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China is the most important steel producer in the world, and its steel industry is one of the most carbon-intensive industries in China. Consequently, research on carbon emissions from the steel industry is crucial for China to achieve carbon neutrality and meet its sustainable global development goals. We constructed a carbon dioxide (CO2) emission model for China's iron and steel industry from a life cycle perspective, conducted an empirical analysis based on data from 2019, and calculated the CO2 emissions of the industry throughout its life cycle. Key emission reduction factors were identified using sensitivity analysis. The results demonstrated that the CO2 emission intensity of the steel industry was 2.33 ton CO2/ton, and the production and manufacturing stages were the main sources of CO2 emissions, accounting for 89.84% of the total steel life-cycle emissions. Notably, fossil fuel combustion had the highest sensitivity to steel CO2 emissions, with a sensitivity coefficient of 0.68, reducing the amount of fossil fuel combustion by 20% and carbon emissions by 13.60%. The sensitivities of power structure optimization and scrap consumption were similar, while that of the transportation structure adjustment was the lowest, with a sensitivity coefficient of less than 0.1. Given the current strategic goals of peak carbon and carbon neutrality, it is in the best interest of the Chinese government to actively promote energy-saving and low-carbon technologies, increase the ratio of scrap steel to steelmaking, and build a new power system.

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ß-caryophyllonic acid (BCA), as an important precursor of aqueous secondary organic aerosols (aqSOA), has adverse effects on the atmospheric environment and human health. However, the key atmospheric chemical reaction process in which BCA participates in the formation of aqueous secondary organic aerosols is still unclear. In this study, the reaction mechanism and kinetics of BCA with ·OH and O3 were investigated by quantum chemical calculations. The initiation reactions between BCA and ·OH include addition and H-abstraction reaction pathways, subsequent intermediates will also react with O2, ultimately undergo a cracking reaction to generate small molecular substances. The reaction of BCA with O3 can generate primary ozone oxides and the Criegee Intermediates oIM3, subsequent main reaction products include keto-BCA, as well as other small molecule aqSOA precursors. The entire reaction process increases the O/C ratio of aqSOA in the aqueous phase and generates products of small molecules such as 4-formylpropionic acid, which plays an important role in the formation of aqSOA. At 298K, the transformation rate constants of BCA initiated by ·OH and O3 are 1.47 × 1010 M-1 s-1 and 3.16 × 105 M-1 s-1, respectively, the atmospheric lifetimes of BCA reacting with ·OH range from 0.86 h-5.40 h, while the lifetimes of BCA reacting with O3 range from 0.44 h-10.04 years. This suggests that BCA primarily reacts with ·OH. However, under higher O3 concentrations, its ozonolysis becomes significant, promoting the formation of aqSOA. According to the risk assessment, the toxicity of most transformation products (TPs) gradually decreased, but the residual developmental toxicity could not be ignored. In this paper, the atmospheric liquid phase oxidation mechanisms of sesquiterpene unsaturated derived acid were studied from the microscopic level, which has guiding significance for the formation and transformation of aqSOA in atmosphere.

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OBJECTIVES: Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM. METHODS: We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-ß was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-ß-induced pathogenic molecules was investigated in vitro. RESULTS: Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-ß upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-ß-induced pathogenic molecules in both myoblasts and myotubes. CONCLUSIONS: We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-ß-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.

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ABSTRACT: We described a 13-year-old girl who presented unexplained paroxysmal sharp pain in the right upper abdomen for 3 days. CT and MRI showed multiple masses in the liver and kidneys, initially diagnosed as lymphoma. The hepatic mass biopsy confirmed B-cell lymphoblastic lymphoma. FDG PET/CT examination found that the liver and kidney masses demonstrated high metabolic activity, with concomitant increased metabolic activity in the skeleton. Bone marrow biopsy revealed extensive skeletal involvement. The final diagnosis was B-cell acute lymphoblastic leukemia. This case highlights the effectiveness of FDG PET/CT as an adjunct imaging modality for diagnosis.

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Besides chemotherapy and hematopoietic stem cell transplantation (HSCT), autologous T cells can also serve as a new treatment approach for AML patients. However, the features of tumor-reactive T cells and their distinctive markers still lack full description. To evaluate the characteristics of tumor-reactive T cells, we collected bone marrow (BM) T cells from newly diagnosed AML patients with RUNX1::RUNX1T1 as examples for paired single-cell RNA sequencing and single-cell V(D)J sequencing. Based on the STARTRAC-like algorithm, we defined bystander T cells and tumor-reactive T cells. Compared with bystander T cells, tumor-reactive T cells presented as senescent-like cytotoxic terminally differentiated T cells (Temra) with upregulated NK-related markers. Additionally, we found ADGRG1 could serve as the specific marker of CD8+ T tumor-reactive T cell and validated it through the Runx1Runx1t1/+; Mx1-Cre mouse model. In chimeric antigen receptor (CAR)-T and target cell system, ADGRG1 was selectively upregulated upon antigen-TCR encounter. Moreover, ADGRG1+CD8+ T cells released a higher level of IFN-γ and showed higher cell-killing ability when exposed to matched AML blasts. Together, our findings depict the single-cell profile of tumor-reactive T cells in AML BM and propose that ADGRG1 can act as an indicator of T cell tumor reactivity in AML, which may be further harnessed for adoptive cell therapy and tumor-reactive TCR enrichment.

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Background: According to statistics, colon adenocarcinoma (COAD) ranks third in global incidence and second in mortality. The role of N6-methyladenosine (m6A) modification-dependent ferroptosis in tumor development and progression is gaining attention. Therefore, it is meaningful to explore the biological functions mediated by m6A ferroptosis related genes (m6A-Ferr-RGs) in the prognosis and treatment of COAD. This study aimed to explore the regulatory mechanisms and prognostic features of m6A-Ferr-RGs in COAD based on the COAD transcriptome dataset. Methods: The expression data of Ferr-RGs and the correlated analysis with prognosis related m6A regulators were conducted to obtain candidate m6A-Ferr-RGs. Then, the differentially expressed genes (DEGs) between COAD and normal samples were intersected with candidate m6A-Ferr-RGs to obtain differentially expressed m6A Ferr-RGs (DE-m6A-Ferr-RGs) in COAD. Cox regression analyses were performed to establish risk model and validated in the GSE17538 and GSE41258 datasets. The nomogram was constructed and verified by calibration curves. Moreover, tumor immune dysfunction and exclusion (TIDE) was used to assess immunotherapy response in two risk groups. Finally, the expression of m6A-Ferr-related prognostic genes was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: In total, 6 model genes (HSD17B11, VEGFA, CXCL2, ASNS, FABP4, and GPX2) were obtained to construct the risk model. The nomogram was established based on the independent prognostic factors for predicting survival of COAD. TIDE assessed that the high-risk group suffered from greater immune resistance. Ultimately, the experimental results confirmed that the expression trends of all model genes were consistent among data from public database. Conclusions: In this study, m6A-Ferr-related prognostic model for COAD was constructed using transcriptome data and clinical data of COAD in public database, which may have potential immunotherapy and chemotherapy guidance implications.

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Background: Acid-sensing ion channel 1a (ASIC1a) plays a critical role in physiological and pathological processes. To further elucidate the biological functions of ASICs and their relationships with disease occurrence and development, it is advantageous to investigate and develop additional regulatory factors for ASICs. Methods: In this study, cation exchange chromatography was used to separate seven chromatographic components from Naja naja atra venom. Capillary electrophoresis was employed to detect that Ⅶ peak component containing a main protein Ⅶ-2, which could bind to ASIC1a. The analgesic effects of Ⅶ-2 protein were determined using hot plate methods, and ASIC1a expression in spinal cord tissue from rats with inflammatory pain was detected using western blot. Results: The purified Ⅶ-2 protein named Naja naja atra venom-Ⅶ-2 (NNAV-Ⅶ-2) was obtained by Sephadex G-50 gel filtration, which exhibited a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of 6.7 kD. Remarkably, the NNAV-Ⅶ-2 protein demonstrated a significant analgesic effect and downregulated ASIC1a expression in the spinal cord tissue of rats with inflammatory pain. Conclusions: The analgesic mechanism of the NNAV-Ⅶ-2 protein may be associated with its binding to ASIC1a, consequently downregulating ASIC1a expression in neural tissues.

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SPRED3 (Sprouty-related EVH1 domain containing 3) mutants are depicted in various cancers, however, nothing is known about its biofunction in thyroid cancer (THCA). Bioinformatic analyses were conducted to ascertain the level of SPRED3 expression in THCA tissues and its importance in the prognosis of THCA patients. Flag-SPRED3 plasmid and SPRED3-knockout vector were developed to overexpress or deplete the SPRED3 expression in THCA cells. The function of SPRED3 on THCA cell proliferation was examined using the colony formation assay and CCK8 assay. The effect of SPRED3 expression on the transcriptional activity of NF-κB was also examined using luciferase reporter assays. High SPRED3 expression was associated with unfavorable clinical outcomes, advanced tumor characteristics, and traditional molecular markers of papillary thyroid cancer in THCA patients. Genetic analysis revealed differences in mutation rates in key genes between SPRED3-high and SPRED3-low THCA cases. It is also revealed that SPRED3 influenced the immune microenvironment, with increased stromal and immune scores and altered immune cell infiltration. Functionally, SPRED3 overexpression enhanced THCA cell viability and colony formation, while its depletion reduced cell growth and proliferation. In vivo experiments in mice confirmed the inhibitory effect of SPRED3 depletion on tumor growth. Mechanically, we found that SPRED3 activated the NF-κB signaling. For the first time, we found that SPRED3 promotes THCA cell proliferation via the NF-κB signaling pathway. This finding may provide insight into SPRED3's prognostic potential in thyroid cancer and provide the rationale for SPRED3-targeted druggable interventions.

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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly metastatic potential and a heterogeneous tumor microenvironment. It exhibits limited sensitivity to conventional therapies, necessitating a deeper understanding of its pathogenesis. The role of the intratumoral microbiome in regulating cancer development in PDAC has been the subject of debate. Previous investigations into intra-tumor microbiomes have yielded uncertain results due to sample size limitations and insufficient decontamination procedures. Further research is imperative to elucidate the intricate relationship between intra-tumor microbiomes, the immune landscape of PDAC, and overall prognosis. RESULTS: Our findings revealed that the intratumor microbiota in PDAC tissue exhibited lower diversity and distinct communities compared to non-tumor tissues. The top microorganisms distinguishing between patients with long or short survival were used to construct the risk signature. We found that Stenotrophomonas is implicated in short survival of PDAC patients, while Neorickettia and Mediterraneibacter are correlated with long survival. This microbiome-based PDAC subtyping, grounded in prognosis-related signatures, exhibited significant correlations with distinct clinical prognoses and immune microenvironments. Microorganisms associated with negative prognoses were linked to pro-tumor immune activation, while those associated with positive prognoses were linked to anti-tumor immune response activation and a more favorable prognosis. CONCLUSIONS: Our PDAC subtyping approach, based on a microbiome-derived prognostic risk signature, unveiled compelling associations between the PDAC microbiota and disparities in both clinical prognosis and the tumor microenvironment. These findings suggest that microbiota may serve as a promising biomarker for predicting the prognosis of PDAC.

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BACKGROUND: Large language models like GPT-3.5-turbo and GPT-4 hold promise for healthcare professionals, but they may inadvertently inherit biases during their training, potentially affecting their utility in medical applications. Despite few attempts in the past, the precise impact and extent of these biases remain uncertain. METHODS: We use LLMs to generate responses that predict hospitalization, cost and mortality based on real patient cases. We manually examine the generated responses to identify biases. RESULTS: We find that these models tend to project higher costs and longer hospitalizations for white populations and exhibit optimistic views in challenging medical scenarios with much higher survival rates. These biases, which mirror real-world healthcare disparities, are evident in the generation of patient backgrounds, the association of specific diseases with certain racial and ethnic groups, and disparities in treatment recommendations, etc. CONCLUSIONS: Our findings underscore the critical need for future research to address and mitigate biases in language models, especially in critical healthcare applications, to ensure fair and accurate outcomes for all patients.

Large language models (LLMs) such as GPT-3.5-turbo and GPT-4 are advanced computer programs that can understand and generate text. They have the potential to help doctors and other healthcare professionals to improve patient care. We looked at how well these models predicted the cost of healthcare for patients, and the chances of them being hospitalized or dying. We found that these models often projected higher costs and longer hospital stays for white people than people from other racial or ethnicity groups. These biases mirror the disparities in real-world healthcare. Our findings show the need for more research to ensure that inappropriate biases are removed from LLMs to ensure fair and accurate healthcare predictions of possible outcomes for all patients. This will help ensure that these tools can be used effectively to improve healthcare for everyone.

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Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

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Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating pre-leukemic clones, here we used a conditional Runx1::Runx1t1 knock-in mouse model to evaluate pre-leukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these pre-leukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.

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Aim: The aim of this study was to develop a validated nomogram to predict the risk of postoperative complications in colorectal cancer (CRC) patients by analyzing the factors that contribute to these complications. Methods: We retrospectively collected clinical information on patients who underwent CRC surgery at a single clinical center from January 2021 to December 2021. Univariate and multivariate logistic regression analysis to identify independent risk factors for postoperative complications and to develop a predictive model. A receiver operating characteristic (ROC) curve was used to calculate the area under the curve (AUC) to assess the predicted probability. Calibration curve was drawn to compare the predicted probability of the nomogram with the actual probability, and decision curve analysis (DCA) was employed to evaluate the clinical utility of the nomogram. Results: A total of 190 CRC patients were included in this study. We retrospectively collected baseline information, clinical information, surgical information, and nutrition-related indicators for all patients. Through multivariate logistic regression analysis, preoperative albumin (p = 0.041, OR = 0.906, 95% CI = 0.824-0.996), surgical time (p = 0.009, OR = 1.006, 95% CI = 1.001-1.010), waistline (p = 0.049, OR = 1.011, 95% CI = 1.002-1.020) and phase angle (PA) (p = 0.022, OR = 0.615, 95% CI = 0.405-0.933) were identified as independent risk factors for postoperative complications in CRC, and a nomogram prediction model was established using the above four variables. The AUC of 0.706 for the ROC plot and the high agreement between predicted and actual probabilities in the calibration curves suggested that the prediction model has good predictive power. The DCA also confirmed the good clinical performance of the nomogram. Conclusion: This study developed a nomogram to predict the risk of postoperative complications in CRC patients, providing surgeons with a reliable reference to personalized patient management in the perioperative period and preoperative nutritional interventions.

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The spin-orbit-assisted Mott insulator α-RuCl3 is proximate to the coveted quantum spin liquid (QSL) predicted by the Kitaev model. In the search for the pure Kitaev QSL, reducing the dimensionality of this frustrated magnet by exfoliation has been proposed as a way to enhance magnetic fluctuations and Kitaev interactions. Here, we perform angle-dependent tunneling magnetoresistance (TMR) measurements on ultrathin α-RuCl3 crystals with various layer numbers to probe their magnetic, electronic, and crystal structures. We observe a giant change in resistance, as large as ∼2500%, when the magnetic field rotates either within or out of the α-RuCl3 plane, a manifestation of the strongly anisotropic spin interactions in this material. In combination with scanning transmission electron microscopy, this tunneling anisotropic magnetoresistance (TAMR) reveals that few-layer α-RuCl3 crystals remain in the high-temperature monoclinic phase at low temperatures. It also shows the presence of a zigzag antiferromagnetic order below the critical temperature TN ≃ 14 K, which is twice the one typically observed in bulk samples with rhombohedral stacking. Our work offers valuable insights into the relation between the stacking order and magnetic properties of this material, which helps lay the groundwork for creating and electrically probing exotic magnetic phases such as QSLs via van der Waals engineering.

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Seasonal influenza is a severe disease that significantly impacts public health, causing millions of infections and hundreds of thousands of deaths each year. Seasonal influenza viruses, particularly the H3N2 subtype, exhibit high antigenic variability, often leading to mismatch between vaccine strains and circulating strains. Therefore, rapidly assessing the alignment between existing seasonal influenza vaccine and circulating strains is crucial for enhancing vaccine efficacy. This study, based on a pseudovirus platform, evaluated the match between current influenza H3N2 vaccine strains and circulating strains through cross-neutralization assays using clinical human immune sera against globally circulating influenza virus strains. The research results show that although mutations are present in the circulating strains, the current H3N2 vaccine strain still imparting effective protection, providing a scientific basis for encouraging influenza vaccination. This research methodology can be sustainably applied for the neutralization potency assessment of subsequent circulating strains, establishing a persistent methodological framework.

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Hyperuricemia (HUA) is a metabolic disorder characterized by an imbalance in uric acid production and excretion, frequently leading to gout and various chronic conditions. Novel bioactive compounds offer effective alternatives for managing HUA, reducing side effects of traditional medications. Recent studies have highlighted the therapeutic potential of protein hydrolysates and peptides in managing HUA. This review focuses on preparing and applying protein hydrolysates to treat HUA and explores peptides for xanthine oxidase inhibition. Particularly, we discuss their origins, enzymatic approaches, and mechanisms of action in detail. The review provides an updated understanding of HUA pathogenesis, current pharmacological interventions, and methodologies for the preparation, purification, identification, and assessment of these compounds. Furthermore, to explore the application of protein hydrolysates and peptides in the food industry, we also address challenges and propose solutions related to the safety, bitterness, oral delivery, and the integration of artificial intelligence in peptide discovery. Bridging traditional pharmacological approaches and innovative dietary interventions, this study paves the way for future research and development in HUA management, contributing to the utilization of proteins from different food sources. In conclusion, protein hydrolysates and peptides show significant promise as safe agents and dietary interventions for preventing and treating HUA.

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The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

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Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ -10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3's role in EM pathogenesis.

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An operando EC-SERS strategy was successfully developed for monitoring the Volmer reaction based on dynamic collisions. Its feasibility and universality were verified, and it provided a promising approach for visualizing a localized surface reaction.

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Precise control of strength is of significant importance in upper limb functional rehabilitation. Understanding the neuro-muscular response in strength regulation can help optimize the rehabilitation prescriptions and facilitate the relative training process for recovery control. This study aimed to investigate the inherent characteristics of neural-muscular activity during dynamic hand strength adjustment. Four dynamic grip force tracking modes were set by manipulating different magnitude and speed of force variations, and thirteen healthy young individuals took participation in the experiment. Electroencephalography were recorded in the contralateral sensorimotor cortex area, as well as the electromyography from the first dorsal interosseous muscle were collected synchronously. The metrics of the Event-related desynchronization, the electromyography stability index, and the force variation, were used to represent the corresponding cortical neural responses, muscle contraction activities, and the level of strength regulation, respectively; and further neuro-muscular coupling between the sensorimotor cortex and the first dorsal interosseous muscle was investigated by transfer entropy analysis. The results indicated a strong relationship that the increase of force regulation demand would result in a force variation increase as well as a stability reduction in muscle motor unit output. Meanwhile, the intensity of neural response increased in both the α and ß frequency bands. As the force regulation demand increased, the strength of bidirectional transfer entropy showed a clear shift from ß to the γ frequency band, which facilitate rapid integration of dynamic strength compensation to adapt to motor task changes.

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