Phase-Transition-Induced Surface Reconstruction of Rh1 Site in Intermetallic Alloy for Propane Dehydrogenation.

The fine-tuning of the geometric and electronic structures of active sites plays a crucial role in catalysis. However, the intricate entanglement between the two aspects results in a lack of interpretable design for active sites, posing a challenge in developing high-performance catalysts. Here, we find that surface reconstruction induced by phase transition in intermetallic alloys enables synergistic geometric and electronic structure modulation, creating a desired active site microenvironment for propane dehydrogenation. The resulting electron-rich four-coordinate Rh1 site in the RhGe0.5Ga0.5 intermetallic alloy can accelerate the desorption of propylene and suppress the side reaction and thus exhibits a propylene selectivity of ∼98% with a low deactivation constant of 0.002 h-1 under propane dehydrogenation at 550 °C. Furthermore, we design a computational workflow to validate the rationality of the microenvironment modulation induced by the phase transition in an intermetallic alloy.

Targeting EFHD2 Inhibits Interferon-γ Signaling and Ameliorates Non-Alcoholic Steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of nonalcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. This study investigates the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in NASH pathogenesis. METHODS: Hepatic EFHD2 expression was characterized in NASH patients and two diet-induced NASH mouse models. Single-cell RNA-sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma (HCC) were assessed. Molecular mechanisms underlying EFHD2 function were investigated, along with its potential as a therapeutic target by chemical and genetic means. RESULTS: EFHD2 expression was significantly elevated in liver tissue macrophages/monocytes in both NASH patients and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related HCC. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of interferon-γ receptor-2 (IFNγR2) onto the plasma membrane. This interaction mediates IFNγ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a developed stapled α-helical peptide targeting EFHD2 demonstrated its efficacy in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all NAFLD patients progress to NASH. A key challenge is identifying the factors triggering inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of IFNγ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings suggest EFHD2 as a promising target for drug development aimed at NASH treatment.

Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity. OBJECTIVES: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-(hCGα) and beta-subunits (hCGß), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex. METHODS: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression. RESULTS: Perfluorohexane sulfonic acid (PFHxS) [hCGß: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: -0.09; 95% CI: -0.16, -0.02) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with hCGα and positively with hCGß. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with hCGß only in Black participants (-0.23; 95% CI: -0.37, -0.09) and in participants with high school education or less (-0.14; 95% CI: -0.26, -0.02); conversely, perfluorononanoic acid (PFNA) was negatively associated with hCGα only in White participants (-0.15; 95% CI: -0.27, -0.03) and with hCGß only in participants with a college education or greater (-0.19; 95% CI: -0.36, -0.01). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was <100%. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with hCGα, and PFNA with h-hCG. CONCLUSIONS: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with hCGα and hCGß differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

The Chemokine CXCL7 is Correlated with LDH-A and Predicts the Prognosis of Patients with Colorectal Cancer.

OBJECTIVE: The aims of this study were to evaluate the correlation between chemokine (C-X-C) ligand 7 (CXCL7) expression and glycolysis and to explore the prognostic significance of CXCL7 in colorectal cancer (CRC). METHODS: The expression of CXCL7 and lactate dehydrogenase A (LDH-A) was measured by immunohistochemistry in tissue from 158 CRC patients. Patients were divided into high expression and low expression groups based on receiver operating characteristic curves and a cut-off value. The correlation between CXCL7 and LDH-A expression was evaluated. The overall survival (OS) times of CRC patients were explored. The risk factors related to prognosis were assessed. RESULTS: Significantly higher expression of CXCL7 and LDH-A was detected in CRC tissue than in non-CRC tissue, and was associated with N stage and tumor-node-metastasis (TNM) stage. CXCL7 expression was strongly correlated with LDH-A expression in CRC tissue. High expression of CXCL7 was validated as an independent risk factor for OS. CONCLUSION: Increased expression of CXCL7 was positively correlated with LDH-A expression and was an independent risk factor for CRC prognosis.

Metal-Sulfur Interfaces as the Primary Active Sites for Catalytic Hydrogenations.

The determination of catalytically active sites is crucial for understanding the catalytic mechanism and providing guidelines for the design of more efficient catalysts. However, the complex structure of supported metal nanocatalysts (e.g., support, metal surface, and metal-support interface) still presents a big challenge. In particular, many studies have demonstrated that metal-support interfaces could also act as the primary active sites in catalytic reactions, which is well elucidated in oxide-supported metal nanocatalysts but is rarely reported in carbon-supported metal nanocatalysts. Here, we fill the above gap and demonstrate that metal-sulfur interfaces in sulfur-doped carbon-supported metal nanocatalysts are the primary active sites for several catalytic hydrogenation reactions. A series of metal nanocatalysts with similar sizes but different amounts of metal-sulfur interfaces were first constructed and characterized. Taking Ir for quinoline hydrogenation as an example, it was found that their catalytic activities were proportional to the amount of the Ir-S interface. Further experiments and density functional theory (DFT) calculations suggested that the adsorption and activation of quinoline occurred on the Ir atoms at the Ir-S interface. Similar phenomena were found in p-chloronitrobenzene hydrogenation over the Pt-S interface and benzoic acid hydrogenation over the Ru-S interface. All of these findings verify the predominant activity of metal-sulfur interfaces for catalytic hydrogenation reactions and contribute to the comprehensive understanding of metal-support interfaces in supported nanocatalysts.

Enhancing Surface Strain of Intermetallic Fuel Cell Catalysts by Composition-Induced Phase Transition.

The lattice parameter of platinum-based intermetallic compounds (IMCs), which correlates with the intrinsic activity of the oxygen reduction reaction (ORR), can be modulated by crystal phase engineering. However, the controlled preparation of IMCs with unconventional crystal structures remains highly challenging. Here, we demonstrate the synthesis of carbon-supported PtCu-based IMC catalysts with an unconventional L10 structure by a composition-regulated strategy. Experiment and machine learning reveal that the thermodynamically favorable structure changes from L11 to L10 when slight Cu atoms are substituted with Co. Benefiting from crystal-phase-induced strain enhancement, the prepared L10-type PtCu0.8Co0.2 catalyst exhibits much-enhanced mass and specific activities of 1.82 A mgPt-1 and 3.27 mA cmPt-2, which are 1.91 and 1.73 times higher than those of the L11-type PtCu catalyst, respectively. Our work highlights the important role of crystal phase in determining the surface strain of IMCs, and opens a promising avenue for the rational preparation of IMCs with different crystal phases by doping.

[Qualitative and semiquantitative analyses of the chemical components of the seed coat and kernel of Ziziphi Spinosae Semen].

Ziziphi Spinosae Semen refers to the dried seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou. The seed is composed of a reddish brown coat and a yellow kernel. A comparative study was conducted to investigate differences in the chemical composition and their relative contents between the seed coat and kernel of Ziziphi Spinosae Semen. First, the chemical compounds found in the seed coat and kernel were characterized and identified using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The analytical results tentatively identified 57 chemical compounds based on reference-compound comparison, literature retrieval, and chemical-database (e. g., MassBank) searches; these compounds included 14 triterpenes, 23 flavonoids, 7 alkaloids, 6 carboxylic acids, and 7 other types of compounds. The mass error of the identified compounds was within the mass deviation range of 5×10-6 (5 ppm). Next, two methods of multivariate statistical analysis, namely, principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), were used to compare the differential compounds between the two seed parts. A total of 17 differential compounds were screened out via OPLS-DA based on a variable importance in projection (VIP) value of >5. The results revealed that betulinic acid, betulonic acid, alphitolic acid, and jujuboside Ⅰ mainly existed in the seed coat whereas the 13 other compounds, such as spinosin, jujuboside A, and 6‴-feruloylspinosin, mainly existed in the seed kernel. Therefore, these 17 differential compounds can be used to distinguish between the two seed parts. Finally, a semiquantitative method was established using UPLC and a charged aerosol detector (CAD) with inverse gradient compensation in the mobile phase. Six representative compounds with different types were selected to examine the CAD response consistency: magnoflorine (alkaloid), spinosin (flavone), 6‴-feruloylspinosin (flavone), jujuboside A (triterpenoid saponin), jujuboside B (triterpenoid saponin), and betulinic acid (triterpenoid acid). The results showed that the relative standard deviation (RSD) of the average response factors at different levels of these six compounds was 7.04% and that their response intensities were similar. Moreover, each compound in the fingerprint demonstrated good response consistency, and the peak areas obtained directly reflected the contents of each compound. Based on the semiquantitative fingerprints obtained, betulinic acid and oleic acid were considered the main components of the seed coat. The betulinic acid content in the seed coat was approximately 7 times higher than that in the seed kernel. Spinosin, jujuboside A, linoleic acid, betulinic acid, and oleic acid were the main components of the seed kernel. The spinosin content in the seed kernel was 18 times higher than that in the seed coat. In addition, the jujuboside A content in the seed kernel was 24 times higher than that in the seed coat. The proposed method can accurately determine the main components and compare the relative contents of these components in different seed parts. In summary, this study identified the differences in chemical components between the seed coat and kernel of Ziziphi Spinosae Semen and clarified the main components and their relative contents in these parts. The findings can not only provide a basis for the identification of chemical compounds and quality research on different parts of Ziziphi Spinosae Semen but also promote the development and utilization of this traditional Chinese medicine.

Breaking the Isolation: Exploring the Impact of Passthrough in Shared Spaces on Player Performance and Experience in VR Exergames.

VR exergames offer an engaging solution to combat sedentary behavior and promote physical activity. However, challenges emerge when playing these games in shared spaces, particularly due to the presence of bystanders. VR's passthrough functionality enables players to maintain awareness of their surrounding environment while immersed in VR gaming, rendering it a promising solution to improve users' awareness of the environment. This study investigates the passthrough's impact on player performance and experiences in shared spaces, involving an experiment with 24 participants that examines Space (Office vs. Corridor) and Passthrough Function (With vs. Without). Results reveal that Passthrough enhances game performance and environmental awareness while reducing immersion. Players prefer an open area to an enclosed room, whether with or without Passthrough, finding it more socially acceptable. Additionally, Passthrough appears to encourage participation among players with higher self-consciousness, potentially alleviating their concerns about being observed by bystanders. Our findings provide valuable insights for designing VR experiences in shared spaces, underscoring the potential of VR's passthrough to enhance user experiences and promote VR adoption in these environments.

Omnidirectional Virtual Visual Acuity: A User-Centric Visual Clarity Metric for Virtual Reality Head-Mounted Displays and Environments.

Users' perceived image quality of virtual reality head-mounted displays (VR HMDs) is determined by multiple factors, including the HMD's structure, optical system, display and render resolution, and users' visual acuity (VA). Existing metrics such as pixels per degree (PPD) have limitations that prevent accurate comparison of different VR HMDs. One of the main limitations is that not all VR HMD manufacturers released the official PPD or details of their HMDs' optical systems. Without these details, developers and users cannot know the precise PPD or calculate it for a given HMD. The other issue is that the visual clarity varies with the VR environment. Our work has identified a gap in having a feasible metric that can measure the visual clarity of VR HMDs. To address this gap, we present an end-to-end and user-centric visual clarity metric, omnidirectional virtual visual acuity (OVVA), for VR HMDs. OVVA extends the physical visual acuity chart into a virtual format to measure the virtual visual acuity of an HMD's central focal area and its degradation in its noncentral area. OVVA provides a new perspective to measure visual clarity and can serve as an intuitive and accurate reference for VR applications sensitive to visual accuracy. Our results show that OVVA is a simple yet effective metric for comparing VR HMDs and environments.

Green manuring reduces cadmium accumulation in rice: Roles of iron plaque and dissolved organic matter.

In southern China, winter green manure is widely used in rice cropping systems for improving grain yields and soil fertility. Cd pollution has recently been reported in some of these paddy fields. Research on the in-depth understanding of how green manuring affects Cd absorption in rice is limited. This study aimed to investigate the impacts of different green manures, including single plantation and mixed plantation on the absorption of Cd by rice and explore the underlying mechanisms. Pot experiments demonstrated that compared with winter fallow-rice, green manuring treatments considerably decreased rice Cd content, promoted the conversion of bioavailable Cd fraction into a more stable form, induced the formation of iron plaque, and increased the content of humic-like fraction (HF) in soil dissolved organic matter (DOM). Treatment with mixed plantation resulted in a greater decrease in rice Cd content and an increase in HF and iron plaque contents than single plantation. Hydroponic experiments confirmed that both iron plaque and green manure-derived DOM significantly reduced the Cd content in rice seedlings. In conclusion, green manure incorporation is an efficient measure for the safe utilization of Cd-contaminated soil, and mixed plantation of different green manures exerts stronger effects.

Air oxidation of carbon supports boosts the low-humidity fuel cell performance.

We introduce a straightforward, yet effective strategy to combat the performance decline of proton-exchange membrane fuel cells in low-humidity environments. Our method centers on air-oxidizing carbon supports, significantly improving proton and oxygen transport within the cathode catalyst layer.

Inhibition of HOXD11 promotes cartilage degradation and induces osteoarthritis development.

The 5'-HOXD genes are important for chondrogenesis in vertebrates, but their roles in osteoarthritis (OA) are still ambiguous. In our study, 5'-HOXD genes involvement contributing to cartilage degradation and OA was investigated. In bioinformatics analysis of 5'-HOXD genes, we obtained the GSE169077 data set related to OA in the GEO and analyzed DEGs using the GEO2R tool attached to the GEO. Then, we screened the mRNA levels of 5'-HOXD genes by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We discovered that OA chondrocyte proliferation was inhibited, and apoptosis was increased. Moreover, it was discovered that SOX9 and COL2A1 were downregulated at mRNA and protein levels, while matrix metalloproteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs) were upregulated. According to the results of differentially expressed genes (DEGs) and qRT-PCR, we evaluated the protein level of HOXD11 and found that the expression of HOXD11 was downregulated, reversed to MMPs and ADAMTSs but consistent with the cartilage-specific factors, SOX9 and COL2A1. In the lentivirus transfection experiments, HOXD11 overexpression reversed the effects in OA chondrocytes. In human OA articular cartilage, aberrant subchondral bone was formed in hematoxylin-eosin (H&E) and Safranin O and fast green (SOFG) staining results. Furthermore, according to immunohistochemistry findings, SOX9 and HOXD11 expression was inhibited. The results of this study established that HOXD11 was downregulated in OA cartilage and that overexpression of HOXD11 could prevent cartilage degradation in OA.

Single-Component Dual-Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase-2 Inhibition for Lung Cancer and Spinal Metastasis.

Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.

Machine-learning-accelerated design of high-performance platinum intermetallic nanoparticle fuel cell catalysts.

Carbon supported PtCo intermetallic alloys are known to be one of the most promising candidates as low-platinum oxygen reduction reaction electrocatalysts for proton-exchange-membrane fuel cells. Nevertheless, the intrinsic trade-off between particle size and ordering degree of PtCo makes it challenging to simultaneously achieve a high specific activity and a large active surface area. Here, by machine-learning-accelerated screenings from the immense configuration space, we are able to statistically quantify the impact of chemical ordering on thermodynamic stability. We find that introducing of Cu/Ni into PtCo can provide additional stabilization energy by inducing Co-Cu/Ni disorder, thus facilitating the ordering process and achieveing an improved tradeoff between specific activity and active surface area. Guided by the theoretical prediction, the small sized and highly ordered ternary Pt2CoCu and Pt2CoNi catalysts are experimentally prepared, showing a large electrochemically active surface area of ~90 m2 gPt‒1 and a high specific activity of ~3.5 mA cm‒2.

Coupling analysis of crane accident risks based on Bayesian network and the N-K model.

Crane usage is pervasive on construction sites, however, it is associated with a notably high accident rate. The analyzing of crane accident risks is essential for accident prevention, control, and ensuring the safety of lifting operations. Hence, significant emphasis should be placed on understanding the interaction among various risk factors. This paper proposes a quantitative coupling method for human, machine, management, and environmental risk factors in crane accidents, leveraging Bayesian networks (BN) and the N-K model. Firstly, text mining technology and fault tree analysis are employed to analyze the causes of crane accidents and categorize the associate risk factors. Secondly, the types of risk coupling resulting from human, machine, management, and environmental risk factors are defined. Thirdly, the BN model is developed based on the analysis of crane accident risksand its N-K model. Fourthly, the parameters of the risk coupling nodes in the developed BN are determined based on the calculation results of the N-K model. Finally, for the risk coupling types with high coupling values and the first-level node and second-level node, the failure probability is analyzed through posterior probability and sensitivity analysis. The results indicate that factors related to man and management significantly impact crane accidents and warrant enhanced attention. The interplay among multiple risk factors significantly influences the probability of crane accidents, necessitating careful attention.

Design and Evaluation of Controller-based Raycasting Methods for Efficient Alphanumeric and Special Character Entry in Virtual Reality.

Alphanumeric and special characters are essential during text entry. Text entry in virtual reality (VR) is usually performed on a virtual Qwerty keyboard to minimize the need to learn new layouts. As such, entering capitals, symbols, and numbers in VR is often a direct migration from a physical/touchscreen Qwerty keyboard-that is, using the mode-switching keys to switch between different types of characters and symbols. However, there are inherent differences between a keyboard in VR and a physical/touchscreen keyboard, and as such, a direct adaptation of mode-switching via switch keys may not be suitable for VR. The high flexibility afforded by VR opens up more possibilities for entering alphanumeric and special characters using the Qwerty layout. In this work, we designed two controller-based raycasting text entry methods for alphanumeric and special characters input (Layer-ButtonSwitch and Key-ButtonSwitch) and compared them with two other methods (Standard Qwerty Keyboard and Layer-PointSwitch) that were derived from physical and soft Qwerty keyboards. We explored the performance and user preference of these four methods via two user studies (one short-term and one prolonged use), where participants were instructed to input text containing alphanumeric and special characters. Our results show that Layer-ButtonSwitch led to the highest statistically significant performance, followed by Key-ButtonSwitch and Standard Qwerty Keyboard, while Layer-PointSwitch had the slowest speed. With continuous practice, participants' performance using Key-ButtonSwitch reached that of Layer-ButtonSwitch. Further, the results show that the key-level layout used in Key-ButtonSwitch led users to parallel mode switching and character input operations because this layout showed all characters on one layer. We distill three recommendations from th results that can help guide the design of text entry techniques for alphanumeric and special characters in VR.

Endothelial Protein C Receptor and 3K3A-Activated Protein C Protect Mice from Allergic Contact Dermatitis in a Contact Hypersensitivity Model.

Endothelial protein C receptor (EPCR) is a receptor for the natural anti-coagulant activated protein C (aPC). It mediates the anti-inflammatory and barrier-protective functions of aPC through the cleavage of protease-activated receptor (PAR)1/2. Allergic contact dermatitis is a common skin disease characterized by inflammation and defective skin barrier. This study investigated the effect of EPCR and 3K3A-aPC on allergic contact dermatitis using a contact hypersensitivity (CHS) model. CHS was induced using 1-Fluoro-2,4-dinitrobenzene in EPCR-deficient (KO) and matched wild-type mice and mice treated with 3K3A-aPC, a mutant form of aPC with diminished anti-coagulant activity. Changes in clinical and histological features, cytokines, and immune cells were examined. EPCRKO mice displayed more severe CHS, with increased immune cell infiltration in the skin and higher levels of inflammatory cytokines and IgE than wild-type mice. EPCR, aPC, and PAR1/2 were expressed by the skin epidermis, with EPCR presenting almost exclusively in the basal layer. EPCRKO increased the epidermal expression of aPC and PAR1, whereas in CHS, their expression was reduced compared to wild-type mice. 3K3A-aPC reduced CHS severity in wild-type and EPCRKO mice by suppressing immune cell infiltration/activation and inflammatory cytokines. In summary, EPCRKO exacerbated CHS, whereas 3K3A-aPC could reduce the severity of CHS in both EPCRKO and wild-type mice.

Green manuring relocates microbiomes in driving the soil functionality of nitrogen cycling to obtain preferable grain yields in thirty years.

Fertilizers are widely used to produce more food, inevitably altering the diversity and composition of soil organisms. The role of soil biodiversity in controlling multiple ecosystem services remains unclear, especially after decades of fertilization. Here, we assess the contribution of the soil functionalities of carbon (C), nitrogen (N), and phosphorus (P) cycling to crop production and explore how soil organisms control these functionalities in a 33-year field fertilization experiment. The long-term application of green manure or cow manure produced wheat yields equivalent to those obtained with chemical N, with the former providing higher soil functions and allowing the functionality of N cycling (especially soil N mineralization and biological N fixation) to control wheat production. The keystone phylotypes within the global network rather than the overall microbial community dominated the soil multifunctionality and functionality of C, N, and P cycling across the soil profile (0-100 cm). We further confirmed that these keystone phylotypes consisted of many metabolic pathways of nutrient cycling and essential microbes involved in organic C mineralization, N2O release, and biological N fixation. The chemical N, green manure, and cow manure resulted in the highest abundances of amoB, nifH, and GH48 genes and Nitrosomonadaceae, Azospirillaceae, and Sphingomonadaceae within the keystone phylotypes, and these microbes were significantly and positively correlated with N2O release, N fixation, and organic C mineralization, respectively. Moreover, our results demonstrated that organic fertilization increased the effects of the network size and keystone phylotypes on the subsoil functions by facilitating the migration of soil microorganisms across the soil profiles and green manure with the highest migration rates. This study highlights the importance of the functionality of N cycling in controlling crop production and keystone phylotypes in regulating soil functions, and provides selectable fertilization strategies for maintaining crop production and soil functions across soil profiles in agricultural ecosystems.

Nuclear-Targeted Nanostrategy Regulates Spatiotemporal Communication for Dual Antitumor Immunity.

Intercellular communication between tumor cells and immune cells regulates tumor progression including positive communication with immune activation and negative communication with immune escape. An increasing number of methods are employed to suppress the dominant negative communication in tumors such as PD-L1/PD-1. However, how to effectively improve positive communication is still a challenge. In this study, a nuclear-targeted photodynamic nanostrategy is developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO2 -Ion@Ce6-NLS nanoparticles (NPs) are designed, whose surface is modified by ionic liquid silicon (Ion) and nuclear localization signal peptide (NLS: PKKKRKV), and their pores are loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion-modified NPs enhance intratumoral enrichment, and NLS-modified NPs exhibit nuclear-targeted characteristics to achieve nuclear-targeted photodynamic therapy (nPDT). mSiO2 -Ion@Ce6-NLS with nPDT facilitate the release of damaged double-stranded DNA from tumor cells to activate macrophages via stimulator of interferon gene signaling and induce the immunogenic cell death of tumor cells to activate dendritic cells via "eat me" signals, ultimately leading to the recruitment of CD8+ T-cells. This therapy effectively strengthens positive communication to reshape the dual antitumor immune microenvironment, further inducing long-term immune memory, and eventually inhibiting tumor growth and recurrence.

EPCR deficiency ameliorates inflammatory arthritis in mice by suppressing the activation and migration of T cells and dendritic cells.

OBJECTIVES: Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with RA, but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms. METHODS: CIA was induced in EPCR gene knockout (KO) and matched wild-type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCR KO and WT mice, RA patients and healthy controls (HCs) were detected by flow cytometry and ELISA. RESULTS: EPCR KO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT mice. EPCR KO mice also had significantly fewer Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCR KO mice expressed fewer chemokine receptors CXCR3, CXCR5 and CCR6 than WT mice. In vitro, EPCR KO spleen cells contained fewer Th1 and more Th2 and Th17 cells than WT and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCR KO bone marrow were less mature and produced less MMP-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro. CONCLUSION: Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment.