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Chemoresistance to 5-fluorouracil (5-FU) is a significant challenge in treating colorectal cancer (CRC). Novel combined regimens to thwart chemoresistance are therefore urgently needed. Herein, we demonstrated that the combination of Avenanthramide A (AVN A) and 5-FU has significant therapeutic advantages against CRC. Mechanistically, AVN A directly binds to the S198 site of the histone lysine demethylase KDM4C to promote its degradation, which subsequently fosters H3K9me3 occupancy on the MIR17HG promoter to block its transcription and derepress Bim expression. AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop. Importantly, the clinical correlation of the KDM4C/MIR17HG/Bim signaling axis with 5-FU response was validated in the refractory CRC patients. We provide evidence for the enhanced effectiveness of 5-FU when combined with AVN A in chemoresistant xenografts, CRC organoids, and ApcMin/+ mouse model. Additionally, AVN A mitigated the systemic adverse effects of 5-FU. Overall, our findings demonstrate that combinatorial therapy with AVN A and 5-FU represents an appealing opportunity and highlights KDM4C/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs.

Combatting desertification through vegetation restoration holds significant potential for soil carbon sequestration. However, understanding the effects of different restoration types on soil organic carbon component and the role of carbohydrate-active enzymes (CAZymes) remains limited. This study assessed soils from four distinct vegetation types, namely grassland desert (GD), desert steppe (DS), typical steppe (TS), and artificial forest (AF), in the eastern part of the Mu Us Desert, China, examining physicochemical properties, carbon chemical composition, microbial community composition, and CAZyme gene abundance. Our research findings demonstrated that TS restoration significantly increased the content of various soil organic carbon (SOC) components. Compared to other vegetation types, the proportion of recalcitrant carbon (20–22%) was notably higher and exhibited a strong correlation with lignin and peptidoglycan, as determined by the analysis of CAZyme subfamily composition. GD and DS soils showed enrichment in cellulose and hemicellulose-decomposing CAZymes, leading to higher polysaccharide and aliphatic carbon levels. Significant changes were observed in the methyl carbon component amidst the decomposition of varied organic matter types, correlating strongly with Proteobacteria and Acidobacteria abundances. Our research elucidates the influence of distinct vegetation types on sandy soil carbon sequestration and stabilization, highlighting the crucial function of microbial communities and their CAZyme activities. These insights can guide enhanced land management strategies for improved carbon dynamics in arid ecosystems.

ABSTRACTThis open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from − 4.3% to − 1.6%, for all poliovirus types, p

Background: Febrile infection-related epilepsy syndrome is a refractory epilepsy syndrome that predominantly affects children, with a higher incidence in school-age children and is associated with infectious factors. Case report: A 6-year-old boy developed sudden symptoms characterized by fever and a disorder of consciousness, rapidly progressing into drug-refractory status epilepticus (SE). The electroencephalogram revealed diffuse slow-wave activity in the background, with partial seizures originating from the left temporal and occipital regions that gradually generalized. Brain MRI showed no abnormalities in the signal. Due to the failure of multi-drug anti-epileptic therapy, a ketogenic diet was administered and the frequency of seizure was reduced, however, a ketogenic diet was administered, which reduced the frequency of seizures; however, the ketogenic diet treatment was discontinued due to intolerance. After discharge, both the ketogenic diet and anti-seizure medications (ASMs) were administered to the patient. Upon follow-up, occasional seizures were reported, accompanied by unconsciousness and a significant decline in cognitive function compared to the pre-onset period. Conclusions: No specific treatment modality is available for febrile infection-related epilepsy syndrome; however, a ketogenic diet and vagus nerve stimulation (VNS) may offer potential efficacy in controlling acute seizures and improving prognosis.

Abstract Background Myelodysplastic syndrome (MDS) is a complicated hematopoietic malignancy characterized by bone marrow (BM) dysplasia with symptoms like anemia, neutropenia, or thrombocytopenia. MDS exhibits considerable heterogeneity in prognosis, with approximately 30% of patients progressing to acute myeloid leukemia (AML). Single cell RNA-sequencing (scRNA-seq) is a new and powerful technique to profile disease landscapes. However, the current available scRNA-seq datasets for MDS are only focused on CD34+ hematopoietic progenitor cells. We argue that using entire BM cell for MDS studies probably will be more informative for understanding the pathophysiology of MDS. Methods Five MDS patients and four healthy donors were enrolled in the study. Unsorted cells from BM aspiration were collected for scRNA-seq analysis to profile overall alteration in hematopoiesis. Results Standard scRNA-seq analysis of unsorted BM cells successfully profiles deficient hematopoiesis in all five MDS patients, with three classified as high-risk and two as low-risk. While no significant increase in mutation burden was observed, high-risk MDS patients exhibited T-cell activation and abnormal myelogenesis at the stages between hematopoietic stem and progenitor cells (HSPC) and granulocyte–macrophage progenitors (GMP). Transcriptional factor analysis on the aberrant myelogenesis suggests that the epigenetic regulator chromatin structural protein-encoding gene HMGA1 is highly activated in the high-risk MDS group and moderately activated in the low-risk MDS group. Perturbation of HMGA1 by CellOracle simulated deficient hematopoiesis in mouse Lineage-negative (Lin-) BM cells. Projecting MDS and AML cells on a BM cell reference by our newly developed MarcoPolo pipeline intuitively visualizes a connection for myeloid leukemia development and abnormalities of hematopoietic hierarchy, indicating that it is technically feasible to integrate all diseased bone marrow cells on a common reference map even when the size of the cohort reaches to 1,000 patients or more. Conclusion Through scRNA-seq analysis on unsorted cells from BM aspiration samples of MDS patients, this study systematically profiled the development abnormalities in hematopoiesis, heterogeneity of risk, and T-cell microenvironment at the single cell level.

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder, leading to various complications and impairments in patients’ health-related quality of life (HRQOL). Limited research has been conducted to evaluate the HRQOL of Chinese patients with PNH. Understanding the HRQOL in this specific population is crucial for providing effective healthcare interventions and improving patient’ health outcomes. This study aimed to assess HRQOL of Chinese patients with PNH, and identify key determinants. Methods A cross-sectional study was conducted during 2022 to recruit patients with PNH in China. The study population was recruited from PNH China, one of the largest public welfare PNH patient mutual aid organization in China. Data were collected via an online questionnaire including the EQ-5D-5L (5L), and social-demographic and clinical characteristics. Descriptive statistics were employed to summarize the characteristics of the participants and their HRQOL. Multiple linear and logistic regression analyses were adopted to explore key factors affecting HRQOL. Results A total of 329 valid questionnaires were collected. The mean (SD) age of the patients was 35.3 (10.0) years, with 52.3% of them being male. The patients reported more problems in Anxiety/Depression (81.5%) and Pain/Discomfort (69.9%) dimensions compared to the other three 5L dimensions. The mean (SD) of 5L health utility score (HUS) and EQ-VAS score were 0.76 (0.21) and 62.61 (19.20), respectively. According to multiple linear regression, initial symptoms (i.e., Anemia [fatigue, tachycardia, shortness of breath, headache] and back pain) and complication of thrombosis were significant influencing factors affecting 5L HUS. Total personal income of the past year, initial symptom of hemoglobinuria and complication of thrombosis were significantly influencing factors of VAS score. Social-demographic and clinical characteristics, such as gender, income, and thrombosis, were also found to be significantly related to certain 5L health problems as well. Conclusion Our study manifested the HRQOL of PNH patients in China was markedly compromised, especially in two mental-health related dimensions, and revealed several socio-demographic and clinical factors of their HRQOL. These findings could be used as empirical evidence for enhancing the HRQOL of PNH patients in China.

ABSTRACT This review discusses observed hydroclimatic trends and future climate projections for the Amazon. Warming over this region is a fact, but the magnitude of the warming trend varies depending on the datasets and length of the analyzed period. The warming trend has been more evident since 1980 and has further enhanced since 2000. Long-term trends in climate and hydrology are assessed. Various studies have reported an intensification of the hydrological cycle and a lengthening of the dry season in the southern Amazon. Changes in floods and droughts, mainly due to natural climate variability and land use change, are also assessed. For instance, in the first half of the 20th century, extreme flood events occurred every 20 years. Since 2000, there has been one severe flood every four years. During the last four decades, the northern Amazon has experienced enhanced convective activity and rainfall, in contrast to decreases in convection and rainfall in the southern Amazon. Climate change in the Amazon will have impacts at regional and global scales. Significant reductions in rainfall are projected for the eastern Amazon.

Background: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. Materials and methods: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. Results: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p -PI3K and p -Akt were notably downregulated Conclusion: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.

Human metallothionein-2A (MT2A) protein participates in metal homeostasis, detoxification, oxidative stress reduction, and immune defense. It decreases heavy metal ions and reactive oxygen species (ROS) during injury of cells and tissues. The single nucleotide polymorphisms at the MT2A gene have been associated in various human diseases including cancer. The current study aimed to elucidate associations between MT2A genotypes with the clinical, biochemical, and molecular characteristics that potentially related to lowered MT2A ex-pression. One hundred and forty-one healthy Taiwanese subjects were enrolled from Changhua Show-Chwan Memorial Hospital. Clinical, biochemical and molecular characteristics including the frequent minor allele SNPs, rs28366003 and rs10636, within the MT2A gene were determined. The genotype distribution of MT2A rs10636 fits the Hardy-Weinberg equilibrium. The significant associations with gradually decline of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were identified with MT2A rs10636 and rs28366003 using analysis of variance (ANOVA) with Tukey's analysis as a post hoc test. We further validated the correlations between the expressions of genes in erythropoiesis, cholesterol synthesis, platelet synthesis, insulin with MT2A using the web-based Gene Expression Profiling Interactive Analysis (GEPIA) databases. The results revealed that hypoxia-inducible factor 1α (HIF-1α), erythropoietin (EPO), lipoprotein lipase (LPL), and lecithin-cholesterol acyltransferase (LCAT) mRNA ex-pression are significantly correlated with MT2A mRNA expression. In conclusion, these results suggested that genetic variations of MT2A rs10636 and rs28366003 might be an important risk factor for erythropoiesis in the Taiwanese general population.

Abstract Background Regular follow-up and medication can effectively reduce the risk of adverse outcomes for patients with hypertension. This study aimed to explore the temporal-spatial distribution characteristics and associated socioeconomic factors of visiting frequency for rural patients with hypertension in Fujian province from 2011 to 2016. Methods The medical records of patients with hypertension were abstracted from the database of New Rural Cooperative Medical Scheme. Geographically and temporally weighted regression model was used to analyze the associations between percentage of patients whose visiting frequency ≥ 4 times within a year and seven socioeconomic factors at the county level. Results The visiting rate of rural patients with hypertension was 0.79%, 1.27%, 1.87%, 2.29%, 2.78%, 3.43% over the six-year study period, respectively. The percentage of patients whose visiting frequency ≥ 4 times within a year gradually increased over time and the percentage ranged from 61 to 80% in a half of the counties by 2016. In general, there was positive association between Gross Domestic Product per capita and the percentage of patients whose visiting frequency ≥ 4 times within a year. The percentage of female patients, percentage of patients who aged ≥ 60 years, percentage of low-income patients, carbon emission intensity, percentage of savings and number of health technicians per 10,000 persons were negatively correlated with the percentage of patients whose visiting frequency ≥ 4 times within a year in most of counties of Fujian Province. In the sensitivity analysis, the percentage of outpatients whose visiting frequency ≥ 4 times within a year was higher than that of all patients. There was positive association between percentage of outpatients who aged ≥ 60 years and the percentage of outpatients whose visiting frequency ≥ 4 times. Conclusions The visiting rate and the visiting frequency within a year for rural patients with hypertension in Fujian province need to be improved. Female and elderly patients should be the focus of health management. Effectively implementing the family doctor services, providing several kinds of free antihypertensive drugs, improving energy utilization efficiency and reasonably allocating the health resources may be the effective strategies to improve the follow-up compliance of patients.

Independent directors are important corporate decision participants and makers. Based on the Chinese cultural background, this paper interprets the listing order of independent directors as independent directors’ status, exploring their influence on the corporate research and development (R&D) behavior. This paper studies A-share listed firms in China from 2008 to 2018 as the sample. The main method is ordinary least square (OLS) regression. We also use other methods to deal with endogenous problems, such as the firm fixed effect method, change model method, two-stage instrumental variable method, and Heckman two-stage method. Findings: (1) Higher independent directors’ status attribute to more effective exertion of supervision and consultation function, and positively enhance the corporate R&D investment. The increase of the independent director’ status by one standard deviation will increase the R&D investment by 4.6%. (2) The above effect is more influential in firms with stronger traditional culture atmosphere, higher information opacity and higher performance volatility. (3) High-status independent directors promote R&D investment by improving the scientificity of R&D evaluation and reducing information asymmetry. (4) The enhancing effect of independent director’ status on R&D investment is positively associated with the firm’s patent output and market value. This paper contributes to understanding the relationship between the independent directors’ status and their duty execution from an embedded cultural background perspective. The findings of the study enlighten the improvement of corporate governance efficiency and the healthy development of the capital market.

Abstract Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy.

Abstract Background Coronary computed tomography angiography stenosis score (CCTA-SS) is a proposed diagnosis score that considers the plaque characteristics, myocardial function, and the diameter reduction rate of the lesions. This study aimed to evaluate the diagnostic performance of the CCTA-SS in seeking coronary artery disease (CAD). Methods The 228 patients with suspected CAD who underwent CCTA and invasive coronary angiography (ICA) procedures were under examination. The diagnostic performance was evaluated with the receiver operating curve (ROC) for CCTA-SS in detecting CAD (defined as a diameter reduction of ≥ 50%) and severe CAD (defined as a diameter reduction of ≥ 70%). Results The area under ROC (AUC) of CCTA-SS was 0.909 (95% CI: 0.864–0.943), which was significantly higher than that of CCTA (AUC: 0.826; 95% CI: 0.771–0.873; P = 0.0352) in diagnosing of CAD with a threshold of 50%. The optimal cutoff point of CCTA-SS was 51% with a sensitivity of 90.66%, specificity of 95.65%, positive predictive value of 98.80%, negative predictive value of 72.13%, and accuracy of 91.67%, whereas the optimal cutoff point of CCTA was 55%, and the corresponding values were 87.36%, 93.48%, 98.15%, 65.15%, and 88.60%, respectively. With a threshold of 70%, the performance of CCTA-SS with an AUC of 0.927 (95% CI: 0.885–0.957) was significantly higher than that of CCTA with an AUC of 0.521 (95% CI: 0.454–0.587) (P

ABSTRACT: The introduction of exotic breeds and the cultivation of new lines by breeding companies have posed challenges to native chickens in South China, including loss of breed characteristics, decreased genetic diversity, and declining purity. Understanding the population genetic structure and genetic diversity of native chickens in South China is crucial for further advancements in breeding efforts. In this study, we analyzed the population genetic structure and genetic diversity of 321 individuals from 10 different breeds in South China. By comparing commercial chickens with native ones, we identified selection signatures occurring between local chickens and commercial breeds. The analysis of population genetic structure revealed that the native chicken populations in South China exhibited a considerable level of genetic diversity. Moreover, the commercial lines of Xiaobai chicken and Huangma chicken displayed even higher levels of genetic diversity, which distinguished them from other native varieties at the clustering level. However, certain individuals within these commercial varieties showed a discernible genetic relationship with the native populations. Notably, both commercial varieties also retained a significant degree of genetic similarity to their respective native counterparts. In order to investigate the genomic changes occurring during the commercialization of native chickens, we employed 4 methods (Fst, ROD, XPCLR, and XPEHH) to identify potential candidate regions displaying selective signatures in Southern Chinese native chicken population. A total of 168 (identified by Fst and ROD) and 86 (identified by XPCLR and XPEHH) overlapping genes were discovered. Functional annotation analysis revealed that these genes may be associated with reproduction and growth (SAMSN1, HYLS1, ROBO3, FGF14, PRSS23), musculoskeletal development (DNER, MYBPC1, DGKB, ORC1, KLF10), disease resistance and environmental adaptability (PUS3, CRB2, CALD1, USP15, SGCD, LTBP1), as well as egg production (ADGRB3, ACSF3). Overall, native chickens in South China harbor numerous selective sweep regions compared to commercial chickens, enriching valuable genomic resources for future genetic research and breeding conservation.

ObjectivesThis study aimed to explore the potential causal associations between serum uric acid (SUA) and the risk of colorectal cancer, colon cancer and rectal cancer.MethodsTwenty-six SUA-related single nucleotide polymorphisms which were identified by a large meta-analysis of genome-wide association studies (GWASs) were used as instrumental variables in the two-sample Mendelian randomization (MR) study. Meta-analyses were used to synthesize the results of multiple GWASs which were extracted from the MRC Integrative Epidemiology Unit GWAS database for each type of cancer. The inverse variance weighted (IVW) method was used as the primary MR method to analyze the association between SUA and colorectal cancer risk. Several sensitivity analyses were performed to test the robustness of results.ResultsThe IVW method showed that there were no causal relationships between SUA and the risk of colorectal cancer [odds ratio (OR): 1.0015; 95% confidence interval (CI): 0.9975–1.0056] and colon cancer (OR: 1.0015; 95% CI: 0.9974–1.0055). The SUA levels were negative correlated with rectal cancer risk (OR: 0.9984; 95% CI: 0.9971–0.9998). The similar results were observed in both males (OR: 0.9987; 95% CI: 0.9975–0.9998) and females (OR: 0.9985; 95% CI: 0.9971–0.9999). The sensitivity analyses suggested no evidence of heterogeneity or horizontal pleiotropy. The leave-one-out analyses showed that one SNP (rs1471633) significantly drove the causal effect of SUA on rectal cancer risk. The MR-Egger regression and weighted median both showed that there were no causal relationships between SUA and the risk of colorectal cancer and its subtypes.ConclusionOverall, there was no linear causal association between SUA and the risk of colorectal cancer. However, further research is needed to investigate the role of higher SUA levels such as hyperuricemia or gout in the occurrence of colorectal cancer.

Abstract T‐bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T‐bet in non‐immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet‐O‐T‐bet transgenic mouse strain is generated for doxycycline‐inducible T‐bet expression in adult animals. Unexpectedly, ubiquitous T‐bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell‐type‐specific analyses reveal that T‐bet‐driven pathology is not attributable to its overexpression in CD4+ T cells or myeloid lineages. Instead, inducible T‐bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T‐bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T‐bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T‐bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases.

ABSTRACT: Lipopolysaccharide (LPS) from Gram-negative bacteria initially induces liver inflammation with proinflammatory cytokines expressions. However, the underlying hepatoprotective mechanism of quercetin on LPS-induced hepatic inflammation remains unclear. Specific pathogen-free chicken embryos (n = 120) were allocated control vehicle, PBS with or without ethanol vehicle, LPS (125 ng/egg) with or without quercetin treatment (10, 20, or 40 nmol/egg, respectively), quercetin groups (10, 20, or 40 nmol/egg). Fifteen-day-old embryonated eggs were inoculated abovementioned solutions via the allantoic cavity. At embryonic d 19, the livers of the embryos were collected for histopathological examination, RNA extraction, real-time polymerase chain reaction, and immunohistochemistry investigation. We found that the liver presented inflammatory response (heterophils infiltration) after LPS induction. The LPS-induced mRNA expressions of inflammation-related factors (TLR4, TNFα, IL-1β, IL-10, IL-6, MYD88, NF-κB1, p38, and MMP3) were upregulated after LPS induction when compared with the PBS group, while quercetin could downregulate these expressions as compared with the LPS group. Quercetin significantly decreased the immunopositivity to TLR4 and MMP3 in the treatment group when compared with the LPS group. Quercetin could significantly downregulate the mRNA expressions of autophagy-related genes (ATG5, ATG7, Beclin-1, LC3A, and LC3B) and necroptosis-related genes (Fas, Bcl-2, Drp1, and RIPK1) after LPS induction. Quercetin significantly decreased the immunopositivity to LC3 in the treatment group when compared with the LPS group; meanwhile, quercetin significantly decreased the protein expressions of LC3-I, LC3-II, and the rate of LC3-II/LC3-I. In conclusions, quercetin can alleviate hepatic inflammation induced by LPS through modulating autophagy and necroptosis.

ABSTRACT: Meat quality traits are essential for producing high-quality broilers, but the genetic improvement has been limited by the complexity of measurement methods and the numerous traits involved. To systematically understand the meat quality characteristics of different broiler breeds, this study collected data on slaughter performance, skin color, fat deposition, and meat quality traits of 434 broilers from 12 different breeds in South China. The results showed that there was no significant difference in the live weight and slaughter weight of various broiler breeds at their respective market ages. Commercial broiler breeds such as Xiaobai and Huangma chickens had higher breast muscle and leg muscle rates. The skin and abdominal fat of Huangma chickens cultivated in the consumer market in South China exhibited significantly higher levels of yellowness compared to other varieties. Concerning fat traits, we observed that Wenchang chickens exhibited a strong ability to fat deposition, while the younger breeds showed lower fat deposition. Additionally, there were significant positive correlations found among different traits, including traits related to weight, traits related to fat, and skin color of different parts. Hierarchical clustering analysis revealed that fast-growing and large broiler Xiaobai chickens formed a distinct cluster based on carcass characteristics, skin color, and meat quality traits. Principal component analysis (PCA) was used to extract multiple principal components as substitutes for complex meat quality indicators, establishing a chicken meat quality evaluation model to differentiate between different breeds of chickens. At the same time, we identified 46, 22, and 20 SNP loci and their adjacent genes that were significantly associated with muscle mass traits, fat deposition, and skin color through genome-wide association studies (GWAS). The above results are helpful for systematically understanding the differences and characteristics of meat quality traits among different breeds.

In recent years, long-short term memory (LSTM) networks have emerged as a promising tool for time-series analysis, offering the ability to capture temporal dependencies effectively, especially for the fault detection in power facilities which is crucial for maintaining operational integrity and ensuring continuous power supply. This paper presents a study on the utilization of LSTM networks for fault detection in power facilities, focusing on evaluating the detection accuracy as a performance metric. We propose a novel LSTM-based fault detection framework that utilizes historical operational data to identify abnormal patterns indicative of faults or anomalies. The framework is trained on labeled data to learn the normal operational behavior of the power facility, enabling it to detect deviations from expected patterns in practical data streams. To assess the effectiveness of the proposed approach, extensive experiments are conducted using real-world operational data from diverse power facilities. We systematically evaluate the detection accuracy of the LSTM-based fault detection system under various operating conditions, including different types of faults and levels of noise in the data. Comparative analyses are performed against traditional fault detection methods to demonstrate the superiority of the LSTM-based approach in terms of accuracy. Moreover, sensitivity analyses are conducted to investigate the impact of key parameters, such as network architecture and training data size, on the detection performance. The results illustrate the robustness and effectiveness of the proposed LSTM-based fault detection framework, highlighting its potential for enhancing the reliability and efficiency of power facility operations.

Summary:. Lingual splints have been used to treat mandibular fractures, particularly in cases of complicated mandibular fractures, and serve as a noninvasive adjunctive procedure for reduction and fixation. Furthermore, when used in conjunction with open reduction and internal fixation, the lingual splint provides feasible external fixation against displacing forces exerted by the robust musculature of the mandible. However, the conventional method for lingual splint fabrication is performed preoperatively, and the procedure is time-consuming. This technical note describes a simplified and efficient technique for the intraoperative manufacture of a lingual splint for mandibular fractures using a thermoplastic material, polycaprolactone. Our results demonstrated satisfactory fixation outcomes, reduced lingual splint fabrication time, and superior cost-effectiveness, offering an alternative option for adjunctive external fixation of mandibular fractures.

The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine β-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.

Abstract Objective To evaluate the effectiveness, safety, and convenience of in‐class transition (iCT) from intravenous bortezomib‐based induction to ixazomib‐based oral regimens. Methods This retrospective real‐world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first‐line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib‐based induction therapy, followed by an ixazomib‐based oral regimen for 2 year or until disease progression or intolerable toxicity. Results The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M‐FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib‐based treatment spanning 6 months. At the 20‐month median follow‐up, 53% of patients remained on therapy. The 24‐month PFS rate was 84.3% from the initiation of bortezomib‐based induction and 83.4% from the start of ixazomib‐based treatment. Overall response rate (ORR) was 100% post‐bortezomib induction and 90% following 6 cycles of the ixazomib‐based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. Conclusion In the real‐world Chinese MM population, NDMM and FRMM patients responded favorably to PI‐based continuous therapy, demonstrating substantial response rates. The ixazomib‐based iCT allows for sustained PI‐based treatment, offering promising efficacy and tolerable AEs.

Abstract For patients with severe aplastic anemia (SAA) in China who have had an insufficient response to the first-line treatment with hematopoietic stem cell transplantation or immunosuppressive therapy, there is no established standard of care other than transfusion support and treatment of infections. This non-randomized, open-label, Phase II multicenter trial investigated the efficacy and safety of eltrombopag in 20 adult Chinese patients with refractory or relapsed (r/r) SAA. The primary endpoint of hematologic response rate at Week 26, defined as the proportion of patients who met any of the International Working Group criteria, was observed in 70% (14/20) of patients, with more than 50% of these having at least bi-lineage response. Reduced red blood cell and platelet transfusion at Week 26 were observed in 57% (8/14) and 80% (8/10) of patients, respectively. Safety findings were consistent with the established safety profile of eltrombopag and no new safety signals were reported. None of the patients discontinued eltrombopag because of safety concerns. Although the sample size was small, this is the first prospective study to show that eltrombopag is efficacious and has a favorable safety profile in a Chinese patient population with r/r SAA. Trial registration: This trial is registered on ClinicalTrials.gov (NCT03988608); registered 17 June 2019.

Abstract Studies have revealed that both extracorporeal shock‐wave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) can accelerate wound healing. This study aimed to compare the effectiveness of ESWT and HBOT in enhancing diabetic wound healing. A dorsal skin defect in a streptozotocin‐induced diabetes rodent model was used. Postoperative wound healing was assessed once every 3 days. Histologic examination was performed with hematoxylin and eosin staining. Proliferation marker protein Ki‐67 (Ki‐67), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) were evaluated with immunohistochemical (IHC) staining. The wound area was significantly reduced in the ESWT and HBOT groups compared to that in the diabetic controls. However, the wound healing time was significantly increased in the HBOT group compared to the ESWT group. Histological findings showed a statistical increase in neovascularization and suppression of the inflammatory response by both HBOT and ESWT compared to the controls. IHC staining revealed a significant increase in Ki‐67, VEGF, and eNOS but suppressed 8‐OHdG expression in the ESWT group compared to the HBOT group. ESWT facilitated diabetic wound healing more effectively than HBOT by suppressing the inflammatory response and enhancing cellular proliferation and neovascularization and tissue regeneration.

Abstract Background Ankyrin repeat domain 49 (ANKRD49) has been found to be highly expressed in multiple cancer including lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). However, the function of ANKRD49 in the pathogenesis of NSCLC still remains elusive. Previously, ANKRD49 has been demonstrated to promote the invasion and metastasis of A549 cells, a LUAD cell line, via activating the p38-ATF-2-MMP2/MMP9 pathways. Considering the heterogeneity of tumor cells, the function and mechanism of ANKRD49 in NSCLC need more NSCLC-originated cells to clarify. Methods Real-time qPCR was employed to test ANKRD49 expression levels in nine pairs of fresh NSCLC tissues and the corresponding adjacent normal tissues. The function of ANKRD49 was investigated using overexpression and RNA interference assays in lung adenocarcinoma cell line (NCI-H1299) and lung squamous carcinoma cell line (NCI-H1703) through gelatin zymography, cell counting kit-8, colony formation, wound healing, migration and invasion assays mmunoprecipitation was performed to in vitro. Immunoprecipitation was performed to test the interaction of c-Jun and ATF2. Chromatin immunoprecipitation was conducted to assess the transcriptional regulation of ATF2/c-Jun on MMP-2/9. Moreover, the tumorigenicity of ANKRD49 was evaluated in nude mice models and the involved signal molecular was also measured by immunohistochemical method. Results We found that the levels of ANKRD49 in cancerous tissues were higher than those in adjacent normal tissues. in vitro assay showed that ANKRD49 promoted the migration and invasion of NCI-H1299 and NCI-H1703 cells via enhancing the levels of MMP-2 and MMP-9. Furthermore, ANKRD49 elevated phosphorylation of JNK and then activated c-Jun and ATF2 which interact in nucleus to promote the binding of ATF2:c-Jun with the promoter MMP-2 or MMP-9. In vivo assay showed that ANKRD49 promoted lung metastasis of injected-NSCLC cells and the high metastatic rate was positively correlated with the high expression of ANKRD49, MMP-2, MMP-9, p-JNK, p-c-Jun and p-ATF2. Conclusion The present study indicated that ANKRD49 accelerated the invasion and metastasis of NSCLC cells via JNK-mediated transcription activation of c-Jun and ATF2 which regulated the expression of MMP-2/MMP-9. The molecular mechanisms of ANKRD49’s function is different from those found in A549 cells. The current study is a supplement and improvement to the previous research.

Abstract Background The epididymis is crucial for post-testicular sperm development which is termed sperm maturation. During this process, fertilizing ability is acquired through the epididymis-sperm communication via exchange of protein and small non-coding RNAs (sncRNAs). More importantly, epididymal-derived exosomes secreted by the epididymal epithelial cells transfer sncRNAs into maturing sperm. These sncRNAs could mediate intergenerational inheritance which further influences the health of their offspring. Recently, the linkage and mechanism involved in regulating sperm function and sncRNAs during epididymal sperm maturation are increasingly gaining more and more attention. Methods An epididymal-specific ribonuclease T2 (RNase T2) knock-in (KI) mouse model was constructed to investigate its role in developing sperm fertilizing capability. The sperm parameters of RNase T2 KI males were evaluated and the metabolic phenotypes of their offspring were characterized. Pandora sequencing technology profiled and sequenced the sperm sncRNA expression pattern to determine the effect of epididymal RNase T2 on the expression levels of sperm sncRNAs. Furthermore, the expression levels of RNase T2 in the epididymal epithelial cells in response to environmental stress were confirmed both in vitro and in vivo. Results Overexpression of RNase T2 caused severe subfertility associated with astheno-teratozoospermia in mice caput epididymis, and furthermore contributed to the acquired metabolic disorders in the offspring, including hyperglycemia, hyperlipidemia, and hyperinsulinemia. Pandora sequencing showed altered profiles of sncRNAs especially rRNA-derived small RNAs (rsRNAs) and tRNA-derived small RNAs (tsRNAs) in RNase T2 KI sperm compared to control sperm. Moreover, environmental stress upregulated RNase T2 in the caput epididymis. Conclusions The importance was demonstrated of epididymal RNase T2 in inducing sperm maturation and intergenerational inheritance. Overexpressed RNase T2 in the caput epididymis leads to astheno-teratozoospermia and metabolic disorder in the offspring.

Abstract Multiple myeloma (MM) is related to immune disorders, recent studys have revealed that immunotherapy can greatly benefit MM patients. Immune checkpoints can negatively modulate the immune system and are closely associated with immune escape. Immune checkpoint-related therapy has attracted much attention and research in MM. However, the efficacy of those therapies need further improvements. There need more thoughts about the immune checkpoint to translate their use in clinical work. In our review, we aggregated the currently known immune checkpoints and their corresponding ligands, further more we propose various ways of potential translation applying treatment based on immune checkpoints for MM patients.

Abstract As an advanced amorphous material, sp 3 amorphous carbon exhibits exceptional mechanical, thermal and optical properties, but it cannot be synthesized by using traditional processes such as fast cooling liquid carbon and an efficient strategy to tune its structure and properties is thus lacking. Here we show that the structures and physical properties of sp 3 amorphous carbon can be modified by changing the concentration of carbon pentagons and hexagons in the fullerene precursor from the topological transition point of view. A highly transparent, nearly pure sp 3−hybridized bulk amorphous carbon, which inherits more hexagonal-diamond structural feature, was synthesized from C70 at high pressure and high temperature. This amorphous carbon shows more hexagonal-diamond-like clusters, stronger short/medium-range structural order, and significantly enhanced thermal conductivity (36.3 ± 2.2 W m−1 K−1) and higher hardness (109.8 ± 5.6 GPa) compared to that synthesized from C60. Our work thus provides a valid strategy to modify the microstructure of amorphous solids for desirable properties.

The effects of the degradation products of fucosylated exopolysaccharide (DFcP) on the infant fecal microflora were evaluated in vitro in this study. The results of single-strain culture showed that DFcP was selectively utilized by Bifidobacterium longum subsp. infantis ATCC 15697, B. breve ATCC 15700 and Lactobacillus plantarum CGMCC 1.19, and promoted the accumulation of short chain fatty acids (SCFAs). Compared with 2’-fucosylactose (2’-FL), DFcP was utilized more quickly by the fecal microbiota and led to higher levels of SCFA production (34.57 mmol/L, P < 0.05) during in vitro fermentation. The results of single-molecule real-time sequencing (SMRT) showed that DFcP increased the proportion of Firmicutes in the fecal microbiota, up-regulated the relative abundance of Enterococcus, Lactobacillus and Bifidobacterium, which was verified by the results of real-time polymerase chain reaction (PCR). In conclusion, DFcP could be rapidly utilized by the infant fecal microbiota, and significantly regulate its structure and promote the accumulation of the beneficial metabolite SCFAs. This study reveals the potential of DFcP as new prebiotics, which provides a theoretical basis for further development of novel fucosylated oligosaccharide resources.

In this work, the homogenized Al–Li alloys were compressed at different strains (20%–80%) under medium (370 °C) and high temperatures (470 °C), and their microstructures were characterized by SEM, EBSD, and TEM. The evolution of dynamic precipitation (DPN) during thermal deformation and its effect on microstructure and flow behavior were investigated. The results show that obvious flow softening appears with the increase of strain at medium temperature deformation while not at high temperatures, associated with the reduction of solid solution strengthening caused by DPN and the fragmentation of T1 precipitates with large aspect ratios. The T1 precipitates undergo fragmentation, dissolution and re-precipitation to develop two types of T1 bands. Deformation at medium temperatures, DPN inhibits dislocations and (sub)grain boundary movement, and mainly dynamic recovery (DRV) accompanied by little dynamic recrystallization (DRX) occurs. The fine secondary phases at high temperatures are dominated by the pre-existing Al3Zr phase, and some precipitates are observed until 80% strain, however, DPN has little influence on precipitation hardening and DRX and occurs later than DRX. DRX mechanism changes from CDRX (20–60%) to CDRX and GDRX (80%) with strain at high temperatures. Furthermore, the deformed grains tend to develop in //CD (compression direction) fiber texture during deformation, and the texture strength increases with increasing strain and decreasing temperature.