Compromised long-lived memory CD8+ T cells are associated with reduced IL-7 responsiveness in HIV-infected immunological nonresponders.

Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long-lived memory CD8+ T cells (LLMCs) are essential executors of long-term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro-inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL-7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7-phosphorylated (p)-signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL-7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.

Dynamics of HIV reservoir decay and naïve CD4 T-cell recovery between immune non-responders and complete responders on long-term antiretroviral treatment.

BACKGROUND: The dynamics of viral reservoir decay and naïve CD4 T-cell recovery between immunological non-responders (INR) and complete responders (CR) during long-term antiretroviral treatment (ART) are not fully known. METHODS: Twenty-eight chronic HIV-infected individuals on 5-year ART were divided into two groups: INR (CD4 counts ≤350 cells/µL, n = 13) and CR (CD4 counts ≥500 cells/µL, n = 15). The levels of HIV DNA and cell-associated HIV RNA (CA-RNA), CD4 counts, naïve CD4 counts and their correlations were analyzed at baseline, years 1, 3 and 5 of ART between the two groups. Expression of PD-1 on CD4 T-cells was quantified by flow cytometry. Linear mixed effect models were used to estimate the change procession in repeated measurements over 5 years. Slopes of the above-mentioned indicators were estimated using participant-specific linear regressions, respectively. RESULTS: INR maintained higher levels of HIV DNA and CA-RNA with higher percentages of PD-1+CD4 T-cells compared with CR during 5-year ART, concurrent with lower naïve CD4 T-cells. However, the rates of HIV DNA and CA-RNA decay in INR were not different from that in CR over time, and INR had higher rates of naïve CD4 T-cell percentage recovery. The baseline levels of HIV DNA were positively associated with the 5-year levels of HIV DNA, but negatively associated with the 5-year naïve CD4 counts. CONCLUSIONS: INR maintained significantly higher viral reservoir and lower naïve CD4 T-cells compared with CR during 5-year ART, however, the rates of reservoir decay and naïve CD4 T-cell percentage growth within INR were not lower than that in CR over time.

Petroleum oil and products recovery from oily sludge: Characterization and analysis of pyrolysis products.

Oily sludge (OS) has attracted special interest because of its hazardous nature and high potential as an energy resource. This study investigated the oil recovery from OS by thermal cracking and catalytic pyrolysis. The oil yield increased when the temperature exceeded 450 °C and reached a maximum (76.84 wt%) at 750 °C. Catalysts significantly improved the quality of oil produced during catalytic pyrolysis. Aromatic hydrocarbons were dominant (10.01-52.69%) in pyrolysis oil (PO) from OS catalytic pyrolysis, and the catalysts significantly reduced the presence of oxygen heterocycles. In addition, KOH and CaO reduced the ID (D-band peak intensity)/IG (G-band peak intensity) of OS char (OC) and increased the degree of graphitization. Owing to its higher iodine adsorption value and methylene blue (MB) adsorption value, OC exhibits potential as an adsorbent. The environmental assessment and potential applications of OC, along with possible reaction mechanisms and kinetic characteristics, are also discussed.

Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment.

UNLABELLED: It is well established that interleukin (IL)-22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly up-regulated in hepatitis B virus (HBV)-infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver-infiltrating IL-22(+) cells were largely increased in HBV-infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells and, preferentially, by T-helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T-cell-mediated chronic liver inflammation and fibrosis, blockade of IL-22 attenuated hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C-X-C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs. CONCLUSIONS: IL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV-infected patients and HBV Tg mice.

HBeAg induces neutrophils activation impairing NK cells function in patients with chronic hepatitis B.

BACKGROUND: The role of neutrophils in hepatitis B virus (HBV) infection has been a subject of debate due to their involvement in antiviral responses and immune regulation. This study aimed to elucidate the neutrophil characteristics in patients with chronic hepatitis B (CHB). METHODS: Through flow cytometry and ribonucleic acid-sequencing analysis, the phenotypes and counts of neutrophils were analyzed in patients with CHB. Moreover, the effects of HBeAg on neutrophils and the corresponding pattern recognition receptors were identified. Simultaneously, the cross-talk between neutrophils and natural killer (NK) cells was investigated. RESULTS: Neutrophils were activated in patients with CHB, characterized by higher expression levels of programmed death-ligand 1 (PD-L1), cluster of differentiation 86, and interleukin-8, and lower levels of CXC motif chemokine receptor (CXCR) 1 and CXCR2. Hepatitis B e antigen (HBeAg) partially induces neutrophil activation through the Toll-like receptor 2 (TLR2). A consistent upregulation of the TLR2 and HBeAg expression was observed in patients with CHB. Notably, the genes encoding molecules pivotal for NK-cell function upon NK receptor engagement enriched in neutrophils after HBeAg activation. The HBeAg-activated neutrophils demonstrated the ability to decrease the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in NK cells, while the PD-1 and PD-L1 pathways partially mediated the immunosuppression. CONCLUSIONS: The immunosuppression of neutrophils induced by HBeAg suggests a novel pathogenic mechanism contributing to immune tolerance in patients with CHB.

Omicron neutralization character in patients with breast cancer and liver cancer after the nationwide omicron outbreak.

BACKGROUND: The surge in omicron variants has caused nationwide breakthrough infections in mainland China since the December 2022. In this study, we report the neutralization profiles of serum samples from the patients with breast cancer and the patients with liver cancer who had contracted subvariant breakthrough infections. METHODS: In this real-world study, we enrolled 143 COVID-19-vaccinated (81 and 62 patients with breast and liver cancers) and 105 unvaccinated patients with cancer (58 and 47 patients with breast and liver cancers) after omicron infection. Anti-spike receptor binding domain (RBD) IgGs and 50% pseudovirus neutralization titer (pVNT50) for the preceding (wild type), circulating omicron (BA.4-BA.5, and BF.7), and new subvariants (XBB.1.5) were comprehensively analyzed. RESULTS: Patients with liver cancer receiving booster doses had higher levels of anti-spike RBD IgG against circulating omicron (BA.4-BA.5, and BF.7) and a novel subvariant (XBB.1.5) compared to patients with breast cancer after breakthrough infection. Additionally, all vaccinated patients produced higher neutralizing antibody titers against circulating omicron (BA.4-BA.5, and BF.7) compared to unvaccinated patients. However, the unvaccinated patients produced higher neutralizing antibody against XBB.1.5 than vaccinated patients after Omicron infection, with this trend being more pronounced in breast cancer than in liver cancer patients. Moreover, we found that there was no correlation between anti-spike RBD IgG against wildtype virus and the neutralizing antibody titer, but a positive correlation between anti-spike RBD IgG and the neutralizing antibody against XBB.1.5 was found in unvaccinated patients. CONCLUSION: Our study found that there may be differences in vaccine response and protective effect against COVID-19 infection in patients with liver and breast cancer. Therefore, we recommend that COVID-19 vaccine strategies should be optimized based on vaccine components and immunology profiles of different patients with cancer.

HLA-mismatched allogeneic adoptive immune therapy in patients with severely immunosuppressed AIDS: a multicenter, open-label, controlled, phase 2a study.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients.

Objective: The aim of this study was to explore the profile of cytokine changes during the combination therapy with pegylated interferon alpha (PEG-IFN-α) and its relationship with HBsAg loss in nucleos(t)ide analogs (NAs)-suppressed chronic hepatitis B patients. Methods: Seventy-six patients with chronic hepatitis B with HBsAg less than 1,500 IU/ml and HBV DNA negative after receiving ≥ 1-year NAs therapy were enrolled. Eighteen patients continued to take NAs monotherapy (the NAs group), and 58 patients received combination therapy with NAs and PEG-IFN-α (the Add-on group). The levels of IFNG, IL1B, IL1RN, IL2, IL4, IL6, IL10, IL12A, IL17A, CCL2, CCL3, CCL5, CXCL8, CXCL10, TNF, and CSF2 in peripheral blood during treatment were detected. Results: At week 48, 0.00% (0/18) in the NAs group and 25.86% (15/58) in the Add-on group achieved HBsAg loss. During 48 weeks of combined treatment, there was a transitory increase in the levels of ALT, IL1RN, IL2, and CCL2. Compared to the NAs group, CXCL8 and CXCL10 in the Add-on group remain higher after rising, yet CCL3 showed a continuously increasing trend. Mild and early increases in IL1B, CCL3, IL17A, IL2, IL4, IL6, and CXCL8 were associated with HBsAg loss or decrease >1 log, while sustained high levels of CCL5 and CXCL10 were associated with poor responses to Add-on therapy at week 48. Conclusions: The serum cytokine change profile is closely related to the response to the combination therapy with PEG-IFN-α and NAs, and may help to reveal the mechanism of functional cure and discover new immunological predictors and new therapeutic targets.

Co-pyrolysis of dyeing sludge and pine sawdust in a fluidized bed: Characterization and analysis of pyrolytic products and investigation of synergetic effects.

Co-pyrolysis of dyeing sludge (DS) and pine sawdust (PS) was carried out in a fluidized bed pyrolyser. The results revealed that addition of PS increased the yields of condensate and gas, and dramatically improved pore structure of co-pyrolysis char, enhancing immobilization of the metals, nutrient and pollution elements. Catalysts (Na-ZSM-5 and HZSM-5) significantly reduced tar and coke, strengthened the integrity of pore structure. Yield of nitrogen-containing compounds declined sharply from 88.66% to 8.14% when 25% of PS was added. Addition of 50% PS promoted ring opening to generate chain compounds and abundant oxygenates (such as ketones, aldehydes and carboxylic acids) in pyrolysis oil (PO) at 650 °C. Correspondingly, yield of gaseous products was inhibited except CO2 and H2 when PS content was dominant. The catalysts greatly increased yield of gaseous products by enhancing primary and secondary cracking depending on different feedstocks and catalysts (e.g., DS over Na-ZSM-5 and PS over HZSM-5). The maximum energy efficiency (69.75%) was obtained at 650 °C when 75% PS was added.

Catalytic degradation of crystal violet and methyl orange in heterogeneous Fenton-like processes.

Metals-loaded (Fe3+, Cu2+ and Zn2+) activated carbons (M@AC) with different loading ratios (0.1%, 0.5%, 1%, 5% and 10%) were prepared and employed for catalytic degradation of dye model compounds (crystal violet (CV) and methyl orange (MO)) in wastewater by heterogeneous Fenton-like technique. Compared with Cu@AC and Zn@AC, 0.5% Fe3+ loaded AC (0.5Fe@AC) had better catalytic activity for dyes degradation. The effects of dyes initial concentration, catalyst dosage, pH and hydrogen peroxide (H2O2) volume on the catalytic degradation process were investigated. Cyclic performance, stability of 0.5Fe@AC and iron leaching were explored. Degradation kinetics were well fitted to the pseudo-second-order model (Langmuir-Hinshelwood). Almost complete decolorization (99.7%) of 400 mg L-1 CV was achieved after 30 min reaction under the conditions of CV volume (30 mL), catalyst dosage (0.05 g), H2O2 volume (1 mL) and pH (7.7). Decolorization of MO reached 98.2% under the same conditions. The abilities of pyrolysis char (PC) of dyeing sludge (DS) and metal loaded carbon to remove dye pollutants were compared. The intermediate products were analyzed and the possible degradation pathway was proposed. This study provided an insight into catalytic degradation of triphenylmethane- and aromatic azo-based substances, and utilization of sludge char.

Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease.

BACKGROUND: Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance. METHODS: The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH). RESULTS: In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs. CONCLUSIONS: The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

BACKGROUND: Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB. METHODS: We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality. RESULTS: We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV). CONCLUSION: These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB.

Co-pyrolysis of biomass and polyvinyl chloride under microwave irradiation: Distribution of chlorine.

Co-pyrolysis of sophora wood (SW) and polyvinyl chloride (PVC) was conducted in a microwave reactor at different temperatures and different mixing ratios, and the transformation and distribution of chlorine in pyrolysis products were investigated. Microwave pyrolysis is a simple and efficient technique with better heating uniformity and process controllability than conventional heating. Compared with PVC pyrolysis, the addition of SW significantly reduced CO2 yield and greatly increased the yield of CO. The yield and quality of pyrolysis oil were effectively improved by SW, and the content of chlorine-containing compounds in the oil was suppressed to <1% at low temperatures (<550 °C). Co-pyrolysis of SW and PVC reduced the chlorine emissions from 59.07% to 28.09% and promoted the retention of chlorine in char (from 0.33% to 4.72%). Cellulose, hemicellulose, and lignin were co-pyrolyzed with PVC to investigate their effects on chlorine distribution. The experiments demonstrated that lignin had the most significant effects on reducing gas phase chlorine emission and achieving chlorine immobilization, and chlorine mainly existed in the form of sodium chloride in the char of lignin-PVC co-pyrolysis. Hence co-pyrolysis of lignocellulosic biomass and PVC provides a practical pathway for utilization of PVC waste in an environmentally friendly manner, realizing efficient chlorine retention and significantly reducing chlorine-related emissions.

Iron-biochar production from oily sludge pyrolysis and its application for organic dyes removal.

In this study, a single-step pyrolysis approach was developed to directly convert oily sludge (OS) with high iron content into a magnetic iron-char catalyst for organic dyes removal. Magnetic iron-char catalysts were employed to degrade crystal violet (CV), methylene blue (MB), and sunset yellow (SY). The OC800 iron-char catalyst prepared from OS was not only rich in iron (mainly stable Fe3O4), but also showed favorable pore structures. Effects of operation parameters like temperature, H2O2 dosage, and pH on dye removal based on Fenton degradation were examined. In OC800 Fenton system (0.5 mL H2O2, 500 mg/L dye concentration, and pH = 2 in 50 mL solution), the maximum dye removal capacities of SY, CV, and MB were 83.61, 639.19, and 414.25 mg/g, respectively. In dyes degradation experiments, the prepared catalyst could be reused (more than 3 successive cycles) due to higher stability and less leaching of iron. One-step pyrolysis of OS with high iron content thereby represents a promising approach to transform sludge waste to functional biochar that removes hazardous dyes.

Pyrolysis of vegetable oil soapstock in fluidized bed: Characteristics of thermal decomposition and analysis of pyrolysis products.

This study investigated the effect of temperature on pyrolysis of soapstock in a fluidized bed reactor, and the characterization of soapstock chars (SCs) and pyrolysis oils (POs) were analyzed. TGA, TG-FTIR, TG-MS, and Py-GCMS were employed to investigate characteristics of SS pyrolysis. Experimental results indicated that the yield of SC decreased with increasing temperature. Pyrolysis oil (PO) yield reached the maximum of 21.05 wt% at 600 °C and the yield of non-condensable gas varied with temperatures. The content of carbon, hydrogen and nitrogen distributed in the SC decreased with the increasing temperature, and sulfur tended to be retained in SC during pyrolysis with the distribution ratio of 0.55-0.62. Ketones, alcohols and hydrocarbons were the dominate substances in PO, and higher temperature promoted the production of short-chain alkanes and the conversion of alkenes to benzene derivatives. SS pyrolysis can be divided into three stages. Stage I was mainly the evaporation of free water and light organics in the raw material. Decomposition and conversion of organics mainly occurred at stage II. Stage III was the decomposition of CaCO3 and secondary cracking of residual organics. Ca2+ delayed the pyrolysis reaction of fatty acids and promoted decarboxylation which was the main deoxygenation pathway, and alkene production. This study provided a theoretical basis for the application of soapstock thermochemical treatment. It is of great significance for the quality improvement of PO and pollution control for pyrolysis processes.

Influence of corn straw on distribution and migration of nitrogen and heavy metals during microwave-assisted pyrolysis of municipal sewage sludge.

This study explored pyrolysis characteristics, nitrogen transformation and migration of heavy metals during microwave-assisted pyrolysis of municipal sewage sludge in a continuously operated auger pyrolyser at different temperatures and corn straw ratios. The results showed higher temperatures and more corn straw resulted in more gas yield (e.g., CO2, CO, CH4 and H2) and less char yield. 5 wt% corn straw addition at 750 °C achieved high-quality bio-oil with less O-containing compounds, which was more favorable for upgrading to transportation fuels. Sludge chars prepared at higher corn straw ratios had lower ratios of H/C and N/C, and higher carbon content. Nitrogen transformation pathways and mechanisms were investigated. The residual ratio of heavy metals (except Cd) in sludge char was 67.74-100%. However, the residual ratio of Cd decreased significantly to 6.46% at 750 °C. Concentrations of all heavy metals in sludge char conformed to national standard (CJ/T 362-2011, China), and the potential ecological risk was slight. Sludge chars prepared in the presence of corn straw had lower ecological risk and higher retention capacity of heavy metals (e.g., Pb, Cr, Mn, Cu, Zn, and Ni) compared with pyrolysis of sewage sludge.

Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. METHODS: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. RESULTS: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. CONCLUSIONS: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution.

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC.

The application of hepatitis B virus (HBV)-T-cell receptor (TCR) T-cell immunotherapy in patients with HBV-related hepatocellular carcinoma (HBV-HCC) has been apathetic, as the expression of HBV antigens by both normal HBV-infected hepatocytes and HCC cells with HBV-DNA integration increases the risk of on-target off-tumor severe liver inflammatory events. To increase the safety of this immunotherapeutic approach, we developed messenger RNA (mRNA) HBV-TCR-redirected T cells that-due to the transient nature of mRNA-are functionally short lived and can be infused in escalating doses. The safety of this approach and its clinical potential against primary HBV-HCC have never been analyzed in human trials; thus, we studied the clinical and immunological parameters of 8 patients with chronic HBV infection and diffuse nonoperable HBV-HCC treated at weekly intervals with escalating doses (1 × 104 , 1 × 105 , 1 × 106 , and 5 × 106 TCR+ T cells/kg body weight) of T cells modified with HBV-TCR encoding mRNA. The treatment was well tolerated with no severe systemic inflammatory events, cytokine storm, or neurotoxicity observed in any of these patients throughout treatment. Instead, we observed a destruction of the tumor lesion or a prolonged stable disease in 3 of 8 patients. Importantly, the patients without clinically relevant reductions of HCC did not display any detectable peripheral blood immunological alterations. In contrast, signs of transient localized liver inflammation, activation of the T-cell compartment, and/or elevations of serum chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL10 levels were detected in patients with long-term clinical benefit. Conclusion: We show that despite the reduced in vivo half-life (3-4 days), adoptive transfer of mRNA HBV-TCR T cells into patients with HBV-HCC show long-term clinical benefit that was associated with transient immunological alterations.