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Abstract The role of the compromised immune microenvironment, including immune checkpoints, in myelodysplastic syndromes (MDS) has been identified as critical This study aimed to investigate the expression patterns of immune checkpoints, particularly soluble PD-1/PD-L1 (sPD-1/sPD-L1) as well as PD-1 on effector T cell subsets, and assess their prognostic value and potential regulatory roles in MDS. 161 MDS patients were enrolled, including 129 patients were primarily diagnosed with de novo MDS, together with 59 MDS patients who underwent hypomethylating agents (HMAs) therapy. Plasma sPD-L1 level was elevated in newly diagnosed MDS patients, which was also found to be associated with MDS disease progression that further increase in higher IPSS-R score group. Patients with increased sPD-L1 expression at diagnosis exhibited notably poorer overall survival, and multivariate Cox analysis indicated that elevated sPD-L1 was an independent risk factor. Furthermore, the levels of multiple cytokines and membrane-bound PD-1 on T cells were found to correlate with sPD-1/sPD-L1 levels in plasma. Importantly, we also found sPD-L1 levels significantly increased in MDS patients who showed progression of disease following HMAs therapy. In conclusion, we found elevated plasma sPD-L1 levels in MDS patients are associated with disease progression and poorer overall survival. This study showed that sPD-L1 is a potential biomarker for prognosis and a target for immunotherapy in MDS.

Lithium-ion batteries (LIBs) are widely used as important energy storage and energy supply devices. The porous design and heteroatomization modification of carbon-based anode materials are crucial for achieving high-capacity and reversible energy storage in LIBs. Sol-gel method and pyrolysis treatment were used to obtain silica/silver composite particles used as templates. Polyphosphazene-coated silica/silver composite composite carbon materials (SiO2/Ag@PZS-C) were synthesized through in-situ self-assembly and carbonization of polyphosphazene. The electrochemical behavior and lithium storage mechanism of SiO2/Ag@PZS-C was also studied. The results reveal that the composite exhibited high specific capacity, stable cycling and superior rate performance. The double modification of silver nanoparticles and polyphosphazene carbon significantly improves the conductivity of silica and reduces the volume change. Moreover, the carbon shell of polyphosphazene facilitated the formation of a stable solid electrolyte interface film (SEI), preventing direct contact between the active material and the electrolyte, thereby substantially enhancing lithium storage performance.

Abstract The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

To reduce the content of free gossypol in cottonseed meal and improve the quality of cottonseed protein, this study used a two-stage fermentation method to treat cottonseed meal. Enterococcus faecalis (E) was first added, and then Aspergillus oryzae (M1) was added for staged fermentation. The fermentation conditions of mixed were optimized by single factor and orthogonal experiments. The results showed that when the inoculation amount of Enterococcus faecium was 1.5%, the fermentation temperature was 37 ℃, the fermentation time was 24 h, the inoculation amount of Aspergillus oryzae was 1.5%, the fermentation temperature was 30 ℃, the fermentation time 96 h, and the initial fermentation moisture of cottonseed meal was 50%, the crude protein content of cottonseed meal increased from 39.6% to 49.64%, the acid-soluble protein content increased from 4.79% to 36.58%, and the free gossypol content decreased from 1370 mg/kg to 45.32 mg/kg, and the detoxification rate reached 96.7%. The results would provide a scientific basis for the high-value utilization of cottonseed meal.

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

ObjectiveTo investigate the clinical manifestations, molecular genetics and gonadal pathology characteristics of patients with disorders of sex development (DSD), and to summarize the clinical experience of identifying rare diseases from common symptoms.MethodsThe clinical data of 416 patients with DSD diagnosed and treated in the multidisciplinary center of DSD of Guangzhou Women and Children′s Medical Center from May 2018 to August 2023 were retrospectively analyzed, summarized and discussed.ResultsAccording to chromosome karyotype, 416 cases of DSD were classified into three types: 92 cases(22.1%) of abnormal sex chromosome karyotype, 285 cases(68.5%) of 46, XY karyotype and 39 cases(9.4%) of 46, XX karyotype. Among the 92 patients with abnormal sex chromosome karyotype, 59 cases were raised as males, 18 cases (30.5%) complained of short penis with hypospadias and cryptorchidism. The most common karyotype was 45, X/46, XY(58 cases, 63.0%).Among the 285 patients with 46, XY karyotype, 238 cases were raised as males, and 63 cases(26.5%)complained of short penis and hypospadias; 47 cases were raised as females, and 13 cases(27.7%) complained of inguinal mass. A total of 216 patients with 46, XY karyotype were subjected to whole exome gene detection, and 155 cases(71.8%) were found to have molecular pathogenesis with the clinical phenotype. Among the 39 patients with 46, XX karyotype, 19 cases were raised as males, and 8 cases(42.1%) complained of short penis and hypospadias. In the 18 cases of gonad biopsy, 17 cases showed testicular tissue in gonads. Whole exome sequencing was performed in 14 cases. NR5A1 gene heterozygous mutation, SRY gene mutation and SOX3 gene mutation were found in 2 cases, respectively(14.3%). Twenty cases were raised as females, and 14 cases(70.0%) complained of clitoral hypertrophy. Gonad biopsy was performed in 8 cases, with 7 cases of ovotestis(87.5%) and 1 case of NR5A1 gene heterozygous mutation(14.3%).ConclusionsThe etiologies of DSD are complex and diverse, and the clinical manifestations are various, which can be manifested as hypospadias, micropenis, cryptorchidism and other common symptoms of the urinary system. Different etiologies have different treatment options. Therefore, chromosome karyotype, molecular genetic testing and gonadal pathology can be used to clarify the cause of disease, especially for rare diseases, improve the detection rate, reduce the rate of missed diagnosis, and ensure reasonable treatment, especially sex selection.

Abstract Background Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. Methods We collected a prospective study cohort of 110 stage I–II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. Results Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942–0.982) in the study cohort, 0.972 (95% CI: 0.953–0.992) in the first validation cohort and 0.937 (95% CI: 0.890–0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. Conclusions We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. Trial registration This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

The title compound, tetraethylammonium triazidotri-μ3-sulfido-[μ3-(trimethylsilyl)azanediido][tris(3,5-dimethylpyrazol-1-yl)hydroborato]triiron(+2.33)molybdenum(IV), (C8H20N)[Fe3MoS3(C15H22BN6)(C3H9NSi)(N3)3] or (Et4N)[(Tp*)MoFe3S3(μ3-NSiMe3)(N3)3] [Tp* = tris(3,5-dimethylpyrazol-1-yl)hydroborate(1−)], crystallizes as needle-like black crystals in space group P\overline{1}. In this cluster, the Mo site is in a distorted octahedral coordination model, coordinating three N atoms on the Tp* ligand and three μ3-bridging S atoms in the core. The Fe sites are in a distorted tetrahedral coordination model, coordinating two μ3-bridging S atoms, one μ3-bridging N atom from Me3SiN2−, and another N atom on the terminal azide ligand. This type of heterometallic and heteroleptic single cubane cluster represents a typical example within the Mo–Fe–S cluster family, which may be a good reference for understanding the structure and function of the nitrogenase FeMo cofactor. The residual electron density of disordered solvent molecules in the void space could not be reasonably modeled, thus the SQUEEZE [Spek (2015). Acta Cryst. C71, 9–18] function was applied. The solvent contribution is not included in the reported molecular weight and density.

Abstract Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of major histocompatibility complexes (MHC) class I molecule and elevated programmed death ligand 1 (PDL1) in MM cells, along with an enriched population of regulatory T cells (Tregs). To investigate Treg's influence on MM cells, we established a co-culture system using Tregs from MM patients and the MM cell lines (MM.1S and SK-MM-1) in vitro and assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo. In vitro, Tregs induced transforming growth factor beta-1 (TGF-β1) production, downregulated MHC I members, and increased PDL1 expression in MM cells. Treg-derived TGF-β1 suppressed the cGAS-STING pathway, contributing to the loss of MHC I molecule expression and PDL1 upregulation. Correspondingly, neutralizing TGF-β1 or activating the cGAS-STING pathway restored MHC I and PDL1 expression, effectively countering the pro-tumorigenic effect of Tregs on MM cells in vivo. These data elucidated how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells, potentially providing therapeutic strategies, such as neutralizing TGF-β1 or activating the cGAS-STING pathway, to address the immune escape and immunosuppressive dynamics in MM.

Abstract The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

Abstract Wildfires, as an environmental filter, are pivotal ecological disturbances that reshape plant communities and soil dynamics, playing a crucial role in regulating biogeographic patterns and ecosystem services. In this study, we aim to explore the effects of wildfires on forest ecosystems, specifically focusing on the plant-soil feedback mechanisms within the northeastern margin of the Qinghai-Tibet Plateau (QTP). Utilizing Partial Least Squares Path Modeling (PLS-PM), we investigated the interrelationships among soil physicochemical properties, enzyme activities, species diversity, and community stability at varying post-fire recovery stages (5, 15, and 23 years). Results indicated that in the early recovery stages, rapid changes in soil properties such as decreased pH (p

Purpose – Adopting an institutional view of entrepreneurship, this study aims to explore the potential mediating role of entrepreneurial self-efficacy (ESE) in the relationship between subjective norms and the entrepreneurial intentions of Malaysian students. Additionally, social role theory (SRT) was used to examine whether gender acts as a boundary condition in the proposed relationship. Design/methodology/approach – Empirical evidence was based on responses from 220 final-year students registered from a final-year entrepreneurship module at a private university in Malaysia. The hypothesised relationships were tested using Model 7 of the PROCESS macro. Findings – The findings indicated that subjective norms had a weak but positive effect on the entrepreneurial intentions of Malaysian students. Moreover, ESE was found to mediate the relationship between subjective norms and entrepreneurial intentions. However, contrary to theoretical expectations, gender did not act as a boundary condition in the proposed mediation relationship. Originality/value – By incorporating SRT with institutional theory, this study sought to address a knowledge gap in the existing literature by investigating and empirically exploring the moderating influence of gender on the mediating effect of ESE in the relationship between subjective norms and entrepreneurial intentions.

Objective To identify the factors influencing postoperative ureteral stenosis following holmium laser lithotripsy. Methods A retrospective study was conducted of 106 patients who underwent ureteroscopic holmium laser lithotripsy. The effects of variables including stone location, stone size, the duration of surgery, water intake, disease duration, and stone-associated polyps were investigated. Results Logistic regression analysis revealed significant associations of ureteral stenosis with stone location, stone size, duration of surgery, water intake, disease duration, and stone-associated polyps. Patients with proximal stones, with large stones, who underwent long surgical procedures, who drank a large amount of water, who had long-term disease, and who had stone-related polyps were more likely to develop postoperative ureteral stenosis. Conclusion Significant perioperative complications of holmium laser lithotripsy are associated with prolonged disease, large ureteral stones, long incarceration periods, and the presence of polyps. Surgeons should consider these risk factors during the preoperative evaluation of patients and surgical planning to minimize the risk of postoperative ureteral stenosis.

ABSTRACT Purpose: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. Methods: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. Results: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. Conclusions: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.

Purpose – Self-assessment is regarded as a complex metacognitive process by scholars. Nevertheless, in the context of English as a Second Language (ESL) speaking, self-assessment practices often rely on assessment criteria and teacher commentaries. However, speaking involves spontaneous expression with limited access to external standards. Therefore, this case study aims to explore the metacognitive strategies that proficient ESL students use during selfassessment in spontaneous speech production contexts. Methodology – Three participants, purposefully selected, participated in two spontaneous group discussions recorded on video. Instances of participants’ dysfluency served as prompts in stimulated recall interviews, complemented by video recordings to validate participants’ responses. The thematic analysis of interview data utilised a conceptual framework integrating O’Malley and Chamot’s (1990) metacognitive strategies and Kormos’ (2006) speech production model. Findings – The analysis revealed that participants employed three key metacognitive strategies – organisational planning, selective attention, and self-monitoring to self-assess their spontaneous speech. Feedback sources, such as their proficiency in the second language (L2) and contextual factors, influenced the application and effectiveness of these strategies during self-assessment (SA). Significance – This study offers insights into how proficient ESL students self-assess their spontaneous speech production, leveraging their available resources. In addition, this study identifies speech challenges the participants encountered and how they applied metacognitive strategies to address them.

Introduction Cardiorespiratory fitness (CRF) in young adulthood is a determinant of chronic disease risk. To better understand whether CRF might also behave as a modifiable risk factor, we examined the associations between longitudinal changes in 2.4 km run times and health outcomes in a cohort of healthy young men.Methods Our dataset comprised individual run times and health outcomes captured in four national registries. Cox proportional hazards models were used to examine the association between baseline run times and relative hazards of first major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Relative hazards associated with longitudinal change in run times were estimated using models that were adjusted for run-time at baseline.Results The study sample comprised 148 825 healthy men ages 18–34 years who had undergone at least two routine fitness tests that were 5–9 years apart. During 1 294 778 person-years of follow-up, we observed 1275 first MACE and 764 ACM events occurring at mean ages of 43.2 (SD 6.0) years and 39.2 (SD 6.6) years, respectively. A 1% increase in run-time per annum was associated with a 1.13 (95% CI 1.10 to 1.16) times greater hazard of first MACE and a 1.06 (95% CI 1.02 to 1.10) times greater hazard of ACM. The association between longitudinal change in run times and first MACE was preserved in sensitivity analyses using models adjusted for body mass index at baseline.Conclusion Among men under the age of 35 years, longitudinal change in run times was associated with the risk of cardiovascular disease two decades onwards.

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), the last member of the proprotein convertase family, functions as a classic regulator of low-density lipoprotein (LDL) by interacting with low-density lipoprotein receptor (LDLR). Recent studies have shown that PCSK9 can affect the occurrence and development of tumors and can be used as a novel therapeutic target. However, a comprehensive pan-cancer analysis of PCSK9 has yet to be conducted. Methods The potential oncogenic effects of PCSK9 in 33 types of tumors were explored based on the datasets of The Cancer Genome Atlas (TCGA) dataset. In addition, the immune regulatory role of PCSK9 inhibition was evaluated via in vitro cell coculture and the tumor-bearing mouse model. Finally, the antitumor efficacy of targeted PCSK9 combined with OVA-II vaccines was verified. Results Our results indicated that PCSK9 was highly expressed in most tumor types and was significantly correlated with late disease stage and poor prognosis. Additionally, PCSK9 may regulate the tumor immune matrix score, immune cell infiltration, immune checkpoint expression, and major histocompatibility complex expression. Notably, we first found that dendritic cell (DC) infiltration and major histocompatibility complex-II (MHC-II) expression could be upregulated by PCSK9 inhibition and improve CD8+ T cell activation in the tumor immune microenvironment, thereby achieving potent tumor control. Combining PCSK9 inhibitors could enhance the efficacies of OVA-II tumor vaccine monotherapy. Conclusions Conclusively, our pan-cancer analysis provided a more comprehensive understanding of the oncogenic and immunoregulatory roles of PCSK9 and demonstrated that targeting PCSK9 could increase the efficacy of long peptide vaccines by upregulating DC infiltration and MHC-II expression on the surface of tumor cells. Summary This study reveals the critical oncogenic and immunoregulatory roles of PCSK9 in various tumors and shows the promise of PCSK9 as a potent immunotherapy target.

Abstract This study aims to explore the factors that affect the prognosis of patients with insomnia who are treated with mobile cognitive behavioral therapy. Patients with insomnia who visited the sleep disorders clinic were selected and completed mobile Cognitive behavioral therapy. Patients completed at least three evaluations (including baseline, monthly evaluations thereafter, and a final evaluation at the end of one year) and responded well to treatment within one year of follow-up. Insomnia, anxiety, and depression symptoms were evaluated using the Pittsburgh Sleep Quality Index (PSQI), the Generalized Anxiety Disorder 7-item (GAD-7) scale, and the 9-item Patient Health Questionnaire (PHQ-9), respectively. Treatment prognosis including relapse, recurrence, and remission group. These 339 patients were divided into three groups: 160 patients who remission, 100 patients who relapsed, and 79 patients who experienced recurrence after remission. Demographic characteristics of the 339 patients showed no significant difference in gender between the three groups (P = 0.978). However, significant differences were found in age (P = 0.006) and onset time (P = 0.000) among the three groups. The remission group had a higher average age than the recurrence group and the relapse group, and the onset time was slower than the other two groups. Multivariate logistic regression analysis showed that age and delayed onset time were protective factors for good treatment prognosis, while low educational level and high GAD-7 scores were independent risk factors for poor prognosis. There are many factors that affect the treatment prognosis of insomnia. Age, low educational level, high GAD-7 scores, and delayed onset time can be used to predict the prognosis of insomnia treatment.

Abstract SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and protection afforded by previous infection and vaccination, are limited. Here we studied ~45,000 reinfections from the UK’s national COVID-19 Infection Survey and quantified the risk of reinfection in multiple waves, including those driven by BA.1, BA.2, BA.4/5, and BQ.1/CH.1.1/XBB.1.5 variants. Reinfections were associated with lower viral load and lower percentages of self-reporting symptoms compared with first infections. Across multiple Omicron waves, estimated protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Estimated protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year). Those 14–180 days after receiving their most recent vaccination had a lower risk of reinfection than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30–45 years, and with either low or high viral load in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; both viral evolution and waning immunity are independently associated with reinfection.

Protection, dispersion and delivery of the functional components can implement in the emulsion-encapsulating systems. Among the stabilizers of the emulsion, specific structure of the cellulose may improve the stability of the system, and supplying the utilization of the bioactive substances on encapsulation and release. Therefore, the recent advances on stabilizing mechanism, cellulosic materials, properties of bioactive substances and factors affecting on the release of cellulosic emulsion-encapsulating systems are summarized in this review. In addition, the paper focuses on the release process and regulated mechanism of cellulose, which shows high length-diameter ratio and mechanical strength in the emulsion-delivery system of bioactive substances, and providing reference for the development of the food-grade delivery system. Studies indicates that cellulose-stabilized emulsion can improve the dispersion and oxidation stability of the bioactive substances, while controlling the release and improving the bioavailability of the functional factors. However, there is still vast research space for its safety evaluation in the food system, and related toxicological experiments urgently need to be carried out.

ABSTRACTGut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Forest fires play a pivotal role in influencing ecosystem evolution, exerting a profound impact on plant diversity and community stability. Understanding post-fire recovery strategies holds significant scientific importance for the ecological succession and restoration of forest ecosystems. This study utilized Partial Least Squares Path Modeling (PLS-PM) to investigate dynamic relationships among plant species diversity, phylogenetic diversity, soil properties, and community stability during various recovery stages (5-year, 15-year, and 23-year) following wildfires on the northeastern margin of the Qinghai-Tibet Plateau. The findings revealed: (1) Over time, species richness significantly decreased (p< 0.05 or p< 0.01), while species diversity and dominance increased, resulting in uniform species distribution. Community stability progressively improved, with increased species compositional similarity. (2) Throughout succession, phylogenetic diversity (PD) significantly decreased (p< 0.01), accompanied by rising Mean Pairwise Distance (MPD) and Mean Nearest Taxon Distance (MNTD). Net Relatedness Index (NRI) shifted from positive to negative, indicating an increasing aggregation and dominance of plants with similar evolutionary traits in burned areas. Early succession witnessed simultaneous environmental filtering and competitive exclusion, shifting predominantly to competitive exclusion in later stages. (3) PLS-PM revealed that in the early recovery stage, soil properties mainly affected community stability, while species diversity metamorphosed into the primary factor in the mid-to-late stages. In summary, this study showed that plant diversity and phylogenetic variation were successful in revealing changes in community structure during the succession process. Soil characteristics functioned as selective barriers for plant communities during succession, and community stability underwent a multi-faceted and dynamic process. The soil-plant dynamic feedback continuously enhanced soil conditions and community vegetation structure thereby augmenting stability. Post-fire vegetation gradually transitioned towards the original native state, demonstrating inherent ecological self-recovery capabilities in the absence of secondary disturbances.

ObjectiveSeveral studies have investigated the correlation between blood lipids and homocysteine, but no clear conclusions have been defined yet. Therefore, we utilized data from National Health and Nutrition Examination Survey (NHANES) to explore the correlation between serum homocysteine (Hcy) levels and hyperlipidemia, which is determined by the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). We believe this study can provide a scientific basis for the prevention and treatment of lipid abnormalities.MethodsThe data used in this study were sourced from NHANES 1999–2006, linked with National Death Index mortality data from January 1999 to December 2019. We employed logistic regression to assess the associations between Hcy levels and the presence of hyperlipidemia. Additionally, survival analysis using Kaplan-Meier estimate and Cox proportional hazards regression model was conducted to evaluate the associations between Hcy levels and all-cause mortality in the hyperlipidemia population.Results(1) A total of 13,661 subjects were included in the study. There were statistically significant differences in Hcy levels across different groups based on gender, age, race, marital status, education level, hypertension status, diabetes status, and Body Mass Index (BMI) (P

Abstract T‐cell receptor (TCR) engineered T‐cell therapy, unlike chimeric antigen receptor T‐cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR‐T‐cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel “universal” TCR‐T “artificial antigen expression” technique that involves the delivery of the antigen to tumor cells using DSPE‐PEG‐NY‐ESO‐1157‐165 liposomes (NY‐ESO‐1 Lips) to express TCR‐T‐cell‐specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor‐specific cytotoxic T‐cell immune response. NY‐ESO‐1 TCR‐T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD‐1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY‐ESO‐1 Lips “cursed” tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR‐T in solid tumor treatment.

Abstract Purpose To characterize the phenotype and genotype of a Chinese family with autosomal‐dominant retinitis pigmentosa (RP) accompanied by iris coloboma. Methods The proband, a 34‐year‐old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full‐field electroretinography (ffERG). Genetic analyses were conducted through whole‐exome sequencing (WES) to screen for variations. Results Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR‐204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. Conclusions In this third independent and the first Asian family, the existence of a miR‐204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR‐204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal‐dominant pattern, including in Chinese patients, miR‐204 aberrations should be considered.

Abstract Background Chimeric antigen receptor T (CAR‐T) cell therapy has emerged as a potent treatment for relapsed or refractory multiple myeloma, demonstrating significant clinical efficacy. Despite these advances, treatment‐related toxicities, particularly infections, pose a significant challenge to patient safety. Methods This review synthesizes current knowledge on the mechanisms underlying post‐CAR‐T therapy infections, focusing on the interplay between immune dysfunction, host factors, and treatment‐induced toxicity. It provides a comprehensive analysis of the temporal and individual variability in infection characteristics and the confounding clinical presentation of cytokine release syndrome. Results The review identifies that patients receiving CAR‐T cells are at increased risk of concurrent infections due to the heterogeneity in infection characteristics across different time periods, individuals, and patient groups. It highlights the diagnostic and therapeutic complexities introduced by the overlapping symptoms of infection and cytokine release syndrome. Conclusion To enhance the infection control post‐CAR‐T therapy, this review proposes preventive strategies tailored to the early and long‐term management of patients. It underscores the need for a nuanced understanding of infection mechanisms and the importance of personalized prevention plans to improve clinical outcomes in multiple myeloma treatment.

Abstract Background Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR‐T) cell therapy. However, a portion of MM patients do not respond to CAR‐T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR‐34a on the immunosuppressive polarization of macrophages obtained from MM patients. Methods The levels of miR‐34a and TLR9 (Toll‐like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co‐culture experiments were conducted to evaluate the immunomodulatory impact of MM‐associated macrophages on CAR‐T cells. Results There was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR‐34a in MM‐associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co‐culture system and an animal model, MM‐associated macrophages suppressed the activity and tumoricidal effect of CAR‐T cells in a miR‐34a‐dependent manner. Conclusion The findings imply that targeting the macrophage miR‐34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR‐T therapy in MM patients.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Anthocyanin accumulation is acknowledged as a phenotypic indicator of phosphate (Pi) starvation. However, negative regulators of this process and their molecular mechanisms remain largely unexplored. In this study, we demonstrate that WRKY33 acts as a negative regulator of phosphorus-status-dependent anthocyanin biosynthesis. WRKY33 regulates the expression of the gene encoding dihydroflavonol 4-reductase (DFR), a rate-limiting enzyme in anthocyanin production, both directly and indirectly. WRKY33 binds directly to the DFR promoter to repress its expression and also interferes with the MBW complex through interacting with PAP1 to indirectly influence DFR transcriptional activation. Under −Pi conditions, PHR1 interacts with WRKY33, and the protein level of WRKY33 decreases; the repression of DFR expression by WRKY33 is thus attenuated, leading to anthocyanin accumulation in Arabidopsis. Further genetic and biochemical assays suggest that PHR1 is also involved in regulating factors that affect WRKY33 protein turnover. Taken together, our findings reveal that Pi starvation represses WRKY33, a repressor of anthocyanin biosynthesis, to finely tune anthocyanin biosynthesis. This “double-negative logic” regulation of phosphorus-status-dependent anthocyanin biosynthesis is required for the maintenance of plant metabolic homeostasis during acclimation to Pi starvation.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Under the condition of a small time scale (e.g. second), distributed photovoltaic (PV) power generation output has the problems of strongly fluctuating and difficult to accurately simulate. It affects the control strategy and operation mode of hybrid energy systems. To address this problem, a data-driven small-scale distributed PV plant power output model on a 1-second time scale is proposed for the generation of second-by-second PV power output scenarios in hybrid energy systems. Firstly, this work analyzes the characteristics of PV power output at the 1-second time scale based on the probability distribution of power output fluctuations. Secondly, an index system that characterizes the PV power output fluctuation characteristics at the 1-second time scale is constructed. Then, using the data-driven method, a BP neural network model is constructed to simulate the PV power output at the 1-second time scale. Finally, a simulation is performed using the measured data from the PV plant. The findings demonstrate that compared to PV power output models in seconds based on Pearson systematic random numbers: (1) The correlation coefficient (r) of the proposed model is more than 0.8, in a higher degree of fit; (2) The root mean square error (RMSE) of the proposed model achieves 0.005, generally representing a 37.12% reduction. Overall, both the time scale and model accuracy of this model have deep potential value in PV power output modeling and system regulation.

As a new connected training of undergraduates and postgraduates model for medical students,the integration of "5 + 3" aims to cultivate advanced medical talents with dual tracks in a short time and brings new challenges to medical education.The supervisor responsibility system runs through the whole stage of medical students is more conducive to complete the smooth transition between the tutor responsibility system and balance clinical and scientific research,so as to improve the teaching quality and achieve the teaching goal.By observing the teaching situation of the college after introducing the tutorial system for undergraduate students,this paper expounds the effects and existing problems,and further designs and considers the reform practice of the supervisor responsibility system in the transitional stage and postgraduate stage.

Extracting buildings from high-resolution remote sensing imagery (HRSI) is of great significance to emergency management, land resource utilization, and analysis, as well as city planning and construction. However, due to the complex backgrounds and diverse appearances and different sizes of buildings in HRSI, most existing methods for automatic building extraction are difficult to obtain strong building feature representation from low-level and high-level features. Furthermore, existing research mainly focused on regional accuracy, whereas less attention was paid to the description of building boundaries. In this article, MSB-Net, an end-to-end neural network, is proposed to address these issues. A multiscale feature fusion module (MSFFM) is designed to capture and fuse multiscale features. A local branch (LB) constructed by the MSFFM and position attention, is used to obtain long range of context information between different positions and extract the essential features of buildings (e.g., shapes, edges) from low-level features. And a global branch (GB) is designed to use the MSFFM and channel attention to enhance high-level features. Therefore, our method can not only obtain information on building-related attribute categories, but also capture the rich context information in channel dimensions. The boundary enhancement and completion module take the output of the GB and LB as input to search for the missing parts and details of buildings to improve the segmentation accuracy and boundary quality. Our method is tested on two public building datasets and achieves superior classification performance.

Abstract Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.

The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Abstract Phosphorus (P) and nitrogen (N) are essential macronutrients necessary for plant growth and development. OsPT4 is a high-affinity phosphate (Pi) transporter that has a positive impact on nutrient uptake and seed development. In this study, the expression patterns of different Pi transporter genes in germinating seeds were determined, and the relative expression of OsPT4 was induced in Pi-deficient seeds and gradually increased with the passage of germination time. The analysis of P, N, Pi, and amino acid concentrations in germinating seeds of OsPT4 mutants showed that the OsPT4 mutation caused P and N retention and a continuous reduction in multiple amino acid concentrations in germinating seeds. Transcriptome analysis and qRT-PCR results also indicated that the OsPT4 mutation inhibits the expression of genes related to P and N transportation and amino acid synthesis in germinating seeds. In addition, the paraffin section and TUNEL assay of OsPT4 mutant germinating seeds suggests that OsPT4 mutation causes programmed cell death (PCD) delayed in the aleurone layer and inhibition of leaf outgrowth. Moreover, we also found that OsPT4 was ubiquitinated by OsAIRP2, which is a C3HC4-type RING E3 Ub ligase. Our studies illustrate that OsPT4 plays a crucial role in P and N collaborative translocation and consumption in germinating seeds. It also provides a theoretical basis for the molecules and physiological mechanisms of P and N cross-talk under suppressed Pi uptake conditions.

Abstract Background Xenopus has served as a valuable model system for biomedical research over the past decades. Notably, ADAR was first detected in frog oocytes and embryos as an activity that unwinds RNA duplexes. However, the scope of A-to-I RNA editing by the ADAR enzymes in Xenopus remains underexplored. Results Here, we identify millions of editing events in Xenopus with high accuracy and systematically map the editome across developmental stages, adult organs, and species. We report diverse spatiotemporal patterns of editing with deamination activity highest in early embryogenesis before zygotic genome activation and in the ovary. Strikingly, editing events are poorly conserved across different Xenopus species. Even sites that are detected in both X. laevis and X. tropicalis show largely divergent editing levels or developmental profiles. In protein-coding regions, only a small subset of sites that are found mostly in the brain are well conserved between frogs and mammals. Conclusions Collectively, our work provides fresh insights into ADAR activity in vertebrates and suggest that species-specific editing may play a role in each animal’s unique physiology or environmental adaptation.

The study aimed to explore the optimal conditions for the extraction of polysaccharide from Elaeagnus angustifolia flower and its effect on probiotic proliferation in vitro. Polysaccharide was extracted from Elaeagnus angustifolia flower using hot water and ultrasonication. The effects of the material-liquid ratio, duration of ultrasonication, extraction time and extraction temperature on the polysaccharide yield were analyzed. The extraction conditions were optimized by response surface methodology, and the effects of different polysaccharide concentrations (0, 0.5%, 1.0%, 1.5%, 2.0%, and 3.0%) on the proliferation and acid production of three probiotics were compared. The results showed that the optimal extraction conditions of Elaeagnus angustifolia flower polysaccharide were as follows: Material-liquid ratio, 1:25 g/mL, duration of ultrasonication, 21 min, extraction temperature, 72℃, extraction time, 62 min. The polysaccharide yield was 12.45%±0.15%, which was close to the theoretical predicted yield (12.587%). The highest OD values of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium adolescentis were obtained at a polysaccharide mass concentration of 2%, being 1.23±0.01, 1.06±0.02, and 1.22±0.02, respectively, and the lowest pH values (5.17±0.04, 5.95±0.04, and 5.52±0.02, respectively). The growth of the three probiotics stabilized after the incubation time reached to 40 h. It indicated that Elaeagnus angustifolia flower polysaccharide promoted the proliferation and acid production of three probiotics. These findings indicate the potential of the polysaccharide from Elaeagnus angustifolia flower as a prebiotic and provide a theoretical basis for further research and the utilization of Elaeagnus angustifolia flower resources.

Microcystin-LR (MC-LR), frequently generated by cyanobacteria, has been demonstrated to raise the likelihood of liver disease. Few previous studies have explored the potential antagonist against MC-LR. Astaxanthin (ASX) has been shown to possess various beneficial effects in regulating lipid metabolism in the liver. However, whether ASX could alleviate MC-LR-induced hepatic lipid metabolic dysregulation is as yet unclear. In this work, the important roles and mechanisms of ASX in countering MC-LR-induced liver damage and lipid metabolic dysregulation were explored for the first time. The findings revealed that ASX not only prevented weight loss but also enhanced liver health after MC-LR exposure. Moreover, ASX effectively decreased triglyceride, total cholesterol, aspartate transaminase, and alanine aminotransferase contents in mice that were elevated by MC-LR. Histological observation showed that ASX significantly alleviated lipid accumulation and inflammation induced by MC-LR. Mechanically, ASX could significantly diminish the expression of genes responsible for lipid generation (Srebp-1c, Fasn, Cd36, Scd1, Dgat1, and Pparg), which probably reduced lipid accumulation induced by MC-LR. Analogously, MC-LR increased intracellular lipid deposition in THLE-3 cells, while ASX decreased these symptoms by down-regulating the expression of key genes in the lipid synthesis pathway. Our results implied that ASX played a crucial part in lipid synthesis and effectively alleviated MC-LR-induced lipid metabolism dysregulation. ASX might be developed as a novel protectant against hepatic impairment and lipid metabolic dysregulation associated with MC-LR. This study offers new insights for further management of MC-LR-related metabolic diseases.

Pyrabactin resistance 1-like (PYL) proteins are abscisic acid (ABA) receptors that play a crucial role in the plant’s response to adverse environmental conditions. However, as of yet, there is limited research on the role of PYL proteins in potato. In this study, a potato PYL gene, StPYL8-like, was identified through transcriptome analysis under drought stress. Molecular characterization revealed that the StPYL8-like protein possesses a highly conserved PYL family domain. Evolutionary analysis demonstrated that StPYL8-like protein clusters with various PYL proteins are involved in stress responses across different species. Functional assays showed that StPYL8-like robustly responds to different abiotic stresses, including drought and ABA treatment. Furthermore, the transient and stable expressions of StPYL8-like in tobacco enhanced their drought resistance, leading to increased plant height, leaf number, and fresh weight, as well as an improved root system. Transgenic tobacco carrying the StPYL8-like gene exhibited lower malondialdehyde (MDA) levels and higher proline accumulation and antioxidant enzyme activity compared to wild-type plants under drought conditions. Moreover, StPYL8-like upregulated the expression of stress-responsive genes (NtRD29A, NtLEA5, NtP5CS, NtPOD, NtSOD, and NtCAT) in transgenic plants subjected to drought stress. Collectively, these findings highlight the positive regulatory role of the StPYL8-like gene in enhancing potato plants’ response to drought stress.

To address the high power consumption associated with image refresh operations in EPDs, this paper proposes a low-power driving waveform that reduces the refresh power of EPDs by lowering the system’s peak power. Compared to traditional waveforms, this waveform first activates the particles before erasing them, thus reducing voltage polarity changes. Additionally, it introduces a specific duration of 0 V voltage during the activation phase based on the physical characteristics of the electrophoretic particles to reduce the voltage span. Finally, a particular duration of 0 V voltage is introduced during the erasure phase to minimize the voltage span while ensuring the stability and consistency of the reference gray scale. The experimental results demonstrate that, in standard power tests, the new driving waveform reduces the power fluctuation value by 1.33% and the energy fluctuation value by 37.24% compared to the traditional driving waveform. This reduction in refresh power also mitigates screen flicker and ghosting phenomena.

PYR/PYL/RCAR proteins are abscisic acid (ABA) receptors that play a crucial role in plant responses to abiotic stresses. However, there have been no research reports on potato PYL so far. In this study, a potato PYL gene named StPYL16 was identified based on transcriptome data under drought stress. Molecular characteristics analysis revealed that the StPYL16 protein possesses an extremely conserved PYL family domain. The tissue expression results indicated that the StPYL16 is predominantly expressed at high levels in the underground parts, particularly in tubers. Abiotic stress response showed that StPYL16 has a significant response to drought treatment. Further research on the promoter showed that drought stress could enhance the activation activity of the StPYL16 promoter on the reporter gene. Then, transient and stable expression of StPYL16 in tobacco enhanced the drought resistance of transgenic plants, resulting in improved plant height, stem thickness, and root development. In addition, compared with wild-type plants, StPYL16 transgenic tobacco exhibited lower malondialdehyde (MDA) content, higher proline accumulation, and stronger superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities. Meanwhile, StPYL16 also up-regulated the expression levels of stress-related genes (NtSOD, NtCAT, NtPOD, NtRD29A, NtLEA5, and NtP5CS) in transgenic plants under drought treatment. These findings indicated that the StPYL16 gene plays a positive regulatory role in potato responses to drought stress.

Chimeric antigen receptor (CAR) -T cell therapy has entered the breakthrough era, characterized by a blend of therapeutic opportunities and challenges. With the integration of genome-editing technology, CAR-T cells will be empowered to become super warriors in eradicating tumor cells and attacking various tumors, including T-cell malignancies and acute myeloid leukemia. Notably, the optimization of CAR-T cells, including efficacy, safety, and manufacturing speed, coupled with other therapeutic strategies such as radiotherapy, hematopoietic stem cell transplantation, small-molecule inhibitors, and bispecific antibodies, could revolutionize the therapeutic landscape of tumors. Consequently, next-generation cellular immunotherapy, including universal CAR-NK cells and synergistic combination approaches, are anticipated to significantly impact cancer treatment in the coming decade. Nevertheless, the failure rates of CAR-T therapy continue to be significant. The challenge lies in determining the optimal combination strategy and identifying reliable and robust biomarkers to effectively select the patients who will derive the greatest benefit from CAR-T therapy. Herein, we highlight recent innovations in CAR-T products, combination strategies and predictive biomarkers of response presented at the 2023 ASH Annual Meeting.

ABSTRACTAltered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1β), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function.IMPORTANCEAltered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.

Relapsed and refractory multiple myeloma (RRMM) and B-cell leukemia/lymphoma with extramedullary disease (EMD) have poor prognosis and high mortality, lack of effective therapeutic approaches. We reported for the first time that 6 patients with malignant hematological diseases with EMD received chimeric antigen receptor (CAR)-T treatment combined with pomalidomide, and CAR-T cells were treated with pomalidomide in vitro to determine its killing activity and cytokine secretion. Three patients with RRMM were given B cell maturation antigen (BCMA)-CAR-T therapy. All 3 patients with B-cell leukemia/lymphoma received CD19/22-CAR-T sequential infusion. There were no treatment-related deaths. The maximum overall response rate (ORR) was 100%. Median follow-up was 211.5 days (75–407 days). Three patients (50%) experienced cytokine release syndrome, all of which were grade 1, and no neurotoxicity was observed. In vitro experiments showed that the killing activity did not differ significantly between BCMA-CAR-T cells with and without pomalidomide (10, 25, or 50 μg/mL) in 8226/U266 cell cocultures (P > .05). Tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion was significantly higher from 8226 and Raji cells cocultured with BCMA-CAR-T and cluster of differentiation (CD)19-CAR-T cells (P < .05). Based on the cocultures, adding pomalidomide significantly promoted IFN-γ and TNF-α secretion (P < .05). Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.

PurposePapillary thyroid cancer (PTC) has grown rapidly in prevalence over the past few decades, and central neck lymph node metastasis (CNLNM) is associated with poor prognoses. However, whether to carry out preventive central neck lymph node dissection (CNLND) is still controversial. We aimed to construct a prediction model of CNLNM to facilitate making clinical surgical regimens.MethodsA total of 691 patients with PTC between November 2018 and December 2021 were included in our study. Univariate and multivariate analyses were performed on basic information and clinicopathological characteristics, as well as ultrasound characteristics (American College of Radiology (ACR) scores). The prediction model was constructed and performed using a nomogram, and then discriminability, calibrations, and clinical applicability were evaluated.ResultsFive variables, namely, male, age >55 years, clinical lymph node positivity, tumor size ≥1 cm, and ACR scores ≥6, were independent predictors of CNLNM in the multivariate analysis, which were eventually included to construct a nomogram model. The area under the curve (AUC) of the model was 0.717, demonstrating great discriminability. A calibration curve was developed to validate the calibration of the present model by bootstrap resampling, which indicated that the predicted and actual values were in good agreement and had no differentiation from the ideal model. The decision curve analysis (DCA) indicated that the prediction model has good clinical applicability.ConclusionsOur non-invasive prediction model combines ACR scores with clinicopathological features presented through nomogram and has shown good performance and application prospects for the prediction of CNLNM in PTCs.

Summary: Background: Although the antibody–drug conjugates (ADCs) have significantly improved the survival outcomes of patients with human epidermal receptor 2 (HER2)-expressing gastric or gastroesophageal junction (G/GEJ) cancer, the efficacy of ADC used as a single agent is limited. Therefore, it is necessary to investigate effective and safe combination regimens. Preclinical data indicated a synergetic antitumour effect of RC48 and programmed cell death protein 1 (PD-1) inhibitors. We aimed to evaluate the safety and efficacy of RC48 plus toripalimab in patients with HER2-expressing G/GEJ cancer and other solid tumours. Methods: This was a open-label, multicentre, phase 1 trial performed at three hospitals in China. Eligible patients had advanced G/GEJ cancer or other solid tumours with HER2 IHC≥1 or ISH positivity and were refractory to at least one line of treatment, or standard treatment was intolerable or unavailable for these patients. This study followed a “3 + 3” design with predefined RC48 dosages of 2.0 mg/kg and 2.5 mg/kg plus toripalimab 3 mg/kg, once every 2 weeks (q2w). The primary objectives were to evaluate the safety and determine the recommended phase II dose (RP2D), and the secondary objectives included assessing the pharmacokinetics (PK) and preliminary efficacy. This study was registered with ClinicalTrials.gov, NCT04280341. Findings: Between July 13, 2020 and August 30, 2022, 56 patients, including 30 patients with G/GEJ cancer and 26 patients with other solid tumours, were enrolled and received RC48 plus toripalimab (n = 7 for RC48 2.0 mg/kg, toripalimab 3 mg/kg, q2w; n = 49 for RC48 2.5 mg/kg, toripalimab 3 mg/kg, q2w). No dose-limiting toxic effects occurred. The RP2D was declared as RC48 2.5 mg/kg plus toripalimab 3 mg/kg, q2w. The most common grade 3 adverse events were a decreased neutrophil count (n = 13), and a decreased white blood cell count (n = 7). The efficacy assessment was completed for 52 patients. Among patients with G/GEJ cancer (n = 30), the confirmed objective response rate (ORR) was 43% (12/28, 95% CI 25, 63), median progression-free survival (PFS) was 6.2 months (95% CI 4.0, 6.9), median overall survival (OS) was 16.8 months (95% CI 7.2, NE). The ORR of patients with G/GEJ cancer receiving RP2D (n = 24) reached 50% (11/22, 95% CI 28, 72), with median PFS of 5.1 months (95% CI 1.4, 7.3) and median OS of 14.0 months (95% CI 6.3, NE). Among patients with G/GEJ cancer who received RP2D, a clinical benefit was observed in both HER2-positive and low HER2 expressing populations, with an ORR of 56% (5/9, 95% CI 21, 86) vs. 46% (6/13, 95% CI 19, 75), median PFS of 7.8 months (95% CI 0.9, NE) vs. 5.1 months (95% CI 1.2, 6.9), median OS of NE months (95% CI 4.3, NE) vs. 14.0 months (95% CI 5.1, NE), respectively. Antitumour activity was also observed for other solid tumours, including breast cancer (5/13) and endometrial carcinoma (1/1). Interpretation: Our findings suggested that RC48 plus toripalimab had a manageable safety profile and showed encouraging efficacy in pretreated patients with HER2-positive and low HER2-expressing G/GEJ cancer. The findings of our phase 1 clinical trial support further investigation of HER2-targeted ADC plus immunotherapy in HER2-expressing G/GEJ cancer and pancancer treatment in the future. Funding: Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute (Z200015).