Compressive Strain Modulation of Single Iron Sites on Helical Carbon Support Boosts Electrocatalytic Oxygen Reduction.

Designing and modulating the local structure of metal sites is the key to gain the unique selectivity and high activity of single metal site catalysts. Herein, we report strain engineering of curved single atomic iron-nitrogen sites to boost electrocatalytic activity. First, a helical carbon structure with abundant high-curvature surface is realized by carbonization of helical polypyrrole that is templated from self-assembled chiral surfactants. The high-curvature surface introduces compressive strain on the supported Fe-N4 sites. Consequently, the curved Fe-N4 sites with 1.5 % compressed Fe-N bonds exhibit downshifted d-band center than the planar sites. Such a change can weaken the bonding strength between the oxygenated intermediates and metal sites, resulting a much smaller energy barrier for oxygen reduction. Catalytic tests further demonstrate that a kinetic current density of 7.922 mA cm-2 at 0.9 V vs. RHE is obtained in alkaline media for curved Fe-N4 sites, which is 31 times higher than that for planar ones. Our findings shed light on modulating the local three-dimensional structure of single metal sites and boosting the catalytic activity via strain engineering.

Sinapic Acid Attenuates Chronic DSS-Induced Intestinal Fibrosis in C57BL/6J Mice by Modulating NLRP3 Inflammasome Activation and the Autophagy Pathway.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that results from repeated inflammation and serious complications. Sinapic acid (SA) is a hydroxycinnamic acid present in a variety of plants that has antioxidant, anti-inflammatory, anticancer, and other protective effects. This study investigated the antifibrotic effect of SA on chronic colitis induced by dextran sulfate sodium salt (DSS) in mice. We observed that SA could significantly reduce clinical symptoms (such as improved body weight loss, increased colon length, and decreased disease activity index score) and pathological changes in mice with chronic colitis. SA supplementation has been demonstrated to repair intestinal mucosal barrier function and maintain epithelial homeostasis by inhibiting activation of the NLRP3 inflammasome and decreasing the expression of IL-6, TNF-α, IL-17A, IL-18, and IL-1ß. Furthermore, SA could induce the expression of antioxidant enzymes (Cat, Sod1, Sod2, Mgst1) by activating the Nrf2/keap1 pathway, thus improving antioxidant capacity. Additionally, SA could increase the protein expression of downstream LC3-II/LC3-I and Beclin1 and induce autophagy by regulating the AMPK-Akt/mTOR signaling pathway, thereby reducing the production of intestinal fibrosis-associated proteins Collagen-I and α-SMA. These findings suggest that SA can enhance intestinal antioxidant enzymes, reduce oxidative stress, expedite intestinal epithelial repair, and promote autophagy, thereby ameliorating DSS-induced colitis and intestinal fibrosis.

Targeting Ferroptosis-Elicited Inflammation Suppresses Hepatocellular Carcinoma Metastasis and Enhances Sorafenib Efficacy.

Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1ß to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1ß precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1ß. Depleting either macrophages or neutrophils or neutralizing IL1ß in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1ß/neutrophil/vasculature axis. SIGNIFICANCE: Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.

[Association between MAOA-u VNTR polymorphism and its interaction with stressful life events and major depressive disorder in adolescents].

OBJECTIVE: To investigate whether the genetic polymorphism, upstream variable number of tandem repeats (uVNTR), in the monoamine oxidase A (MAOA) gene, is associated with major depressive disorder (MDD) in adolescents and to test whether there is gene-environment interaction between MAOA-uVNTR polymorphism and stressful life events (SLEs). METHODS: A total of 394 Chinese Han subjects, including 187 adolescent patients with MDD and 207 normal students as a control group, were included in the study. Genotyping was performed by SNaP-shot assay. SLEs in the previous 12 months were evaluated. The groups were compared in terms of the frequency distributions of MAOA-uVNTR genotypes and alleles using statistical software. The binary logistic regression model of gene-environment interaction was established to analyze the association of the gene-environment interaction between MAOA-u VNTR genotypes and SLEs with adolescent MDD. RESULTS: The distribution profiles of MAOA-u VNTR genotypes and alleles were not related to the onset of MDD, severity of depression, comorbid anxiety and suicidal ideation/behavior/attempt in adolescents. The gene-environment interaction between MAOA-u VNTR genotypes and SLEs was not associated with MDD in male or female adolescents. CONCLUSIONS: It is not proven that MAOA-u VNTR polymorphism is associated with adolescent MDD. There is also no gene-environment interaction between MAOA-u VNTR polymorphism and SLEs that is associated with adolescent MDD.

c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.

B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27-CD38-CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells.

Ammonia Synthesis Using Single-Atom Catalysts Based on Two-Dimensional Organometallic Metal Phthalocyanine Monolayers under Ambient Conditions.

We have identified three novel metal phthalocyanine (MPc, M = Mo, Re, and Tc) single-atom catalyst candidates with excellent predicted performance for the production of ammonia from electrocatalytic nitrogen reduction reaction (NRR) through a combination of high-throughput screening and first-principles calculations on a series of 3d, 4d, and 5d transition metals anchored onto extended Pc monolayer catalysts. Analysis of the energy band structures and projected density of states of N2-MPc revealed significant orbital hybridization and charge transfer between the adsorbed N2 and catalyst MPc, which accounts for the high catalytic activity. Among 30 MPc catalysts, MoPc and TcPc monolayers were found to be the most promising new NRR catalysts, as they exhibit excellent stability, low onset potential, and high selectivity. A comprehensive reaction pathway search found that the maximum free energy changes for the MoPc and TcPc monolayers are 0.33 and 0.54 eV, respectively. As a distinctive nature of this work, the hybrid reaction pathway was considered extensively and searched systematically. The onset potential of the hybrid pathway is found to be smaller than or comparable to that of the commonly known pure pathway. Thus, the hybrid path is highly competitive with low onset potential and high activity. The hybrid pathway is expected to have an important impact on future research on the mechanism of NRR, and it will open up a new way to explore the mechanism of the NRR reaction. We hope that our work will provide impetus to the creation of new catalysts for reduction of N2 to NH3. This work provides new insights into the rational design of NRR catalysts and explores novel reaction pathways under ambient or mild conditions.

Electrocatalytic Mechanism of N2 Reduction Reaction by Single-Atom Catalyst Rectangular TM-TCNQ Monolayers.

Herein, the catalytic properties and reaction mechanisms of the 3d, 4d, and 5d transition metals embedded in 2D rectangular tetracyanoquinodimethane (TM-rTCNQ) monolayers as single-atom catalysts (SACs) for the electrocatalytic N2 reduction reaction (NRR) were systematically investigated, using first-principles calculations. A series of high-throughput screenings were carried out on 30 TM-rTCNQ monolayers, and all possible NRR pathways were explored. Three TM-rTCNQ (TM = Mo, Tc, and W) SACs were selected as promising new NRR catalyst candidates because of their high structural stability and good catalytic performance (low onset potential and high selectivity). Our results show that the Mo-rTCNQ monolayer can catalyze NRR through a distal mechanism with an onset potential of -0.48 V. Surprisingly, the NH3 desorption energy on the Mo-rTCNQ monolayer is only 0.29 eV, the lowest one reported in the literature so far, which makes the Mo-rTCNQ monolayer a good NRR catalyst candidate. In-depth research studies on the structures of N2-TM-rTCNQ (TM = Mo, Tc, and W) found that strong adsorption and activation performance of TM-rTCNQ for N2 may be due to the strong charge transfer and orbital hybridization between the TM-rTCNQ catalyst and the N2 molecules. Our work provides new ideas for achieving N2 fixation under environmental conditions.

B cell heterogeneity, plasticity, and functional diversity in cancer microenvironments.

B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.

[DRD2/ANKK1 Taq IA polymorphism and early infant temperament].

OBJECTIVE: To investigate whether there is an association between DRD2/ANKK1 Taq IA polymorphism and early infant temperament. METHODS: DRD2/ANKK1 Taq IA polymorphism (rs1800497) was determined using polymerase chain reaction-ligase detection reaction (PCR-LDR) techniques in 149 Chinese Han infants from Changsha City. Their mothers were asked to complete the Early Infant Temperament Questionnaires (EITQ) when the infants were 1 to 4 months old (mean: 2.75 months). There were three genotypes found in these infants: C/C, T/T and C/T. The subjects were subdivided into T-carrier (CT, TT) and non-T-carrier (CC) groups for statistical analysis. RESULTS: There were no differences in the temperament style distribution between the T-carrier and non-T carrier groups. There were also no statistically significant differences between the two groups in the score of the nine temperament dimensions. CONCLUSIONS: DRD2/ANKK1 Taq IA polymorphism is not associated with early infant temperament.

B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis.

B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (TH) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor-primed TH cells. ICOS/ICOSL axis-mediated glucose incorporation and utilization were crucial for inflammatory TH subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory TH subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory TH cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory TH subsets.

The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy.

PD-L1 is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors, as well as their roles in determining therapeutic efficacies are unknown. Here we identified, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent IFN-γ signature and potentially signified pro-inflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune checkpoint blockade. Therapeutic strategy combining immune checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited caner regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune checkpoint blockade therapy.

Association analysis of serotonin transporter promoter gene polymorphism with ADHD and related symptomatology.

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop attention deficit hyperactivity disorder. Several investigations have reported associations between ADHD and serotonin transporter promoter polymorphisms, but the results have been inconsistent. The present study did not find significant association between ADHD and serotonin transporter promoter polymorphisms, but did find an effect of serotonin transporter promoter polymorphisms on some ADHD symptomatology. Patients homozygous for the short allele showed more Withdrawn or Somatic complaint scores than subjects with the long allele.