidation of aldehydes in a traditional liquid-solid system. Herein, we report a novel liquid-liquid-solid system to regulate the selectivity of benzyl alcohol electrooxidation. The selectivity of benzaldehyde is a 200-fold increase from 0.4% to 80.4% compared with the liquid-solid system, simultaneously, the current density of 136 mA cm-2 can be reached, which is the highest current density to our knowledge. In the presented system, the is suppressed efficiently after using the l-l-s system, with the conversion of Ph-CHO being decreased from 87.6% to 3.8%. The produced benzaldehyde could be in-situ extracted to toluene and separated from the electrolyte to achieve purification of benzaldehyde. This strategy provides an efficient way to modulate the selectivity of electrocatalytic cascade reactions.

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs. Enzymes in the cytidine diphosphate–ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (TFH) cells, by regulating the chemokine receptor CXCR5.

It is urgent to obtain targeted drugs that selectively bind to pathological targets rather than physiological targets in the early stage of drug screening. G-Quadruplex has become one of the important targets in the development of anti-tumor drugs. However, drugs that target quadruplexes may also bind to dsDNA, which may lead to adverse reactions. In this study, a new three-phase laminar flow chip was constructed to enable the multi-components of a traditional Chinese medicine extract to dynamically and competitively bind with G-quadruplex DNA (on target) and double-stranded DNA (off target), so as to select high-efficiency and low-toxicity anti-tumor drugs. The results showed that there were five compounds in the extracts of Macleaya cordata seeds that exhibited obvious differences in binding to the two targets. Furthermore, the binding constants and modes of four identified alkaloids as they bound to two DNA targets were verified by fluorescence spectra and molecular docking methods. The toxicity to HepG2 and LO2 cells from the four alkaloids was also compared. The results showed that sanguinarine and chelerythrine could be used as candidate drugs with stronger binding to HT24 than DNA26. The chip can also be used for other types of double-target screening of other traditional Chinese medicine extracts or compound libraries.

Ammonia, as a significant chemical for fertilizer production and also a promising energy carrier, is mainly produced through the traditional energy-intensive Haber–Bosch process. Recently, the electrocatalytic N2 reduction reaction (NRR) for ammonia synthesis has received tremendous attention with the merits of energy saving and environmental friendliness. To date, the development of the NRR process is primarily hindered by the competing hydrogen evolution reaction (HER), whereas the corresponding strategies for inhibiting this undesired side reaction to achieve high NRR selectivity are still quite limited. Furthermore, for such a complex reaction involving three gas–liquid–solid phases and proton/electron transfer, it is also rather meaningful to decouple and summarize the current strategies for suppressing H2 evolution in terms of NRR mechanisms, kinetics, thermodynamics, and electrocatalyst design in detail. Herein, on the basis of the NRR mechanisms, we systematically summarize the recent strategies to inhibit the HER for a highly selective electrocatalytic NRR, focusing on limiting the proton- and electron-transfer kinetics, shifting the chemical equilibrium, and designing the electrocatalysts. Additionally, insights into boosting the NRR selectivity and efficiency for practical applications are also presented in detail with regard to the determination of ammonia, the activation of the N2 molecule, the regulation of the gas–liquid–solid three-phase interface, the coupled NRR with value-added oxidation reactions, and the development of flow cell reactors.

The identification of mechanisms to promote memory T cells (T(MEM)) has important implications for vaccination and anti-cancer immunotherapy(1–4). Using a CRISPR-based screen for negative regulators of T(MEM) generation in vivo(5), we discovered multiple components of the mammalian canonical Brg1/Brg-associated factor (cBAF)(6,7). Several components of the cBAF complex are essential for the differentiation of activated CD8(+) T cells into T effector (T(EFF)) cells, and their loss promotes T(MEM) formation in vivo. During the first division of activated CD8(+) T cells, cBAF and c-Myc(8) frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high c-Myc and high cBAF display a cell fate trajectory towards T(EFF) cells, while those with low c-Myc and low cBAF preferentially differentiate towards T(MEM) cells. The cBAF complex and c-Myc physically interact to establish the chromatin landscape in activated CD8(+) T cells. Treatment of naïve CD8(+) T cells with a putative cBAF inhibitor during the first 48 hours of activation, prior to the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a solid tumor model. Our results establish cBAF as a negative determinant of T(MEM) cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.

Functional materials with tuned nanostructure derived from metal–organic frameworks (MOF) hold great promise in energy storage/conversion and catalysis. Herein, we report a novel strategy to fabricate carbon fiber (CF)-supported cobalt nanocatalysts (Co-NC/CF) by a self-made “microreactor” consisted of randomly stacked graphene powder with the help of the microwave field. This newly-developed methodology can not only lead to a significantly enhanced yield of MOF-derived Co-NC up to 48.7 wt%, but also dramatically reduce the pyrolysis time (in just 60 s) and energy consumption (only 0.37% of traditional pyrolysis method). The experimental results combined with theoretical calculations revealed that the synthesized Co-NC/CF with optimized surface binding capability for reaction intermediates featured high-efficient catalytic activities for OER and HER owing to the electron transfer from cobalt to the surface carbon layers. The present microwave pyrolysis technique with an ultra-short synthesis cycle, high product yield and excellent energy efficiency, also demonstrated broad applicability for the synthesis of other MOF-derived functional materials.

With the increasingly prominent energy issues and environment problems, the electrocatalytic production of value-added fine chemicals by hybrid water electrolysis has shown much hope for replacing conventional energy-intensive chemical technology. However, the low current density caused by the competition of the oxygen evolution reaction at the anode has hindered the large-scale production of fine chemicals and H2. Besides, the separation of products from the complicated electrolyte also remains a significant barrier. Herein, we present the integration of hybrid water electrolysis and conventional crystallization separation for the first time, achieving the electrocatalytic production and separation of benzoic acid without impurities. An amorphous nanosheet composed of Ni, Co hydroxide supported on Ni foam (A-Ni-Co-H/NF), with a large active area and low charge transfer resistance, is prepared for the first time and applied to catalyze the electrocatalytic benzyl alcohol oxidation reaction. A-Ni-Co-H/NF enables us to achieve an industrial-scale current density over 400 mA cm−2 without the occurrence of the OER, and delivers ultrafast reaction kinetics. The yield of Ph-COOH is close to 100%, only spending 15 min at room temperature and atmosphere pressure. In situ Raman spectroscopy reveals that the as-made A-Ni-Co-H/NF catalyst features reversible structure evolution and recovery during the EBA reaction. The converted nickel oxyhydroxide containing Co species (Co-NiOOH) is confirmed as the real active species. This presents a novel electrocatalyst to achieve industrial-scale prodution for value-added chemicals and the novel integrated technology also provides guidance for the separation and collection of products during the electrocatalytic process.

The Pd/C catalysts are widely used in synthesis of fine chemicals in industry, but their production suffers from a complicated two-step process involving impregnation and reduction, and requires large amounts of solvents and reductant, which would lead to a series of issues such as time consumption, resource waste and environmental pollution. Herein, ultra-small Pd nanoparticles uniformly anchored on carbon nanotubes (Pd/CNTs) were synthesized by using a one-pot and low-temperature reduction strategy. The present process/technology is very sensitive to and controlled by the supports and solvents, and the carbon support and acetic acid synergistically play crucial and decisive roles in the fast production of Pd/C catalysts. Also, the used solvents can be recycled and reutilized, which meets the requirements of sustainable chemistry and green economy. When the as-obtained Pd/CNTs catalyst was used to catalyze the oxidation of benzyl alcohol to benzaldehyde, it achieved a conversion efficiency as high as 99.3 % and a high selectivity up to >99.9 %. The simple, scalable and environmentally friendly strategy can be extended to anchor Pd nanoparticles on various carbon substrates, which sheds a new light on the synthesis of Pd/C catalysts.

Recently, tailor-made NiCo bimetallic phosphides hold a promising platform material in many fields such as catalysis and electrochemical energy storage and conversion. Typically, the traditional one-step phosphorization route offers limited phase control, with hexagonal phosphide phase structure (Ni 2 P type). Moreover, the phase component sensitively depends on the metal ratio to a great degree, posing great challenges to synthesize NiCo bimetallic phosphides with tuned composition and phase structure. Herein, we report a carbon encapsulated Ni 2+ post-modified CoP nanowire (denoted as Ni CoP@C) with single orthorhombic CoP phase structure and tuned Ni doping content via a facile & novel in-situ isomorphous-substitution method. More importantly, no any phase separation occurs, also further achieving a high Ni doping content (57 at%) that is less realized previously. As an example application, the as-made Ni CoP@C nanowire exhibits excellent oxygen evolution reaction (OER) activity and stability, showing promising potential in the field of water splitting. The present novel strategy will pave the way for further phase controllable fabrication of bi/multi-metal-based materials in catalysis and energy storage & conversion fields.

Cobalt oxides with abundant defects, including those with fully exposed active sites and abundant oxygen vacancies, exhibit superb catalytic activities towards oxygen evolution reaction (OER). Herein, we report a facile in-situ electrochemical self-optimization strategy to produce carbon-fiber-supported defective CoOx (E-CoOx/CF), in which the partial self-dissolution of acidic oxides under alkaline OER operational conditions and releasing of in-situ generated oxygen molecules are taken as advantages for reconstruction of Co species with abundant defects, Co2+ and oxygen vacancies. The resultant E-CoOx/CF can achieve 10 mA cm−2 at a low overpotential of 249 mV with a remarkable stability (>100 h without performance decay). Moreover, this electrochemical etching method can also be extended to the preparation of highly active transition metal nickel oxides for enhanced OER. This study represents a new yet efficient strategy for rationally designing and developing advanced transition metal oxides for various electrochemical applications and beyond.

Electrochemical reduction of carbon dioxide to hydrocarbons, driven by renewable power sources, is a fascinating and clean way to remedy greenhouse gas emission as a result of overdependence on fos...

It is urgent to obtain targeted drugs that selectively bind to pathological targets rather than physiological targets in the early stage of drug screening. G-Quadruplex has become one of the important targets in the development of anti-tumor drugs. However, drugs that target quadruplexes may also bind to dsDNA, which may lead to adverse reactions. In this study, a new three-phase laminar flow chip was constructed to enable the multi-components of a traditional Chinese medicine extract to dynamically and competitively bind with G-quadruplex DNA (on target) and double-stranded DNA (off target), so as to select high-efficiency and low-toxicity anti-tumor drugs. The results showed that there were five compounds in the extracts of Macleaya cordata seeds that exhibited obvious differences in binding to the two targets. Furthermore, the binding constants and modes of four identified alkaloids as they bound to two DNA targets were verified by fluorescence spectra and molecular docking methods. The toxicity to HepG2 and LO2 cells from the four alkaloids was also compared. The results showed that sanguinarine and chelerythrine could be used as candidate drugs with stronger binding to HT24 than DNA26. The chip can also be used for other types of double-target screening of other traditional Chinese medicine extracts or compound libraries.

Background Breast cancer (BC), the most common cause of cancer death in women, overtook lung cancer as the leading cause of cancer worldwide in 2020. Although many studies have proposed KIN17 as a biomarker of tumorigenesis in different cancer types, its role in tumor metastasis, particularly in BC metastasis, has been underexplored. This study aimed to explore the role of KIN17 in BC metastasis. Methods Survival analyses was performed to identify the association between KIN17 expression and BC patient survival in silico. Using lentivirus constructs, we developed bidirectional KIN17 expression (KD, knockdown; OE, overexpression) cellular models of luminal‐A (Lum‐A) breast cancer MCF‐7 cells. We performed in vitro wound healing, transwell with and without Matrigel assays, and in vivo tail‐vein metastasis assay to evaluate the migration and invasion abilities of MCF‐7 with stable KIN17 knockdown or overexpression. Western blotting was performed to compare the changes in protein expression. Results We found that KIN17 expression was associated with poor overall survival (OS), relapse‐free survival (RFS), distant metastasis‐free survival (DMFS) and post‐progression survival (PPS), particularly in Lum‐A breast cancer patients. Later, we found that KIN17 knockdown inhibited migration and invasion of MCF‐7 cells via regulating EMT‐associated signaling pathways in vitro and decreases metastatic spread of the disease in vivo. In contrast, KIN17 overexpression promoted migration and invasion of MCF‐7 cells in vitro and increased the metastatic spread of the disease in vivo. Conclusions Overall, our findings provide preliminary data which suggests KIN17 of importance to target in metastatic Lum‐A patients., KIN17 expression is associated with poor overall survival (OS), relapse‐free survival (RFS), distant metastasis‐free survival (DMFS) and post‐progression survival (PPS), particularly in luminal‐A breast cancer patients. KIN17 knockdown inhibits whereas its overexpression promotes migration and invasion of MCF‐7 cells via regulating EMT‐associated signaling pathways in vitro and in vivo. ​

The identification of mechanisms to promote the generation of memory T cells (TMEM) has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of TMEM generation in vivo, we discovered many components of the mammalian canonical SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also called canonical Brg1/Brg-associated factor (cBAF). cBAF is essential for the differentiation of activated, naïve CD8+ T cells into T effector (TEFF) cells, and loss of cBAF promotes TMEM formation of CD8+ T cells in vivo upon infection with Listeria monocytogenes and influenza A virus (IAV). During the first division of activated CD8+ T cells, we found that cBAF and c-Myc frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high c-Myc are enriched for cBAF expression and display a cell fate trajectory towards TEFF cells, while those with low c-Myc have reduced cBAF, and preferentially differentiate towards TMEM cells. Moreover, the cBAF complex and c-Myc physically interact, and act in concert to establish the chromatin landscape in activated CD8+ T cells. Treatment of naïve CD8+ T cells with an inhibitor of cBAF during the first 48 hours of activation, prior to the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves anti-cancer immunity in a solid tumor model. Our results establish cBAF as a key negative determinant of TMEM cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve adoptive immunotherapy for cancer treatment. Supported by AI123322

A green, cost-effective and sustainable route was proposed for the production of nitrogen-doped porous biochar with a sheet-shaped structure. Gelatin (G) served as carbon and nitrogen sources, and sodium chloride (SC) functioned as not only a porogen but also a two-dimensional structure-directing template. In particular, the used SC salt can be easily recovered for reutilization, which eventually leads to a closed-loop process. Furthermore, a G/SC mass ratio of 1/30 and a carbonization temperature of 750 °C were demonstrated to be the optimal conditions for producing biochar which integrates advantages including the abundant pore structure, the high graphitization degree and the optimized doping of nitrogen species and thus affords an enhanced charge storage capacity. This work takes a step towards green chemistry for the large-scale production of functional biochar, and the correlation of the microstructure and surface chemistry with electrochemical performance provides valuable guidance for the design and configuration of functional carbon nanomaterials.

The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T-cell development, homeostasis, activation, and effector-cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T-cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T-cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.

T follicular helper (Tfh) cells are crucial for B cell-mediated humoral immunity(1). Although transcription factors, such as Bcl6, drive Tfh cell differentiation(2,3), whether and how posttranscriptional and metabolic programs enforce Tfh cell programming are unclear. Here, we show that the cytidine diphosphate (CDP)-ethanolamine pathway coordinates the expression and localization of CXCR5 with Tfh responses and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation, we uncover Etnk1, Pcyt2 and Selenoi – enzymes in the CDP-ethanolamine pathway for de novo phosphatidylethanolamine (PE) synthesis – as selective posttranscriptional regulators of Tfh cell differentiation, by promoting CXCR5 surface expression and functional effects. Tfh cells show unique lipid metabolic programs and PE distribution to the plasma membrane outer layer where it co-localizes with CXCR5. De novo PE synthesis via the CDP-ethanolamine pathway coordinates these events to prevent CXCR5 internalization and degradation. Genetic deletion of Pcyt2, but not the CDP-choline pathway enzyme Pcyt1a, in activated T cells impairs Tfh cell differentiation, associated with reduced humoral immune responses. Surface PE levels and CXCR5 expression on B cells also depend upon Pcyt2. Our results reveal that phospholipid metabolism coordinates posttranscriptional mechanisms for Tfh cell differentiation and humoral immunity, highlighting metabolic control of context-dependent immune signaling and effector programs.

Nickel, nitrogen-codoped carbon materials (Ni,N-C) are flourishing as high-efficiency electrocatalysts for CO2 electroreduction reaction (CO2RR). Nevertheless, the preparation of Ni,N-C electrocatalysts with high performance towards CO2RR is still blind, without any guidelines, due to the lack of defined and available activity descriptor. Herein, we explored the correlation between the ratio of N species and CO2RR activity with taking a series of well-defined Ni,N-C materials as representative electrocatalysts. By smartly utilizing the ratio of Ni-N specie as an activity descriptor, the correlation between the ratio of N specie (Ni-N) and CO partial current density over all samples presents a well volcanic trend. At the optimal ratio of Ni-N specie, a high CO Faradaic efficiency (FE) of 94.8 % can be achieved with a good stability for 29 h. More significantly, the activity range for a library of Ni,N-C electrocatalysts for CO2RR is distinctly divided according to the activity descriptor.

The aim of this study was to investigate the effect of FTY720, an agonist of the sphingosine 1-phosphate (S1P) receptor, on the embryo loss rate in mice of spontaneous abortion model and the underlying mechanism.The effect of intraperitoneal injection of FTY720 on the embryo loss rate in mice of spontaneous abortion model was observed. The expression of S1PR on the dendritic cell (DC) surface was detected by reverse transcription polymerase chain reaction. The quantity and maturation of DCs in peripheral blood and local tissues of pregnant mice, and the expression of CCL19 as well as its receptor C-C chemokine receptor 7 (CCR7) were detected by flow cytometry and immunohistochemistry. Chemotaxis assay was performed to verify the effect of FTY720 on the chemotaxis of DCs.(1) FTY720 had no significant effect on the embryo loss rate in normal pregnant rats. In contrast, adoptive transferring of FTY720 significantly reduced the embryo loss rate of the spontaneous abortion mouse model (P 0.05). (2) S1PR was extensively expressed on DC surface. The S1P receptor agonist FTY720 reduced the expressions of DC surface chemokines and its receptor (P 0.05), resulting in a significant reduction in the number of DCs that were chemoattracted to maternal-fetal interface flow cytometry (P 0.05). (3) FTY720 had no significant effect on the differentiation and apoptosis rate of DCs (P 0.05).We hypothesized that FTY720 may reduce the number of DCs that were chemoattracted to the maternal-fetal interface by downregulating the expression of CCR7, which ultimately induces maternal-fetal immune tolerance.

Oxygen-evolution reaction (OER), a kinetically sluggish half-reaction involved in water splitting, generally needs large overpotentials to drive the catalytic process, leading to relatively low energy conversion efficiency. Therefore, the development of efficient, low-cost, and stable electrocatalysts based on earth abundant elements is highly desired. Herein, we develop a novel method to construct Ni3N@Fe3N heterostructure anchored on carbon fiber (Ni3N@Fe3N/CF-6) consisting of Fe3N nanoparticles grafted on the metallic Ni3N nanosheets. The results show that of the as-synthesized electrocatalysts, the Ni3N@Fe3N/CF-6 features abundantly exposed interface and active sites, as well as open structure for intimate contact of electrolyte ions and easy release of generated gas. Hence, this Ni3N@Fe3N/CF-6 exhibits a great enhanced OER electrocatalytic performance, including overpotentials as low as 294 mV to achieve a current density of 10 mA cm–2, a small Tafel slope of 40 mV dec–1, and a superior stability at ...

Coordination tuning of catalysts is a highly effective strategy for activating and improving the intrinsic activity. Herein, a Co-engineered FeOOH catalyst integrated on carbon fiber paper (Co-FeOOH/CFP) is reported, which realized a great improvement of the oxygen evolution activity by tuning the coordination geometry of the Fe species with an electrochemically driven method. Experiments and theoretical calculation demonstrate that the FeO bonds of FeOOH are partially broken, which is rooted in the Co incorporation, thus resulting in unsaturated FeO6 ligand structures and a relatively narrow bandgap. Consequently, the reorganized Fe sites on the surface show an enhanced capability for adsorbing OH- species and the Co-FeOOH exhibits an improved conductivity. As expected, the Co-FeOOH/CFP hybrids exhibit an extremely low overpotential of ≈250 mV at 10 mA cm-2 and a small Tafel slope, which far outperforms that of electrochemically sluggish FeOOH. The present work emphasizes the importance of local Fe coordination in catalysis and provides an in-depth insight into the mechanism of the enhanced catalytic activity.

Electrochemical reduction of carbon dioxide to hydrocarbons, driven by renewable power sources, is a fascinating and clean way to remedy greenhouse gas emission as a result of overdependence on fossil fuels and produce value-added fine chemicals. The Cu-based catalysts feature unique superiorities; nevertheless, achieving high hydrocarbon selectivity is still inhibited and remains a great challenge. In this study, we report on a tailor-made multifunction-coupled Cu-metal-organic framework (Cu-MOF) electrocatalyst by time-resolved controllable restructuration from Cu

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8+ T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8+ T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.

How early events in effector T cell (TEFF) subsets tune memory T cell (TMEM) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of TEFF and TMEM cells using in vivo pooled CRISPR screening, focusing on negative regulators of TMEM responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of TMEM differentiation, in part through modulating mTORC1 signaling. By integrating genetic and systems approaches, we identified cellular and metabolic heterogeneity among TEFF cells, with terminal effector differentiation associated with establishment of metabolic quiescence and exit from the cell cycle. Importantly, Pofut1 (protein-O-fucosyltransferase-1) linked GDP-fucose availability to downstream Notch-Rbpj signaling, and perturbation of this nutrient signaling axis blocked terminal effector differentiation but drove context-dependent TEFF proliferation and TMEM development. Our study establishes that nutrient uptake and signaling are key determinants of T cell fate and shape the quantity and quality of TMEM responses.

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo. ispartof: Nature vol:542 issue:7639 pages:49-+ ispartof: location:England status: published

Nickel hydroxide represents a technologically important material for energy storage, such as hybrid supercapacitors. It has two different crystallographic polymorphs, α- and β-Ni(OH)2 , showing advantages in either theoretical capacity or cycling/rate performance, manifesting a trade-off trend that needs to be optimized for practical applications. Here, the synergistic superiorities in both activity and stability of corrugated β-Ni(OH)2 nanosheets are demonstrated through an electrochemical abuse approach. With ≈91% capacity retention after 10 000 cycles, the corrugated β-Ni(OH)2 nanosheets can deliver a gravimetric capacity of 457 C g-1 at a high current density of 30 A g-1 , which is nearly two and four times that of the regular α- and β-Ni(OH)2 , respectively. Operando spectroscopy and finite element analysis reveal that greatly enhanced chemical activity and structural robustness can be attributed to the in situ tailored lattice defects and the strain-induced highly curved micromorphology. This work demonstrates a multi-scale defect-and-strain co-design strategy, which is helpful for rational design and tuned fabrication of next-generation electrode materials for stable and high-rate energy storage.

Integration/alternation of the short- and long-range order carbon species into one is always a trade-off between exposed armchair or zig-zag sites for enhancing the density of local charge states and electronic conductivity for fastening charge transfer. However, the strategies available now for coupling suffer from multiple/complicated steps, which makes the carbon-conjugated microstructure and electronic structure of the carbon as well as the process difficult to be controlled. Herein, surface coupling engineering mediated by external gravity field enables the assembling of carbon quantum dots (CQDs) with short-range periodicity on carbon sphere (CS) with long-range periodicity. The concentration gradient of CQDs on the surface of CS (CQDs/CS-x) can be finely controlled by the tuned gradient field strength, finally achieving the controllable regulation of defective density and electron transfer capability in carbon-conjugated CQDs. The resultant CQDs/CS-4 composite exhibits a high power conversion efficiency up to 8.42% with a low Epp value of 0.11 V, as probed by triiodide reduction. Taken together, density functional theory calculations and experimental results reveal that the edge/defective sites derived from CQDs modulate the charge density of local sites for enhanced capability of the adsorption for I2 molecule, and meanwhile the long-range π-π conjugated configuration of CS sites promotes the fast electron transfer in the carbon-conjugated CQDs. The design concept in this work presents a simple & facile technology for integration of the micro/nano-structured carbon materials with different scales to achieve the delicate regulation. Also, this provides fundamental guidance towards the assembly of ultrafine structure especially small-sized/ultrathin materials at atomic scales.

Interface engineering has been recognized as a highly effective strategy for regulating the surface properties and improving the catalytic activities of materials, while the traditional interface construction methods are energy consumption and time-consuming. Herein, an ultrafast (30 s) interfacial reaction strategy is developed to construct the NiCo-LDH@FeOOH hetero-interface structure integrated on carbon fiber paper (NiCo-LDH@FeOOH/CFP) by a wet chemical etching method, which is involved in the Fe3+-triggered H+ ions formation and etching as well as the Fe3+ ions hydrolysis. The as-made NiCo-LDH@FeOOH/CFP features enriched interfacial active sites and finely modulated electron structure, thus realizing the remarkable electrocatalytic activity and durability for water oxidation with an ultralow overpotential of only 224 mV to deliver 10 mA cm−2. Furthermore, this ultrafast interfacial reaction strategy can be expanded to construct other Ni-containing hydroxide@FeOOH hetero-interface structure, which will shed a new light on the further construction of bi/multi component hetero-structure materials in electrocatalysis and energy-related fields.

Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation. ispartof: NATURE vol:561 issue:7721 pages:63-+ ispartof: location:England status: published

The Hippo pathway plays a stage-specific role in regeneration and fibrogenesis after ischaemia/reperfusion-induced acute kidney injury. The proper modulation of this pathway might be the key point of transition from acute kidney injury to chronic kidney disease., Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI–CKD transition after I/R injury.

The evolutionarily conserved Hippo signaling pathway plays an important role in organ size control by regulating cell proliferation and apoptosis. Here, we identify Lingerer (Lig) as a growth suppressor using RNAi modifying screen in Drosophila melanogaster. Loss of lig increases organ size and upregulates bantam (ban) and the expression of the Hippo pathway target genes, while overexpression of lig results in diminished ban expression and organ size reduction. We demonstrate that Lig C-terminal exhibits dominant-negative function on growth and ban expression, and thus plays an important role in organ size control and ban regulation. In addition, we provide evidence that both Yki and Mad are essential for Lig-induced ban expression. We also show that Lig regulates the expression of the Hippo pathway target genes partially via Yorkie. Moreover, we find that Lig physically interacts with and requires Salvador to restrict cell growth. Taken together, we demonstrate that Lig functions as a critical growth suppressor to control organ size via ban and Hippo signaling.

Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting. ispartof: EMBO Journal vol:36 issue:16 pages:2334-2352 ispartof: location:England status: published

Recent studies have revealed that zinc phosphate is an important transformation product of zinc oxide nanoparticles (ZnO NPs) in the environment, and the role of soluble phosphate in the transformation of ZnO NPs to zinc phosphate has been confirmed. However, whether insoluble phosphate that exists widely in the environment can induce chemical transformation of ZnO NPs has not been addressed. Therefore, transformation of ZnO NPs in the presence of hydroxyapatite (HAP), selected as representative of insoluble phosphate, at different pH was investigated in the present study. Transformation products were identified by employing X-ray diffraction and synchrotron based X-ray absorption fine structure spectroscopy. The results indicate that under acidic condition (pH 5) phosphate ion (PO43-) and calcium anion (Ca2+) were released from HAP in aqueous solution, inducing a rapid transformation of about 80% ZnO NPs to scholzite within 4 h. Under neutral or basic conditions (pH 7 and 9) the adsorption of Zn2+ on HAP resulted in a slow transformation of about 60% ZnO NPs to amorphous inner-sphere Zn adsorption complexes within 30 days. This work suggests the important role of HAP in the transformation of ZnO NPs and may affect the behavior, fate and toxic effects of ZnO NPs in the environment. (C) 2014 Elsevier B.V. All rights reserved.

The Drosophila midgut has emerged as an attractive model system to study stem cell biology. Extensive studies have been carried out to investigate the mechanisms of how the signaling pathways integrate to regulate intestinal stem cells (ISCs), yet, whether the microRNAs are involved in ISC self-renewal and maintenance is unknown. Here we demonstrate that the bantam microRNA is expressed specifically at high levels in Drosophila midgut precursor cells (including ISCs and enteroblasts) and secretory enteroendocrine cells while at extremely low levels in enterocytes. Furthermore, overexpression of bantam microRNA results in increase of the division of the midgut precursor cells, whereas loss of bantam microRNA decreases their proliferation. The mechanical studies show that bantam microRNA is essential for the Hpo pathway induced cell-autonomous ISC self-renewal, while it is disposable for EGFR and Notch pathways mediated ISC proliferation. More interestingly, we find that bantam microRNA is not required for the Hpo pathway mediated non-cell-autonomous ISC proliferation, revealing a novel mechanism by which the Hpo signaling pathway specifies its transcriptional targets in specific tissue to exhibit its biological functions.

We report a general method for the synthesis of the substituted 6H-pyrido[2′,3′:5,6] [1,3]oxazino[3,4-a]indole ring system (structure 1) via the cyclization from an indoline precursor with aldehydes or ketones followed by oxidative re-aromatization.

Pez functions as an upstream negative regulator of Yorkie (Yki) to regulate intestinal stem cell (ISC) proliferation and is essential for the activity of the Hippo pathway specifically in the Drosophila midgut epithelium. Here we report that Suppressor of Deltex (Su(dx)) acts as a negative regulator of Pez. We show that Su(dx) targets Pez for degradation both in vitro and in vivo. Overexpression of Su(dx) induces proliferation in the fly midgut epithelium, which can be rescued by overexpressed Pez. We also demonstrate that the interaction between Su(dx) and Pez, bridged by WW domains and PY/PPxY motifs, is required for Su(dx)-mediated Pez degradation. Furthermore, we find that Kibra, a binding partner of Pez, stabilizes Pez via WW-PY/PPxY interaction. Moreover, PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. These results reveal a previously unrecognized mechanism of Pez degradation in maintaining the homeostasis of Drosophila midgut.

The project is based on Sun Yat-sen University, Xinhua College, using 3Ds Max as the main modeling software, and by the method of combination of the modeling of the campus static scene model, rendering and baking a mapping scenario model with a high degree of simulation. And then we use the Max-for-VRP plugin to import static model into VRP-Builder platform of scene and edit function. Finally, we use VRP-Builder platform to realize the interactive between users and various objects in virtual environment, and in the way of optimizing and collision test to the system scene, improve the authenticity and flexibility and interactivity of the system further, providing great convenience for the users to understand geographical environment and campus information of Sun Yat-sen university, Xinhua College.