RhoGDI phosphorylation by PKC promotes its interaction with death receptor p75NTR to gate axon growth and neuron survival.

How receptors juggle their interactions with multiple downstream effectors remains poorly understood. Here we show that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation. These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways.

Effect of prophylactic antiviral intervention on T cell immunity in hepatitis B virus-infected pregnant women.

BACKGROUND: Antiviral intervention in hepatitis B virus (HBV)-infected pregnant women can effectively reduce mother-to-child transmission. However, the immunological characteristics of pregnant women with chronic HBV infection and the effects of antiviral intervention during pregnancy on maternal immune response remain unknown. We aimed to investigate these effects by comparing mothers who received antiviral intervention during pregnancy with those who did not. METHODS: Pregnant women positive for hepatitis B surface antigen and hepatitis B e-antigen (HBsAg+ HBeAg+) were enrolled at delivery, including 34 received prophylactic antiviral intervention during pregnancy (AVI mothers) and 15 did not (NAVI mothers). T lymphocyte phenotypes and functions were analysed using flow cytometry. RESULTS: At delivery, maternal regulatory T cell (Treg) frequency in AVI mothers was significantly higher than that in NAVI mothers (P < 0.002), and CD4+ T cells in AVI mothers displayed a decreased ability to secrete IFN-γ (P = 0.005) and IL-21 (P = 0.043), but an increased ability to secrete IL-10 and IL-4 (P = 0.040 and P = 0.036), which represented a higher Treg frequency, enhanced Th2 response and suppressed Th1 response. Treg frequency among AVI mothers was correlated negatively with serum HBsAg and HBeAg levels. After delivery, the ability of CD4+ T cells or CD8+ T cells to secrete IFN-γ or IL-10 was similar and no significant difference in Treg frequency was found between the two groups. CONCLUSIONS: Prophylactic antiviral intervention during pregnancy has an effect on T cell immunity in pregnant women, which was characterised by increased maternal Treg frequency, enhanced Th2 response and suppressed Th1 response at delivery.

CTLA4+CD4+CXCR5-FOXP3+ T cells associate with unfavorable outcome in patients with chronic HBV infection.

BACKGROUND: A major barrier to achieving a favorable outcome of chronic HBV infection is a dysregulated HBV-specific immune response resulting from immunosuppressive features of FOXP3+ T cells. A better definition of FOXP3+ T cells is essential for improving the prognosis of HBV infection. We aimed to investigate the role of CD4+CXCR5-FOXP3+ T cells with CTLA4 expression in patients with chronic HBV infection. METHODS: Treatment-naïve chronic HBV-infected patients, HBV-related hepatic failure, and a longitudinal cohort of chronic hepatitis B (CHB) patients with nucleos(t)ide analogue treatment were enrolled for analysis of CD4+CXCR5-FOXP3+ T cell responses by flow cytometry and single-cell RNA sequencing (scRNA-seq). RESULTS: ScRNA-seq revealed that circulating CD4+CXCR5-FOXP3+ T cells presented distinct inhibitory features compared to spleen tissue. Meanwhile, patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure showed an upregulation of immune-suppressive features (PD-1, CTLA4, GITR) on CD4+CXCR5-FOXP3+T cells; in vitro analysis found HBeAg and HBcAg stimulation induced elevated levels of inhibitory molecules. Notably, the frequency of CTLA4+CD4+CXCR5-FOXP3+ T cells was positively correlated with HBV DNA levels, and longitudinal analysis demonstrated a high frequency of this subset at 12 weeks of antiviral treatment predicted unfavorable outcome in CHB patients. CONCLUSIONS: CTLA4+CD4+CXCR5-FOXP3+ T cells are related to unfavorable outcomes in HBV-infected patients; these data indicated that alleviating CTLA4+CD4+CXCR5-FOXP3+ T cells may improve the prognosis of HBV infection.

Novel Insight into Rechargeable Aluminum Batteries with Promising Selenium Sulfide@Carbon Nanofibers Cathode.

Due to the unique electronic structure of aluminum ions (Al3+ ) with strong Coulombic interaction and complex bonding situation (simultaneously covalent/ionic bonds), traditional electrodes, mismatching with the bonding orbital of Al3+ , usually exhibit slow kinetic process with inferior rechargeable aluminum batteries (RABs) performance. Herein, to break the confinement of the interaction mismatch between Al3+ and the electrode, a previously unexplored Se2.9 S5.1 -based cathode with sufficient valence electronic energy overlap with Al3+ and easily accessible structure is potentially developed. Through this new strategy, Se2.9 S5.1 encapsulated in multichannel carbon nanofibers with free-standing structure exhibits a high capacity of 606 mAh g-1 at 50 mA g-1 , high rate-capacity (211 mAh g-1 at 2.0 A g-1 ), robust stability (187 mAh g-1 at 0.5 A g-1 after 3,000 cycles), and enhanced flexibility. Simultaneously, in/ex-situ characterizations also reveal the unexplored mechanism of Sex Sy in RABs.

Evaluation and Analysis of Design Elements for Sustainable Renewal of Urban Vulnerable Spaces.

The sustainable renewal design of urban vulnerable spaces is critical for urban space quality improvement. Taking Zhengzhou and surrounding cities as examples, a cognitive framework of urban vulnerable spaces is constructed. The three types of urban vulnerable spaces are vulnerable population, vulnerable cultural, and vulnerable forgotten spaces. Their sustainable renewal design elements comprise multidimensional factors, such as functional requirement, space organization, activity facility, urban context continuation, and material texture. The design elements for the sustainable update of urban vulnerable spaces are evaluated by grey relation analysis (GRA), and update strategies are proposed. The result shows that (1) vulnerable population spaces were shown to have the highest sensitivity to functional requirements and activity facility design elements, while vulnerable cultural spaces have high relevance to urban context continuation and functional requirement design elements. Furthermore, space organization, activity facility, and urban context continuation design elements all show high relevance and importance in vulnerable forgotten spaces. (2) The update of vulnerable population spaces should be designed to achieve functional communion; vulnerable cultural spaces can be reshaped through urban context implantation, and vulnerable forgotten spaces can use space creation to enhance ecological space continuity, achieving sustainable renewal. The study provides a reference for decision-making for improving urban vulnerable habitats and the sustainable renewal design of atypical urban space types.

Impaired CD8+ T cells in term pregnancy decidua with chronic hepatitis B virus infection.

PROBLEM: Hepatitis B virus (HBV) infection is more likely to develop a state of chronicity in early life, particularly mother-to-child transmission (MTCT) of HBV in the fetus during pregnancy. Till now, little is known about the impact of chronic HBV infection on the immune status of the maternal-fetus interface, and the immune profile of placental lymphocytes in MTCT of HBV is poorly understood. METHOD OF STUDY: Thirteen term pregnant women with chronic HBV infection (HBV-PW) and thirteen normal pregnant women as healthy control (HC-PW) were enrolled. The profile of placental immune cells and paired peripheral blood were analyzed by flow cytometry and immunohistochemistry. RESULTS: Compared with HC-PW, the frequency of CD8+ T cells from the term placenta of HBV-PW was significantly reduced. These cells showed decreased expression of activation molecules CD69 and HLA-DR; thus, decidual CD8+ T cells from HBV-PW demonstrated hypofunctional signature as evidenced by significantly reduced production of IFN-γ, as well as compromised ability of degranulation and proliferation. CONCLUSIONS: These findings supported that hypoactivated decidual CD8+ T cells might possess compromised ability in chronically HBV-infected term pregnant women. Our study provides robust evidence for the necessity and importance of antiviral intervention in HBV-PW to prevent MTCT of HBV.

Analyzing the mechanism of nitrous oxide production in aerobic phase of anoxic/aerobic sequential batch reactor from the perspective of key enzymes.

How the vast majority of nitrous oxide (N2O) in the aerobic zone of nitrogen bio-removal process is produced is still a controversial issue. To solve this issue, this study measured the activities of two key denitrifying enzymes (nitric oxide reductase (Nor) and nitrous oxide reductase (N2OR)) in an A/O SBR with different chemical nitrogen demand (COD)/total nitrogen (TN) ratios. By analyzing the Spearman's correlations between the N2O production, the enzyme activities, and the factors, the main N2O production process was identified. By comparing the activities of these enzymes, this study analyzed the reasons for the N2O production. Results show that Nor activities had a linear relationship with total N2O concentrations (y = 0.34749 + 31.31365x, R2 = 0.83362) and were not affected by COD (r = 0.299, N = 15, P = 0.279 > 0.05), which showed that most of the N2O released and produced came from the autotrophic denitrification. N2OR activities had a positive correlation with COD (r = 0.692, N = 15, P = 0.004 < 0.01), which showed that heterotrophic denitrification played a role as an N2O consumer. Nor activities were much higher than N2OR activities and the gap between them increased when the total N2O concentration increased, showing that the heterotrophic denitrification was difficult to consume all the N2O produced by the autotrophic denitrification. Reducing autotrophic denitrification is the best way to reduce N2O production in aerobic phase.

DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3.

Myelin sheath is an important structure to maintain functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane, however, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development. Loss of Zdhhc5 in oligodendrocytes inhibits myelination and remyelination by reducing total myelinating oligodendrocyte population. STAT3 is the primary substrate for DHHC5 palmitoylation in oligodendrocytes. Zdhhc5 ablation reduces STAT3 palmitoylation and suppresses STAT3 phosphorylation and activation. As a result, the transcription of the myelin-related and anti-apoptosis genes is inhibited, leading to suppressed oligodendrocyte development and myelination. Our findings demonstrate a key role DHHC5 in controlling myelinogenesis.

Identification and Mapping of HBsAg Loss-Related B-Cell Linear Epitopes in Chronic HBV Patients by Peptide Array.

Identification of immunogenic targets against hepatitis B virus (HBV)-encoded proteins will provide crucial advances in developing potential antibody therapies. In this study, 63 treatment-naïve patients with chronic HBV infection and 46 patients who achieved hepatitis B surface antigen loss (sAg loss) following antiviral treatment were recruited. Moreover, six patients who transitioned from the hepatitis B e antigen-positive chronic infection phase (eAg+CInf) to the hepatitis phase (eAg+CHep) were enrolled from real-life clinical practice. Additionally, telbivudine-treated eAg+CHep patients and relapsers or responders from an off-treatment cohort were longitudinally studied. The frequencies and function of B cells were assessed by flow cytometry. We devised a peptide array composed of 15-mer overlapping peptides of HBV-encoded surface (S), core (C), and polymerase (P) proteins and performed a screening on B-cell linear epitopes with sera. Naïve B cells and plasmablasts were increased, whereas total memory, activated memory (AM), and atypical memory (AtM) B cells were reduced in sAg- patients compared with sAg+ patients. Importantly, longitudinal observations found that AtM B cells were associated with successful treatment withdrawal. Interestingly, we identified six S-specific dominant epitopes (S33, S34, S45, S76, S78, and S89) and one C-specific dominant epitope (C37) that reacted with the majority of sera from sAg- patients. Of note, more B-cell linear epitopes were detected in CHep patients with alanine aminotransferase (ALT) flares than in nonflare CInf patients, and five B-cell linear epitopes (S4, S5, S10, S11, and S68) were overwhelmingly recognized by ALT flare patients. The recognition rates of epitopes on C and P proteins were significantly increased in CHep patients relative to CInf patients. Strikingly, a statistically significant elevation in the number of positive epitopes was observed when ALT nonflare patients shifted into the flare phase. Moreover, S76 identified at baseline was confirmed to be associated with a complete response after 48 weeks of telbivudine therapy. Taken together, we identified several functional cure-related B-cell linear epitopes of chronic HBV infection, and these epitopes may serve as vaccine candidates to elicit neutralizing antibodies to treat HBV infection.

Expanded circulating follicular dendritic cells facilitate immune responses in chronic HBV infection.

BACKGROUND: The restoration of host hepatitis B virus (HBV)-specific antiviral immunity is an effective strategy for hepatitis B recovery. Follicular dendritic cells (FDCs) play a crucial role in immune regulation. The goal of the present study was to investigate the characteristics and functions of FDCs in chronic HBV infection. METHODS: The frequencies of FDCs in peripheral blood, liver, and spleen were measured in patients with chronic HBV infection. Isolated FDCs from splenic tissues of HBV-related liver cirrhosis-induced hypersplenism patients were cultured with autologous intrasplenic CD4+ T cells and CD19+ B cells. RESULTS: We observed that patients with chronic HBV infection had a significantly increased frequency of circulating FDCs compared to that of healthy controls. Additionally, the frequency of circulating FDCs was positively correlated with that of intrahepatic and intrasplenic counterparts. Moreover, positive correlations were observed between the frequencies of circulating FDCs and plasmablast and memory B cells, as well as C-X-C motif chemokine receptor type 5 (CXCR5)+CD4+ T cells and CXCR5+CD8+ T cells. Notably, in vitro experimental results demonstrated that FDCs derived from splenic tissues of chronic HBV patients facilitated interferon-γ and interleukin-21 production from autologous intrasplenic CD4+ T cells and promoted the proliferation of autologous intrasplenic CD19+ B cells. CONCLUSIONS: Expanded FDCs in patients with chronic HBV infection may favor host immune responses against HBV. The identification of this unique population of cell may contribute to a better understanding of the immune regulatory mechanisms associated with chronic HBV infection and provide a potential immunotherapeutic target for this disease.

Hierarchical Fe3 C-Mo2 C-Carbon Hybrid Electrocatalysts Promoted through a Strong Charge-Transfer Effect.

Highly efficient, stable, and low-cost catalysts for electrochemical water splitting play a critical role in promoting energy efficiency in the renewable hydrogen power-related industries. In this study, nonprecious metal carbides composed of Fe3 C and Mo2 C supported by carbon nanoplates are prepared and utilized as bifunctional electrocatalysts for overall water splitting. Spatially confined annealing of the polydopamine-coated metal precursors affords a structure containing porous cubes isolated by carbon nanoplates encapsulated with Fe3 C and Mo2 C nanoparticles. The hybrid electrocatalyst with a hierarchical structure, large surface area, and abundant exposed active sites benefits from efficient mass transport and more importantly the strong charge-transfer effect between the iron and molybdenum moieties. Under strong alkaline conditions, the optimized Fe3 C-Mo2 C hybrid (with a Fe/Mo ratio of 1 : 2) requires a low overpotential of 274 and 301 mV for the electrocatalytic oxygen evolution reaction at current densities of 10 and 100 mA cm-2 , respectively, accompanied with decent hydrogen evolution activity, thereby demonstrating efficient bifunctional electrocatalytic activity towards overall water splitting.

Effects of intrauterine exposure to maternal-derived HBeAg on T cell immunity in cord blood.

Immature immune system and immune tolerance induced by exposure to HBeAg in utero and/or shortly after infection in newborns were reportedly the causes of chronic HBV infection. To investigate the effect of maternal-derived HBeAg on neonatal T cell immunity, we analysed and compared T cell phenotypes and functions among neonates born to HBsAg+ /HBeAg+ mothers (HBeAg+ neonates), HBsAg+ /HBeAg- mothers (HBeAg- neonates) and healthy control mothers (HC neonates), using flow cytometry. The results showed that neonatal T cell phenotypes were similar regardless of HBeAg exposure. Upon anti-CD3 and anti-CD28 stimulation in HBeAg+ neonates, CD4+ T cell production of IFN-γ (P < .05) was significantly enhanced, while CD8+ T cells secreted significantly more IL-2 compared with those in HBeAg- and HC groups (P < .05). Moreover, similar levels of IFN-γ and IL-10 were observed in the culture supernatant after stimulation with rHBsAg, rHBcAg or rHBeAg among HBeAg+ , HBeAg- and HC neonates, whereas HBeAg+ neonates produced more TNF-α than HBeAg- neonates upon stimulation with rHBcAg. In conclusion, the results indicated that the HBsAg+ /HBeAg+ maternal environment did not influence the phenotypes of cord blood T cells but boosted neonatal non-specific Th1-type cytokine production.

A GPR17-cAMP-Lactate Signaling Axis in Oligodendrocytes Regulates Whole-Body Metabolism.

The CNS plays a pivotal role in energy homeostasis, but whether oligodendrocytes are involved has been largely unexplored. Here, we show that signaling through GPR17, a G-protein-coupled receptor predominantly expressed in the oligodendrocyte lineage, regulates food intake by modulating hypothalamic neuronal activities. GPR17-null mice and mice with an oligodendrocyte-specific knockout of GPR17 have lean phenotypes on a high-fat diet, suggesting that GPR17 regulates body weight by way of oligodendrocytes. Downregulation of GPR17 results in activation of cAMP-protein kinase A (PKA) signaling in oligodendrocytes and upregulated expression of pyruvate dehydrogenase kinase 1 (PDK1), which promotes lactate production. Elevation of lactate activates AKT and STAT3 signaling in the hypothalamic neurons, leading to increased expression of Pomc and suppression of Agrp. Our findings uncover a critical role of oligodendrocytes in metabolic homeostasis, where GPR17 modulates the production of lactate, which, in turn, acts as a metabolic signal to regulate neuronal activity.

Olig2-Targeted G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Survival in Response to Lysolecithin-Induced Demyelination.

Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1 The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination. SIGNIFICANCE STATEMENT: Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.