USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity.

UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8+ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment.

Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy.

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

Influence of pH on the leaching behavior of a solidified arsenic contaminated soil.

Stabilization/solidification is widely used for treatment of arsenic (As)-contaminated soils. The stability of the soil may deteriorate significantly when exposed to acid or alkaline leachate. In this study, semi-dynamic leaching tests under different pH were carried out to investigate the leaching behavior of As from the solidified soils. Spectroscopic and microscopic analyses were performed to reveal the related mechanisms. The results showed that the leaching of As was closely correlated with the pH of the leachate, because the encapsulation effect of the cementitious matrix and the chemical speciation and valence of As were all significantly influenced by pH. In the strongly acidic leachant (pH 3.0), the leached As concentration increased by an order of magnitude, and the effective diffusion coefficient of As reached 3.71 × 10-13 m2/s. This is because that pores and cracks increased owing to the acidic corrosion of CSH, such that the physical encapsulation effect was reduced and the mobility of As increased. The leachability index showed that the solidified soil was unsuitable for 'controlled utilization' under strongly acidic conditions. The leached As concentration was the lowest in the weakly alkaline leachant (pH 9.0) because under weakly alkaline conditions the hydration process of the cement was facilitated, and more CSH gels were attached to the surface of the soil particles, forming a tighter structure for As encapsulation. However, as pH increased from 9.0-11.0 the leached As concentration increased due to an increased content of As(III)-O in the solidified soil.

Serological responses to smallpox A33 antigen and monkeypox A35 antigen in healthy people and people living with HIV-1 from Guangzhou, China.

People are expected to have been previously vaccinated with a Vaccinia-based vaccine, as until 1980 smallpox vaccination was a standard protocol in China. It is unclear whether people with smallpox vaccine still have antibody against vaccinia virus (VACV) and cross-antibody against monkeypox virus (MPXV). Herein, we assessed the binding antibodies with antigen of VACV-A33 and MPXV-A35 in the general population and HIV-1 infected patients. Firstly, we detected VACV antibody with A33 protein to evaluate the efficiency of smallpox vaccination. The result show that 29% (23 of 79) of hospital staff (age ≥ 42 years) and 63% (60 of 95) of HIV-positive patients (age ≥ 42 years) from Guangzhou Eighth People's Hospital were able to bind A33. However, among the subjects below 42 years of age, 1.5% (3/198) of the hospital volunteer samples and 1% (1/104) of the samples from HIV patients were positive for antibodies against A33 antigen. Then, we assessed the specific cross-reactive antibodies against MPXV A35 protein. 24% (19 of 79) hospital staff (age〉 = 42 years) and 44% (42 of 95) of HIV-positive patients (age〉 = 42 years) were positive. 98% (194/198) of the hospital staff and 99% (103/104) of the HIV patients had no A35-binding antibodies. Further, we found significant sex differences for the reactivity to A35 antigen were observed in HIV population, but no significant sex differences in hospital staff. Further, we analyzed the positivity rate of anti-A35 antibody of men who have sex with men (MSM) and non-MSM in HIV patients (age〉 = 42years). We found that 47% of no-MSM population and 40% of MSM population were positive for A35 antigen, with no significant difference. Lastly, we found only 59 samples were positive for anti-A33 IgG and anti-A35 IgG in all participants. Together, we demonstrated A33 and A35 antigens binding antibodies were detected in HIV patients and general population who were older than 42 years, and cohort studies only provided data of serological detection to support early response to monkeypox outbreak.

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants.

SARS-CoV-2 Omicron variants feature highly mutated spike proteins with extraordinary abilities in evading antibodies isolated earlier in the pandemic. Investigation of memory B cells from patients primarily with breakthrough infections with the Delta variant enables isolation of a number of neutralizing antibodies cross-reactive to heterologous variants of concern (VOCs) including Omicron variants (BA.1-BA.4). Structural studies identify altered complementarity determining region (CDR) amino acids and highly unusual heavy chain CDR2 insertions respectively in two representative cross-neutralizing antibodies-YB9-258 and YB13-292. These features are putatively introduced by somatic hypermutation and they are heavily involved in epitope recognition to broaden neutralization breadth. Previously, insertions/deletions were rarely reported for antiviral antibodies except for those induced by HIV-1 chronic infections. These data provide molecular mechanisms for cross-neutralization of heterologous SARS-CoV-2 variants by antibodies isolated from Delta variant infected patients with implications for future vaccination strategy.

High titers of neutralizing antibodies in the blood fail to eliminate SARS-CoV-2 viral RNA in the upper respiratory tract.

Retest-positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA, as a unique phenomenon among discharged individuals, has been demonstrated to be safe in the community. Still, the underlying mechanism of viral lingering is less investigated. In this study, first, we find that the frequency of viral RNA-positive retesting differs among variants. Higher ratios of viral RNA-positive retest were more frequently observed among Delta (61.41%, 514 of 837 cases) and Omicron (39.53%, 119 of 301 cases) infections than among ancestral viral infection (7.27%, 21 of 289 cases). Second, the tissues where viral RNA reoccurred were altered. Delta RNA reoccurred mainly in the upper respiratory tract (90%), but ancestral virus RNA reoccurred mainly in the gastrointestinal tract (71%). Third, vaccination did not reduce the frequency of viral RNA-positive retests, despite high concentrations of viral-specific antibodies in the blood. Finally, 37 of 55 (67.27%) Delta-infected patients receiving neutralizing antibody therapy become viral RNA retest positive when high concentrations of neutralizing antibodies still patrol in the blood. Altogether, our findings suggest that the presentence of high titers of neutralizing antibodies in the blood is incompetent in clearing residual viral RNA in the upper respiratory tract.

Electrocatalytic CO2 Upgrading to Triethanolamine by Bromine-Assisted C2 H4 Oxidation.

The electrocatalytic carbon dioxide (CO2 ) reduction is a promising approach for converting this greenhouse gas into value-added chemicals, while the capability of producing products with longer carbon chains (Cn >3) is limited. Herein, we demonstrate the Br-assisted electrocatalytic oxidation of ethylene (C2 H4 ), a major CO2 electroreduction product, into 2-bromoethanol by electro-generated bromine on metal phthalocyanine catalysts. Due to the preferential formation of Br2 over *O or Cl2 to activate the C=C bond, a high partial current density of producing 2-bromoethanol (46.6 mA⋅cm-2 ) was obtained with 87.2 % Faradaic efficiency. Further coupling with the electrocatalytic nitrite reduction to ammonia at the cathode allowed the production of triethanolamine with six carbon atoms. Moreover, by coupling a CO2 electrolysis cell for in situ C2 H4 generation and a C2 H4 oxidation/nitrite reduction cell, the capability of upgrading of CO2 and nitrite into triethanolamine was demonstrated.

Sorafenib inhibits interferon production by plasmacytoid dendritic cells in hepatocellular carcinoma.

BACKGROUND: Sorafenib is a multi-kinase inhibitor that shows antitumor activity in advanced hepatocellular carcinoma. Sorafenib exerts a regulatory effect on immune cells, including T cells, natural killer cells and dendritic cells. Studies have shown that plasmacytoid dendritic cells (pDCs) are functionally impaired in cancer tissues or produce low type I interferon alpha (IFNα) in cancer microenvironments. However, the effects of sorafenib on the function of pDCs have not been evaluated in detail. METHODS: Normal and patient PBMCs were stimulated with CpG-A to evaluate IFNα production with Flow cytometry and ELISA. RESULT: We analyzed the production of IFNα by PBMCs in patients with advanced HCC under sorafenib treatment. We found that sorafenib-treated HCC patients produced less IFNα than untreated patients. Furthermore, we demonstrated that sorafenib suppressed the production of IFNα by PBMCs or pDCs from heathy donors in a concentration-dependent manner. CONCLUSION: Sorafenib suppressed pDCs function. Given that sorafenib is a currently recommended targeted therapeutic agent against cancer, our results suggest that its immunosuppressive effect on pDCs should be considered during treatment.

CPACK: An Intelligent Cyber-Physical Access Control Kit for Protecting Network.

Access Control Lists (ACL) are critical to protecting network and cyber-physical systems. Traditional firewalls mostly use reactive methods to enforce ACLs, so that new ACL updates cannot take effect immediately. In this paper, based on our previous work, we propose CPACK, an intelligent cyber-physical access control kit, which uses a smart algorithm to upgrade the ACL list. CPACK adopts a proactive way to enforce ACL and reacts to a new ACL update and network view update in real time. We implement CPACK on both Floodlight and ONOS controller. We then conduct a large number of experiments to compare CPACK with the Floodlight firewall application. The experimental results show that CPACK has a better performance than the existing Floodlight firewall application. CPACK is also integrated into the new version of Floodlight and ONOS controller.

Reduction, stabilization, and solidification of Cr(VI) in contaminated soils with a sustainable by-product-based binder.

This study evaluated the use of a sustainable GFD binder for the stabilization/solidification (S/S) of chromium VI (Cr(VI))-contaminated soil. The GFD binder was composed of ground granulated blast furnace slag (GGBFS), fly ash and desulfurization ash, named after the initials of the three materials. The effects of curing time and binder dosage on soil unconfined compressive strength (UCS), Cr leachability, soil pH, and reduction ratio of Cr (VI) were tested. The immobilization mechanisms of Cr(VI) in contaminated soil were further explored using X-ray diffraction (XRD), scanning electron microscopy (SEM), and sequential extraction procedure (SEP). The results showed that the UCS and pH of the soil increased substantially after the GFD binder was added. After 28 days of curing with a 20% binder dosage, the leached total Cr concentration decreased from 34.4 mg/L in the contaminated soil to 1.44 mg/L in the treated soil, and the leached Cr(VI) concentration decreased from 28.0 mg/L to 0.45 mg/L. A Cr(VI) reduction ratio of 96.2% was achieved, indicating the strong reducibility of GGBFS. XRD revealed that the main hydration products of the GFD binder were hydrated calcium silicate (C-S-H) and ettringite. SEM results showed that the formation of hydration products and Cr-bearing precipitates filled the soil pores, resulting in a dense soil structure. The SEP results demonstrated that the levels of the unstable fraction F1 decreased considerably, and that the levels of the stable fractions F3 and F5 increased after treatment. Encapsulation by C-S-H, reduction by sulfides, adsorption of C-S-H, and precipitation of Cr-bearing hydroxides were the main mechanisms involved in Cr immobilization using the GFD binder.

Clinical characteristics and immune profile alterations in vaccinated individuals with breakthrough Delta SARS-CoV-2 infections.

Despite timely immunization programs, and efficacious vaccines conveying protection against SARS-CoV-2 infection, breakthrough infections in vaccinated individuals have been reported. The Delta variant of concern (VOC) outbreak in Guangzhou resulted in local transmission in vaccinated and non-vaccinated residents, providing a unique opportunity to study the protective effects of the inactivated vaccines in breakthrough infection. Here, we find that the 2-dose vaccinated group has similar peak viral titers and comparable speeds of viral RNA clearance to the non-vaccinated group but accelerated viral suppression in the middle course of the disease. We quantitatively demonstrate that peak viral pneumonia is significantly mitigated in the 2-dose vaccine group (median 0.298%) compared with the non-vaccinated (5.77%) and 1-dose vaccine (3.34%) groups. Pneumonia absorbance is approximately 6 days ahead in the 2-dose group (median 10 days) than in the non-vaccinated group (16 days) (p = 0.003). We also observe reduced cytokine inflammation and markedly undisturbed gene transcription profiles of peripheral blood mononuclear cells (PBMCs) in the 2-dose group. In short, our study demonstrates that prior vaccination substantially restrains pneumonia development, reduces cytokine storms, and facilitates clinical recovery.

Atomic controllable anchoring of uranium into zirconate pyrochlore with ultrahigh loading capacity.

Efficient immobilization of actinide wastes is challenging in the nuclear energy industry. Here, we reported that 100% substitution of Zr4+ by U6+ in a La2Zr2O7 matrix has been achieved for the first time by the molten salt (MS) method. Importantly, we observed that uranium can be precisely anchored into Zr or La sites of the La2Zr2O7 matrix, as confirmed by X-ray diffraction, Raman, and X-ray absorption spectra. This work will guide the construction of site-controlled and high-capacity actinide-immobilized pyrochlore materials and could be extended to other perovskite materials.

Controllable sites and high-capacity immobilization of uranium in Nd2Zr2O7 pyrochlore.

As potential nuclear waste host matrices, two series of uranium-doped Nd2Zr2O7 nanoparticles were successfully synthesized using an optimized molten salt method in an air atmosphere. Our combined X-ray diffraction, Raman and X-ray absorption fine-structure (XAFS) spectroscopy studies reveal that uranium ions can precisely substitute the Nd site to form an Nd2-xUxZr2O7+δ (0 ≤ x ≤ 0.2) system and the Zr site to form an Nd2Zr2-yUyO7+δ (0 ≤ y ≤ 0.4) system without any impurity phase. With increasing U concentration, there is a phase transition from pyrochlore (Fd3m) to defect fluorite (Fm3m) structures in both series of U-doped Nd2Zr2O7. The XAFS analysis indicates that uranium exists in the form of high-valent U6+ in all samples. To balance the extra charge for substituting Nd3+ or Zr4+ by U6+, additional oxygen is introduced accompanied by a large structural distortion; however, the Nd2Zr1.6U0.4O7+δ sample with high U loading (20 mol%) still maintains a regular fluorite structure, indicating the good solubility of the Nd2Zr2O7 host for uranium. This study is, to the best of our knowledge, the first systematic study on U-incorporated Nd2Zr2O7 synthesized via the molten salt method and provides convincing evidence for the feasibility of accurately immobilizing U at specific sites.

Disturbance Observer-Based Feedback Linearization Control for a Quadruple-Tank Liquid Level System.

A novel input/output feedback linearization control method by utilizing nonlinear disturbance observer (NDOB) is proposed for a quadruple-tank liquid level (QTLL) system in this paper. Firstly, the mathematical model of QTLL system is established by using Bernoulli's law and mass conservation. Secondly, in view of the nonlinear and coupling characteristics of the QTLL system, a input/output feedback linearization controller is designed. Then, a NDOB is proposed to estimate disturbances and applied to compensation control. Finally, simulation and experimental results show that the proposed strategy has better control performances than PID control and the disturbance observer-based sliding mode control (DOBSMC).

Funnel tracking control for nonlinear servo drive systems with unknown disturbances.

In this paper, a novel robust tracking control strategy based on funnel control is proposed for servo drive systems with unknown disturbances. A modified funnel variable is defined and incorporated into the control design to guarantee the tracking error within a prescribed boundary. To reject the bounded disturbances, a robust integral of the sign of the error (RISE) controller based on the funnel variable is proposed for servo drive systems. Moreover, the desired compensation technique is incorporated into the developed controller to reduce the sensor noise. The proposed robust controller theoretically guarantees asymptotic tracking control performance with external disturbances. The closed-loop system convergence is analyzed via the Lyapunov stability theory. Comparative numerical and experimental results of the servo drive system are provided.