IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69+CD103+CD8+ tissue-resident memory T cells in autoimmune hepatitis by regulating the JAK3/STAT3/P53 signalling pathway.

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.

Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort.

Objectives: Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. Methods: The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. Results: A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4 min vs. 237.6 ± 68.4 min, P=0.732), intraoperative blood loss (157.8 ± 75.9 ml vs. 149.1 ± 92.5 ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Conclusion: Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.

Secondary organic aerosol formation from straw burning using an oxidation flow reactor.

Herein, we use an oxidation flow reactor, Gothenburg: Potential Aerosol Mass (Go: PAM) reactor, to investigate the secondary organic aerosol (SOA) formation from wheat straw burning. Biomass burning emissions are exposed to high concentrations of hydroxyl radicals (OH) to simulate processes equivalent to atmospheric oxidation of 0-2.55 days. Primary volatile organic compounds (VOCs) were investigated, and particles were measured before and after the Go: PAM reactor. The influence of water content (i.e. 5% and 11%) in wheat straw was also explored. Two burning stages, the flaming stage, and non-flaming stages, were identified. Primary particle emission factors (EFs) at a water content of 11% (∼3.89 g/kg-fuel) are significantly higher than those at a water content of 5% (∼2.26 g/kg-fuel) during the flaming stage. However, the water content showed no significant influence at the non-flaming stage. EFs of aromatics at a non-flaming stage (321.8±46.2 mg/kg-fuel) are larger than that at a flaming stage (130.9±37.1 mg/kg-fuel). The OA enhancement ratios increased with the increase in OH exposure at first and decreased with the additional increment of OH exposure. The maximum OA enhancement ratio is ∼12 during the non-flaming stages, which is much higher than ∼ 1.7 during the flaming stages. The mass spectrum of the primary wheat burning organic aerosols closely resembles that of resolved biomass burning organic aerosols (BBOA) based on measurements in ambient air. Our results show that large gap (∼60%-90%) still remains to estimate biomass burning SOA if only the oxidation of VOCs were included.

The particle phase state during the biomass burning events.

The phase state of biomass burning aerosols (BBA) remains largely unclear, impeding our understanding of their effects on air quality, climate and human health, due to its profound roles in mass transfer between gaseous and particulate phase. In this study, the phase state of BBA was investigated by measuring the particle rebound fraction ƒ combining field observations and laboratory experiments. We found that both ambient and laboratory-generated BBA had unexpectedly lower rebound fraction ƒ (<0.6) under the dry conditions (RH = 20-50%), indicating that BBA were in non-solid state at such low RH. This was obviously different from the secondary organic aerosols (SOA) derived from the oxidation of both anthropogenic and biogenic volatile organic compounds, typically with a rebound fraction ƒ larger than 0.8 at RH below 50%. Therefore, we proposed that the diffusion coefficient of gaseous molecular in the bulk of BBA might be much higher than SOA under the dry conditions.

Enhancement in Particulate Organic Nitrogen and Light Absorption of Humic-Like Substances over Tibetan Plateau Due to Long-Range Transported Biomass Burning Emissions.

To elucidate the influence of long-range transported biomass burning organic aerosols (BBOA) on the Tibetan Plateau, the molecular compositions and light absorption of HUmic-Like Substances (HULIS), major fractions of brown carbon, were characterized during the premonsoon season. Under the significant influence of biomass burning, HULIS concentrations increased to as high as 26 times of the background levels, accounting for 54% of water-soluble organic carbon (WSOC) and 50% of organic carbon (OC). The light absorption of HULIS also enhanced up to 42 times of the background levels, contributing 61% of the WSOC absorption and 50% of OC absorption. Meanwhile, elevated nitrogen-containing compounds (NOCs) among HULIS were observed. The NOCs from fresh and aged BBOA were unambiguously identified on the molecular level, through comparing with the molecular compositions of NOCs from lab-controlled and field burning experiments. N-Heterocyclic bases represent major fractions in the reduced nitrogen compounds from fresh BBOA, and nitroaromatic compounds are important groups among the oxidized nitrogen compounds from aged BBOA. The nitrogen-containing compounds, including nitroaromatics and N-heterocyclic compounds, were also important chromophores, which contributed to the enhanced light absorption of extracted HULIS during biomass burning-influenced periods.

Development of an on-line measurement system for water-soluble organic matter in PM2.5 and its application in China.

Water-soluble organic matter (WSOM) represents a critical fraction of fine particles (PM2.5) in the air, but its changing behaviors and formation mechanisms are not well understood yet, partly due to the lack of fast techniques for the ambient measurements. In this study, a novel system for the on-line measurement of water-soluble components in PM2.5, the particle-into-liquid sampler (PILS)-Nebulizer-aerosol chemical speciation monitor (ACSM), was developed by combining a PILS, a nebulizer, and an ACSM. High time resolution concentrations of WSOM, sulfate, nitrate, ammonium, and chloride, as well as mass spectra, can be obtained with satisfied quality control results. The system was firstly applied in China for field measurement of WSOM. The mass spectrum of WSOM was found to resemble that of oxygenated organic aerosol, and WSOM agreed well with secondary inorganic ions. All evidence collected in the field campaign demonstrated that WSOM could be a good surrogate of secondary organic aerosol (SOA). The PILS-Nebulizer-ACSM system can thus be a useful tool for intensive study of WSOM and SOA in PM2.5.

Source apportionment of PM2.5 light extinction in an urban atmosphere in China.

Haze in China is primarily caused by high pollution of atmospheric fine particulates (PM2.5). However, the detailed source structures of PM2.5 light extinction have not been well established, especially for the roles of various organic aerosols, which makes haze management lack specified targets. This study obtained the mass concentrations of the chemical compositions and the light extinction coefficients of fine particles in the winter in Dongguan, Guangdong Province, using high time resolution aerosol observation instruments. We combined the positive matrix factor (PMF) analysis model of organic aerosols and the multiple linear regression method to establish a quantitative relationship model between the main chemical components, in particular the different sources of organic aerosols and the extinction coefficients of fine particles with a high goodness of fit (R2=0.953). The results show that the contribution rates of ammonium sulphate, ammonium nitrate, biomass burning organic aerosol (BBOA), secondary organic aerosol (SOA) and black carbon (BC) were 48.1%, 20.7%, 15.0%, 10.6%, and 5.6%, respectively. It can be seen that the contribution of the secondary aerosols is much higher than that of the primary aerosols (79.4% versus 20.6%) and are a major factor in the visibility decline. BBOA is found to have a high visibility destroying potential, with a high mass extinction coefficient, and was the largest contributor during some high pollution periods. A more detailed analysis indicates that the contribution of the enhanced absorption caused by BC mixing state was approximately 37.7% of the total particle absorption and should not be neglected.

Molecular Characterization of Nitrogen-Containing Organic Compounds in Humic-like Substances Emitted from Straw Residue Burning.

The molecular composition of humic-like substances (HULIS) in different aerosol samples was analyzed using an ultrahigh-resolution mass spectrometer to investigate the influence of biomass burning on ambient aerosol composition. HULIS in background aerosols were characterized with numerous molecular formulas similar to biogenic secondary organic aerosols. The abundance of nitrogen-containing organic compounds (NOC), including nitrogen-containing bases (N-bases) and nitroaromatics, increased dramatically in ambient aerosols affected by crop residue burning in the farm field. The molecular distribution of N-bases in these samples exhibited similar patterns to those observed in smoke particles freshly emitted from lab-controlled burning of straw residues but were significantly different with those observed from wood burning. Signal intensity of the major N-bases correlated well with the atmospheric concentrations of potassium and levoglucosan. These N-bases can serve as molecular markers distinguishing HULIS from crop residue burning with from wood burning. More nitroaromatics were detected in ambient aerosols affected by straw burning than in fresh smoke aerosols, indicating that many of them are formed in secondary oxidation processes as smoke plumes evolve in the atmosphere. This study highlights the significant contribution of crop residue burning to atmospheric NOC. Further study is warranted to evaluate the roles of NOC on climate and human health.

[Characterising seasonal variation and spatial distribution of PM2.5 species in Shenzhen].

To investigate the effect of meteorological characteristics on PM2.5 chemical composition and the spatial distribution of different PM2.5 species in Shenzhen, 24-h PM2.5 samples were collected every six days from December 2008 to December 2009. The sampling network included an industrial site at Baoan, an urban site at Luohu and a seaside site at Yantian. Water-soluble inorganic ions and carbonaceous material (organic carbon and elemental carbon) were analyzed. The industrial site showed a much higher concentration than that of other two sites of organic matter, elemental carbon and nitrate, which presented the obvious difference of local emissions. But for the concentration of sulfate and ammonium of three different sites nearly stayed at the same level and indicated that they were mainly influenced by regional transport. OC/EC had the characteristics of the industrial site < the urban site < the seaside site, which implied that the industrial site had less secondary organic matter and more primary pollution sources. As the subtropical maritime monsoon climate is the dominant meteorological feature of the Pearl River Delta with a southwesterly transport and abundant rain in spring and summer, in contrast to a northwesterly transport and little rain in fall and winter, the PM2.5 pollution was much more serious in winter than in summer. Compared with the results of the similar experiment in 2004, the concentration of sulfate in PM2.5 has significantly declined because of the measures of reducing the emission of sulfer dioxide. But the pollution of vehicle emissions has become significant.