SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation.

During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased ß-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The ß-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.

Unlocking Plant Resilience: Advanced Epigenetic Strategies Against Heavy Metal and Metalloid Stress.

The escalating threat of heavy metal and metalloid stress on plant ecosystems requires innovative strategies to strengthen plant resilience and ensure agricultural sustainability. This review provides important insights into the advanced epigenetic pathways to improve plant tolerance to toxic heavy metals and metalloid stress. Epigenetic modifications, including deoxyribonucleic acid (DNA) methylation, histone modifications, and small ribonucleic acid (RNA) engineering, offer innovative avenues for tailoring plant responses to mitigate the impact of heavy metal and metalloid stress. Technological advancements in high-throughput genome sequencing and functional genomics have unraveled the complexities of epigenetic regulation in response to heavy metal and metalloid contamination. Recent strides in this field encompass identifying specific epigenetic markers associated with stress resilience, developing tools for editing the epigenome, and integrating epigenetic data into breeding programs for stress-resistant crops. Understanding the dynamic interaction between epigenetics and stress responses holds immense potential to engineer resilient crops that thrive in environments contaminated with heavy metals and metalloids. Eventually, harnessing epigenetic strategies presents a promising trajectory toward sustainable agriculture in the face of escalating environmental challenges. Plant epigenomics expands, the potential for sustainable agriculture by implementing advanced epigenetic approaches becomes increasingly evident. These developments lay the foundation for understanding the growing significance of epigenetics in plant stress biology and its potential to mitigate the detrimental effects of heavy metal and metalloid pollution on global agriculture.

Remediation of heavy metals polluted soil environment: A critical review on biological approaches.

Heavy metals (HMs) pollution is a globally emerging concern. It is difficult to cost-effectively combat such HMs polluted soil environments. The efficient remediation of HMs polluted soil is crucial to protect human health and ecological security that could be carried out by several methods. Amidst, biological remediation is the most affordable and ecological. This review focused on the principles, mechanisms, performances, and influential factors in bioremediation of HMs polluted soil. In microbial remediation, microbes can alter metallic compounds in soils. They transform these compounds into their metabolism through biosorption and bioprecipitation. The secreted microbial enzymes act as transformers and assist in HMs immobilization. The synergistic microbial effect can further improve HMs removal. In bioleaching, the microbial activity can simultaneously produce H2SO4 or organic acids and leach HMs. The production of acids and the metabolism of bacteria and fungi transform metallic compounds to soluble and extractable form. The key bioleaching mechanisms are acidolysis, complexolysis, redoxolysis and bioaccumulation. In phytoremediation, hyperaccumulator plants and their rhizospheric microbes absorb HMs by roots through absorption, cation exchange, filtration, and chemical changes. Then they exert different detoxification mechanisms. The detoxified HMs are then transferred and accumulated in their harvestable tissues. Plant growth-promoting bacteria can promote phytoremediation efficiency; however, use of chelants have adverse effects. There are some other biological methods for the remediation of HMs polluted soil environment that are not extensively practiced. Finally, the findings of this review will assist the practitioners and researchers to select the appropriate bioremediation approach for a specific soil environment.

Effect of subcutaneous vs. intravenous tocilizumab in patients with severe COVID-19: a systematic review.

OBJECTIVE: To systematically evaluate the efficacy of subcutaneous tocilizumab in the treatment of patients with severe COVID-19 and provide evidence for the rational use of subcutaneous tocilizumab in patients with severe COVID-19. METHODS: This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched the Cochrane Library, PubMed, Embase, CNKI, SinoMed, and Wanfang Medical Network electronic databases up to 11 January 2023 to identify relevant studies. To obtain the most recent clinical studies of subcutaneous injection of tocilizumab for the treatment of patients with severe COVID-19, we also searched the preprint platforms medRxiv and ChinaXiv. Furthermore, we searched ClinicalTrials.gov for relevant unpublished studies. The studies were screened based on the PICOS principle. The included studies were classified and evaluated for quality based on research type. The RevMan 5.3 software was used to conduct the meta-analysis, and a descriptive analysis was performed to examine relevant outcome indicators. RESULTS: Five observational studies were obtained, involving a total of 498 patients (240 patients in the subcutaneous injection group and 258 patients in the intravenous injection group). All of the studies were of the highest quality. The meta-analysis of the included studies revealed that the mortality rate of patients who received subcutaneous tocilizumab to treat COVID-19 was not significantly higher than that of the intravenous injection group [23.3% (45/193) vs. 18.4% (39/212), RD = 0.06, 95% CI = - 0.01 ~ 0.13, P = 0.11]. Furthermore, there was no significant difference in the proportion of patients requiring mechanical ventilation between the two groups [24.5% (35/143) vs. 22% (35/159), RD = 0.03, 95% CI = - 0.07 ~ 0.12, P = 0.56]. CONCLUSIONS: The meta-analyses do not provide evidence that subcutaneous and intravenous tocilizumab formulations for the treatment of severe COVID-19 infection differ regarding their effectiveness. Considering that the meta-analyses cannot replace an appropriately powered non-inferiority study, subcutaneous formulations still need to be used with caution and only when intravenous formulations are in short supply. At present, there is a lack of randomized controlled trials of subcutaneous injection of tocilizumab for the treatment of severe COVID-19, and more clinical research should be conducted.

Ecotoxicological effects of tungsten on celery (Apium graveolens L) and pepper (Capsicum spp.).

Background: Tungsten (W) is an emerging heavy metal pollutant, yet research remains scarce on the biomonitor and sensitive biomarkers for W contamination. Methods: In this study, celery and pepper were chosen as study subjects and subjected to exposure cultivation in solutions with five different levels of W. The physiological and biochemical toxicities of W on these two plants were systematically analyzed. The feasibility of utilizing celery and pepper as biomonitor organisms for W contamination was explored and indicative biomarkers were screened. Results: The results indicated that W could inhibit plants' root length, shoot height, and fresh weight while concurrently promoting membrane lipid peroxidation. Additionally, W enhanced the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and total antioxidant capacity (TAOC) to counteract oxidative damage. From a physiological perspective, pepper exhibited potential as a biomonitor for W contamination. Biochemical indicators suggested that SOD could serve as a sensitive biomarker for W in celery, while TAOC and POD were more suitable for the roots and leaves of pepper. In conclusion, our study investigated the toxic effects of W on celery and pepper, contributing to the understanding of W's environmental toxicity. Furthermore, it provided insights for selecting biomonitor organisms and sensitive biomarkers for W contamination.

Effective model and electron correlations in trilayer nickelate superconductor La4Ni3O10.

Recently, signatures of superconductivity with critical temperature from 20 to 30 K have been reported in pressured trilayer nickelate La4Ni3O10through a pressure-induced structure transition. Here we explore the evolution of electronic structures and electronic correlations in different phases of La4Ni3O10under corresponding pressure regions, by using density functional theory (DFT) combined with dynamical mean-field theory (DMFT). Similar to bilayer superconductor La3Ni2O7, the electronic bands in superconducting La4Ni3O10are dominated by Ni-3dx2-y2and 3dz2orbits near the Fermi level, in contrast, the inner Ni-O plane in La4Ni3O10generates a doublet hole-pocket Fermi surfaces around the Brillouin-zone corner, meanwhile one branch of the Ni-3dz2bands is pushed very close above the Fermi level, which can induce an electron pocket through small electron doping. The DFT+DMFT simulations suggest that the electronic correlations only give minor modification to the Fermi surfaces, meanwhile the Ni-3dz2and 3dx2-y2states on outer Ni-O layers have considerable greater mass enhancements than on the inner layer. The sensitiveness of electronic structure under doping and unique layer dependence of correlation suggest a distinct superconducting mechanism with respect to bilayer La3Ni2O7. Based on the DFT and DFT+DMFT simulations, we eventually derive a trilayer effective tight-binding model, which can produce rather precise electronic bands and Fermi surfaces, hence can serve as an appropriate model to further study the superconducting mechanism and paring symmetry in trilayer La4Ni3O10.

Development and validation of a machine learning model to improve precision prediction for irrational prescriptions in orthopedic perioperative patients.

OBJECTIVE: Our objective was to develop a machine learning model capable of predicting irrational medical prescriptions precisely within orthopedic perioperative patients. METHODS: A dataset comprising 3047 instances of suspected irrational medication prescriptions was collected from a sample of 1318 orthopedic perioperative patients from April 2019 to March 2022. Four machine learning models were employed to forecast irrational prescriptions, following which, the performance of each model was meticulously assessed. Subsequently, a thorough variable importance analysis was conducted on the model that performed the best predictive capabilities. Thereafter, the efficacy of integrating this optimal model into the existing audit prescription process was rigorously evaluated. RESULTS: Of the models utilized in this study, the RF model yielded the highest AUC of 92%, whereas the NB model presented the lowest AUC of 68%. Also, the RF model boasted the most robust performance in terms of PPV, reaching 82.4%, and NPV, reaching 86.6%. The ANN and the XGBoost model were neck and neck, with the ANN slightly edging out with a higher PPV of 95.9%, while the XGBoost model boasted an impressive NPV of 98.2%. The RF model singled out the following five factors as the most influential in predicting irrational prescriptions: the type of drug, the type of surgery, the number of comorbidities, the date of surgery after hospitalization, as well as the associated hospital and drug costs. CONCLUSION: The RF model showcased significantly high level of proficiency in predicting irrational prescriptions among orthopedic perioperative patients, outperforming other models by a considerable margin. It effectively enhanced the efficiency of pharmacist interventions, displaying outstanding performance in assisting pharmacists to intervene with irrational prescriptions.

Quality appraisal of clinical guidelines for Helicobacter pylori infection and systematic analysis of the level of evidence for recommendations.

OBJECTIVES: To systematically assess the quality of clinical practice guidelines (CPGs) for Helicobacter pylori (HP) infection and identify gaps that limit their development. STUDY DESIGN AND SETTING: CPGs for HP infection were systematically collected from PubMed, Embase, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and six online guideline repositories. Three researchers independently used the AGREE Ⅱ tool to evaluate the methodological quality of the eligible CPGs. In addition, the reporting and recommendation qualities were appraised by using the RIGHT and AGREE-REX tools, respectively. The distribution of the level of evidence and strength of recommendation among evidence-based CPGs was determined. RESULTS: A total of 7,019 records were identified, and 24 CPGs met the eligibility criteria. Of the eligible CPGs, 19 were evidence-based and 5 were consensus-based. The mean overall rating score of AGREE II was 50.7% (SD = 17.2%). Among six domains, the highest mean score was for scope and purpose (74.4%, SD = 17.7%) and the lowest mean score was for applicability (24.3%, SD = 8.9). Only three of 24 CPGs were high-quality. The mean overall score of recommendation quality was 35.5% (SD = 12.2%), and the mean scores in each domain of AGREE-REX and RIGHT were all ≤ 60%, with values and preferences scoring the lowest (16.6%, SD = 11.9%). A total of 505 recommendations were identified. Strong recommendations accounted for 64.1%, and only 34.3% of strong recommendations were based on high-quality evidence. CONCLUSION: The overall quality of CPGs for HP infection is poor, and CPG developers tend to neglect some domains, resulting in a wide variability in the quality of the CPGs. Additionally, CPGs for HP infection lack sufficient high-quality evidence, and the grading of recommendation strength should be based on the quality of evidence. The CPGs for HP infection have much room for improvement and further researches are required to minimize the evidence gap.

Investigating bleeding adverse events associated with BTK inhibitors in the food and drug administration adverse event reporting system (FAERS).

BACKGROUND: This study analyzed the bleeding adverse events (AEs) resulting from the treatment of B-cell lymphoma with Bruton tyrosine kinase (BTK) inhibitors, according to reports in the US Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Bleeding AEs associated with BTK inhibitors (including ibrutinib, zanubrutinib, and acalabrutinib) from the first quarter of 2013 to the third quarter of 2023 were extracted. Reporting odds ratio (ROR) and proportional reporting ratio (PRR) were reported. Preferred Terms (PTs) of Medical Dictionary for Regulatory Activities (MedDRA) terms were mapped to System Organ Class terms (SOC) terms and analyzed bleeding AEs associated with three BTK inhibitors. RESULTS: A total of 463 cases of bleeding AEs were included. Contusion, subcutaneous hemorrhage, hematuria, and cerebral hemorrhage were included in PTs. Blood urine was present and subdural hematoma were also reported. The incidence of bleeding AEs was higher with ibrutinib (Case number = 10,696) than with zanubrutinib (Case number = 213) and acalabrutinib (Case number = 314). CONCLUSION: Our findings indicate that bleeding AEs linked to BTK inhibitors in various conditions underscore the need for cautious clinical decision-making, particularly in nervous system disorders, injuries, poisoning, surgical complications, vascular disorders, and others.

Zinc as a Mediator Through the ROCK1 Pathway of Cognitive Impairment in Aluminum-Exposed Workers: A Clinical and Animal Study.

Aluminum (Al) exposure was implicated in neurodegenerative diseases and cognitive impairment, yet the involvement of zinc (Zn) and its mechanism in Al-induced mild cognitive impairment (MCI) remains poorly understood. The objective is to explore the role of Zn in Al-induced cognitive impairment and its potential mechanisms. Montreal cognitive assessment (MoCA) test scores and serum Al, Zn from Al industry workers were collected. A mediation analysis was performed to evaluate the role of serum Zn among serum Al and MoCA test scores. Subsequently, an Al-exposure study was conducted on a rat model categorized into control, low-, medium-, and high-dose groups. After a Morris Water Maze test and detection of Al, Zn content in the hippocampus, integrated transcriptomic and proteomic analyses between the control group and the high-dose group were performed to identify the differentially expressed genes (DEPs), proteins (DEPs), and pathways. To corroborate these findings, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were selected to identify the gene and protein results. Zn overall mediates the relationship between serum Al and cognitive function (mediation effect 17.82%, effect value = - 0.0351). In the Al-exposed rat model, 734 DEGs, 18 miRNAs, 35 lncRNAs, 64 circRNAs, and 113 DEPs were identified between the high-dose group and the control group. Among them, ROCK1, DMD, and other four DEPs were identified as related to zinc finger proteins (ZNF). Co-enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) linked these changes to the RHOA/ROCK1 signaling axis. ZNF-related proteins Rock1, DMD, and DHX57 in the high-dose group were downregulated (p = 0.006, 0.003, 0.04), and the expression of Myl9, Rhoa, miR431, and miR182 was also downregulated (p = 0.003, 0.032, 0.032, and 0.046). These findings also show correlations between Al, Zn levels in the hippocampus, water maze performance, and expressions of Myl9, Rhoa, miR431, miR182, DMD, ROCK1, and DHX57, with both negative and positive associations. Based on the results, we determined that Zn was involved in Al-induced MCI in Al workers and Al-exposed rat models. Al exposure and interaction with Zn could trigger the downregulation of ZNF of ROCK1, DMD, and DHX57. miR431, miR182 regulate RHOA/ROCK1 was one of the Zn-involved pathways in Al-induced cognitive impairment.

Performance evaluation on vaccination rates monitoring report system of Shenzhen, China.

To evaluate the performance of "Vaccination Rates Monitoring Report System" implemented by Shenzhen CDC, we conducted an analysis of the data quality and identify key areas for system improvement. Following evaluation guidelines provided by WHO and United States CDC, we established six evaluation attributes: representativeness, simplicity, acceptability, data reliability, stability and timeliness. In eastern, central and western regions of Shenzhen, we selected one district from each region, of which the local CDC and ten CHSCs under jurisdiction were chosen for evaluation. On-site inspections, questionnaires survey and interviews were utilized for data collection, while the Likert scale method was used for attributes rating evaluation. A total of 70 participants were surveyed, consisting of 60 CHSCs and 10 CDCs staff. The gender ratio was 1:2.5 (males to females), with the majority falling within the 25-34 age range (46%). Most participants held full-time positions (80%) and had more than 5 years of work experience (62%). The system achieved 100% coverage of all CHSCs and CDCs (100%). The cumulative percentage scores for the overall favorable options of simplicity, acceptability, data reliability, stability, and timeliness were 79%, 85%, 73%, 50%, and 71% respectively. The system operates normally with strong representativeness. Acceptability was rated as "good." Simplicity, data reliability, and system timeliness were rated as "average," while system stability was rated as "poor." Based on these survey results, developers should urgently investigate reasons for poor stability, particularly addressing concerns from CHSCs users. Additionally, the issues and shortcomings identified in other attributes should also be gradually improved.

Leaching of heavy metals from tungsten mining tailings: A case study based on static and kinetic leaching tests.

Heavy metal (HM) leaching from tungsten mine tailings is a serious environmental risk. In this study, we assess the HM pollution level of tungsten tailings, determine the HM leaching patterns and mechanisms, and estimate the HM fluxes from a tailings reservoir. The results showed that the comprehensive pollution index (CRSi) values that decreased in order of the HM pollution levels in the tailings were cadmium (Cd) > tungsten (W) > lead (Pb) > copper (Cu) = zinc (Zn) > arsenic (As) > manganese (Mn). This result indicated that Cd, W, and Pb were priority pollutants in tailings. The Res fraction of all HMs was greater than 50%. Pb and Cd had similar species fractions with high Exc fractions, and tungsten had a considerable proportion of the Wat fraction. The general acid neutralizing capacity (GANC) test divides the leaching process of HMs into two stages, and each of stage is affected by different mechanisms. A neutral environment promoted tungsten leaching in the column leching test, while an acidic environment promoted Cd and Pb leaching. In addition, the pH effect was more obvious in the early stage. The kinetic fitting results showed that the second-order dynamic model well simulated the leaching of W, Pb, and Cd in most cases. Based on column kinetic leaching test results and tailings parameters, the annual W, Pb, and Cd fluxes were estimated to be 6.35 × 108, 1.3288 × 109, and 1.012 × 108 mg/year, respectively. The above results can guide the environmental management of tungsten tailing reservoirs, such as selecting suitable repair materials and estimating repair service times.

Knowledge mapping of acupoint sensitization and acupoint specificity: a bibliometric analysis.

Objective: The relationship between acupoint sensitization and acupoint specificity is a topic of significant interest in acupuncture research. Numerous clinical studies have demonstrated that needling pain sensitive acupoints yields superior therapeutic outcomes compared to traditional acupoints, particularly in the context of pain disorders. However, there is a lack of bibliometric analysis in acupuncture area. Therefore, the objective of this study is to offer a comprehensive overview of the knowledge structure and research hotspots pertaining to acupoint sensitization and acupoint specificity. Methods: The search for publications pertaining to acupoint sensitization and acupoint specificity was conducted in the Web of Science Core Collection (WoSCC) database from its inception until August 11, 2023. Subsequently, bibliometric analyses were carried out using VOSviewer, CiteSpace, R software (Bibliometrix package), and GraphPad Prism software. Results: This study includes 4,940 articles from 72 countries, with China and the United States being the leading countries. The number of publications related to acupoint sensitization and specificity has been increasing annually. Major research institutions involved in this field include the Shanghai University of Traditional Chinese Medicine, Kyung Hee University, Beijing University of Chinese Medicine, Chinese Academy of Chinese Medical Sciences, and China Medical University, among others. "Evidence-based Complementary and Alternative Medicine" is the most popular journal in acupuncture field, and "PAIN" is the most co-cited journal. Publications are contributed by 20,325 authors from all over the world, with Wu Huangan, Fang Jianqiao, Lin Yi-Wen, Liu Huirong, and Chen Rixin having published the most articles. Han Ji-Sheng is the most cited author in this research area. The main directions include the study of temperature specificity of acupoints, the diagnosis of acupoint sensitization diseases, and the study of the mechanism of acupoint sensitization. The most listed keywords in recent years are "TRPV1," "signaling pathway," and "diagnosis." Conclusion: This is the first bibliometric study to comprehensively summarize research trends and advances in acupoint sensitization and acupoint specificity, and the information highlights recent research preliminary and main directions that serve as a reference for acupoint sensitization and acupoint specificity research.

Dichloromethane-Induced Poisoning from Acrylic Paint Cleaner - Shenzhen City, Guangdong Province, China, 2023.

What is already known about this topic?: Dichloromethane (DCM) is a colorless and transparent organic solvent that commonly causes poisoning during occupational contact. What is added by this report?: Unknown to teachers and students, they were utilizing an acrylic paint cleaner that contained DCM. At the time of the poisoning incident, the art room was occupied beyond its capacity with inadequate local ventilation. The primary cause of the incident was determined to be the students' inhalation of DCM during the cleaning process. What are the implications for public health practice?: The unclear composition of environmental cleaning products available for purchase online presents a major obstacle for consumers trying to assess their toxicity. It is imperative that robust regulatory measures and proactive public education campaigns are implemented to mitigate instances of poisoning.

Impact of Spartina alterniflora Invasion in Coastal Wetlands of China: Boon or Bane?

Invasive plants, like Spartina alterniflora (SA), have a competitive advantage over native flora due to their rapid utilization of vital soil nutrients. This results in the depletion of resources for native plant species, significantly impacting ecosystem diversity and stability. This comprehensive review addresses several key aspects related to SA's spread and spatial distribution in China's wetlands. The rapid expansion of Spartina alterniflora is attributed to its high reproductive ability, adaptability to environmental factors like elevated salinity, and ability to disperse its seeds via tides. Spartina alterniflora mainly were found in Zhejiang, Jiangsu, Fujian, and Shanghai provinces, accounting for more than 90% of China's total Spartina alterniflora area. Spartina alterniflora rapid growth results in displacement of native species and loss of vital microbial, plant, and animal diversity. Some studies reported that Spartina alterniflora increases carbon storage, while others argue that it weakens this function. The impact of Spartina alterniflora on organic and inorganic carbon requires further research for better understanding dynamics of carbon in coastal wetlands. The controlled growth of Spartina alterniflora can be beneficial in many aspects of the coastal wetlands' ecosystem. In China, various methods have been employed to control the invasion of SA. Physical control, such as removing the plants and converting them into fertilizer or bioenergy, has been commonly used but has limitations like air pollution and the potential for re-invasion. Chemical herbicides like Imazapyr and Haloxyfop-R-methyl have effectively controlled and prevented re-invasion in specific areas, but their potential adverse impacts are still uncertain. Wetland Park construction, aquaculture development, and substituting native or exotic species with mangroves or reed communities have also been successful. It becomes evident that a long-standing and Contextual approach is necessary to effectively manage the advantages and curtail the drawbacks associated with S. alterniflora across China.

IL-1ß-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance.

Interleukin-1ß (IL-1ß) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1ß in cancer is ambiguous or even contradictory. Here, we found that upon IL-1ß stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1ß-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1ß expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1ß-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1ß and tumor cells by inhibiting NNT acetylation.

In-gap states and strain-tuned band convergence in layered structure trivalent iridate K0.75Na0.25IrO2.

Iridium oxides (iridates) provide a good platform to study the delicate interplay between spin-orbit coupling (SOC) interactions, electron correlation effects, Hund's coupling and lattice degrees of freedom. An overwhelming number of investigations primarily focus on tetravalent (Ir4+, 5d5) and pentavalent (Ir5+, 5d4) iridates, and far less attention has been paid to iridates with other valence states. Here, we pay our attention to a less-explored trivalent (Ir3+, 5d6) iridate, K0.75Na0.25IrO2, crystallizing in a triangular lattice with edge-sharing IrO6 octahedra and alkali metal ion intercalated [IrO2]- layers, offering a good platform to explore the interplay between different degrees of freedom. We theoretically determine the preferred occupied positions of the alkali metal ions from energetic viewpoints and reproduce the experimentally observed semiconducting behavior and nonmagnetic (NM) properties of K0.75Na0.25IrO2. The SOC interactions play a critical role in the band dispersion, resulting in NM Jeff = 0 states. More intriguingly, our electronic structure not only uncovers the presence of intrinsic in-gap states and nearly free electron character for the conduction band minimum, but also explains the abnormally low activation energy in K0.75Na0.25IrO2. Particularly, the band edge can be effectively modulated by mechanical strain, and the in-gap states feature enhanced band-convergence characteristics by 6% compressive strain, which will greatly enhance the electrical conductivity of K0.75Na0.25IrO2. The present work sheds new light on the unconventional electronic structures of trivalent iridates, indicating their promising application as a nanoelectronic and thermoelectric material, which will attract extensive interest and stimulate experimental works to further understand the unprecedented electronic structures and exploit potential applications of the triangular trivalent iridate.

Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.

OBJECTIVE: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined. DESIGN: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated. RESULTS: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients. CONCLUSIONS: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

[Acupuncture mitigates ocular surface inflammatory response via α7nAChR/NF-κB p65 signaling in dry eye guinea pigs].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the ocular surface inflammation and α7 nicotinic acetylcholine receptor (α7nAChR) / nuclear factor kappa-B (NF-κB) p65 signal pathway in guinea pigs with dry eye, so as to explore its underlying mechanism. METHODS: A total of 32 male British tricolor short haired guinea pigs were randomized into blank control, model, EA and sham acupuncture groups, with 8 guinea pigs in each group. The dry eye model was established by subcutaneous injection of scopolamine hydrobromide solution (0.6 mg/0.2 mL each time, 4 times a day for 10 days). Guinea pigs of the EA group was treated with EA at bilateral "Cuanzhu" (BL2) and "Taiyang" (HN5), and manual acupuncture at bilateral "Jingming" (BL1), "Sizhukong" (SJ23), "Tongziliao" (GB1) for 15 min, once daily for 14 days. For animals of the sham acupuncture group, a blunt needle was used to prick the skin surface of the acupoints, the acupoint selection and stimulation time were the same as those in the EA group. Before and after modeling and after the intervention, the breakup time (BUT) of lacrimal film, sodium fluorescein coloring (Fl) state of corneal epithelium and phenol red thread (PRT) moist length were recorded for assessing the severity of dry eye. The density of activated immune cells around the corneal epithelial stromal cells was determined by corneal confocal microscopy. The contents of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in the cornea and lacri-mal gland tissues were determined by ELISA, and the expression levels of α7nAChR and NF-κB p65 in the cornea and lacrimal gland were detected by immunohistochemistry and Western blot, separately. RESULTS: Compared with the blank control group, the corneal Fl, density of activated immune cells of corneal epithelium, contents of IL-6, IL-10 and TNF-α in both corneal and lacrimal gland tissues, NF-κB p65 cell positive rate and protein expression of lacrimal gland and corneal tissues were significantly increased (P<0.01, P<0.05), while the BUT, PRT and lacrimal gland α7nAChR cell positive rate considerably decreased (P<0.01) in the model group. In comparison with the model group, the level of corneal Fl, density of the activated immune cells of corneal epithelium, contents of corneal and lacrimal IL-6 and TNF-α, and corneal and lacrimal NF-κB p65 cell positive rates and protein expressions were remarkably down-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except content of corneal IL-10, lacrimal NF-κB p65 cell positive rate and lacrimal α7nAChR protein expression, whereas the levels of BUT, PRT, corneal and lacrimal IL-10 and corneal and lacrimal α7nAChR cell positive rates and protein expressions significantly up-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except corneal TNF-α and corneal NF-κB p65 protein expression. CONCLUSION: EA can improve corneal and lacrimal function in dry eye guinea pigs, which may be associated with its actions in increasing the expression of α7nAChR, inhibiting the nuclear translocation of NF-κB, and reducing the activated immune cells and inflammatory reaction.

Spatiotemporal characterization of aerosols and trace gases over the Yangtze River Delta region, China: impact of trans-boundary pollution and meteorology.

Background: The spatiotemporal variation of observed trace gases (NO2, SO2, O3) and particulate matter (PM2.5, PM10) were investigated over cities of Yangtze River Delta (YRD) region including Nanjing, Hefei, Shanghai and Hangzhou. Furthermore, the characteristics of different pollution episodes, i.e., haze events (visibility < 7 km, relative humidity < 80%, and PM2.5 > 40 µg/m3) and complex pollution episodes (PM2.5 > 35 µg/m3 and O3 > 160 µg/m3) were studied over the cities of the YRD region. The impact of China clean air action plan on concentration of aerosols and trace gases is examined. The impacts of trans-boundary pollution and different meteorological conditions were also examined. Results: The highest annual mean concentrations of PM2.5, PM10, NO2 and O3 were found for 2019 over all the cities. The annual mean concentrations of PM2.5, PM10, and NO2 showed continuous declines from 2019 to 2021 due to emission control measures and implementation of the Clean Air Action plan over all the cities of the YRD region. The annual mean O3 levels showed a decline in 2020 over all the cities of YRD region, which is unprecedented since the beginning of the China's National environmental monitoring program since 2013. However, a slight increase in annual O3 was observed in 2021. The highest overall means of PM2.5, PM10, SO2, and NO2 were observed over Hefei, whereas the highest O3 levels were found in Nanjing. Despite the strict control measures, PM2.5 and PM10 concentrations exceeded the Grade-1 National Ambient Air Quality Standards (NAAQS) and WHO (World Health Organization) guidelines over all the cities of the YRD region. The number of haze days was higher in Hefei and Nanjing, whereas the complex pollution episodes or concurrent occurrence of O3 and PM2.5 pollution days were higher in Hangzhou and Shanghai.The in situ data for SO2 and NO2 showed strong correlation with Tropospheric Monitoring Instrument (TROPOMI) satellite data. Conclusions: Despite the observed reductions in primary pollutants concentrations, the secondary pollutants formation is still a concern for major metropolises. The increase in temperature and lower relative humidity favors the accumulation of O3, while low temperature, low wind speeds and lower relative humidity favor the accumulation of primary pollutants. This study depicts different air pollution problems for different cities inside a region. Therefore, there is a dire need to continuous monitoring and analysis of air quality parameters and design city-specific policies and action plans to effectively deal with the metropolitan pollution. Supplementary Information: The online version contains supplementary material available at 10.1186/s12302-022-00668-2.