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Abstract Background Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) serves as an important option for patients without an HLA matched donor in treating hematological disorders, while patients may experience various complications after transplantation. Mycophenolate mofetil (MMF), a cornerstone drug for graft-versus-host disease (GvHD) prophylaxis, effectively reduces the incidence of acute GvHD, and the efficacy of MMF varies among individuals associated with MMF-related transporters and metabolic enzymes single nucleotide polymorphisms (SNPs). However, limited studies have systematically reported the correlations between the MMF-related SNPs and post-transplant complications. Methods Here, we conducted a retrospective study involving 90 pediatric patients with hematological disorders who underwent haplo-HSCT at a single center. All patients were subjected to MMF-related SNP testing, combined with common clinical characteristics, to be correlated with post-transplant complications. Results We observed that all 15 MMF-related SNPs were in Hardy-Weinberg equilibrium. Based on multivariate Cox regression analysis of post-transplant complications, we discovered that SLCO1B1 (521T > C) variant genotype was an independent protective factor for chronic GvHD (HR = 0.25, 95% confidence interval (CI) (0.08–0.84)). For viral infection, CYP2C8 (1291 + 106T > C) variant genotype was an independent risk factor for cytomegalovirus infection (HR = 2.98, 95% CI (1.18–7.53)). As to hemorrhagic cystitis, SLCO1B1 (1865 + 4846T > C) variant genotype was an independent protective factor, while older age was considered as an independent risk factor (HR = 0.41, 95% CI (0.19–0.85); HR = 2.52, 95% CI (1.14–5.54), respectively). No statistical significance was discovered between common clinical characteristics and MMF-related SNPs with other complications, including grade II-IV/III-IV acute GvHD, Epstein-Barr virus infection, peri-engraftment syndrome, and capillary leak syndrome. We also discovered SLCO1B1 (597 C > T) and SLC29A1 (-162 + 228 A > C) variant genotypes are both independent factors for cumulative incidence of relapse after haplo-HSCT (HR = 4.02, 95% CI (1.42–11.44); HR = 0.18, 95% CI (0.07–0.43), respectively). Conclusions Our findings highlight the significance of MMF-related transporters and metabolic enzymes SNPs in the development of post-transplant complications, contributing to facilitating personalized risk assessment and improving the clinical management in haplo-HSCT patients.

In this paper, the directional modification behavior of rare earth Ce on sulfide inclusions in steel is studied by thermodynamic calculation and experiment methods, and the mechanism of directional modification of rare earth Ce on sulfide inclusions in U71Mn heavy rail steel is proved. The results show that U71Mn heavy rail steel contained more large-sized inclusions and their distribution is more concentrated without the addition of rare earth Ce element. After the addition of rare earth Ce element, the average size of sulfur-containing inclusions in the steel decrease from 5.22 μm to 1.85 μm, and the number density of sulfur-containing inclusions in the steel increase from 83.65 mm−2 to 217.68 mm−2, indicating that the number of sulfur-containing inclusions in the steel increases after the addition of Ce element, and more small-sized sulfur-containing inclusions will form in the steel. The addition of rare earth Ce element can effectively reduce the existence of large-sized inclusions in the steel and modify large-sized inclusions into small-sized inclusions.

The 3-ketoacyl-CoA thiolase is the rate-limiting enzyme for linear dicarboxylic acids production. However, the promiscuous substrate specificity and suboptimal catalytic performance have restricted its application. Here we present both biochemical and structural analyses of a high-efficiency 3-ketoacyl-CoA thiolase Tfu_0875. Notably, Tfu_0875 displayed heightened activity and substrate specificity for succinyl-CoA, a key precursor in adipic acid production. To enhance its performance, a deep learning approach (DLKcat) was employed to identify effective mutants, and a computational strategy, known as the greedy accumulated strategy for protein engineering (GRAPE), was used to accumulate these effective mutants. Among the mutants, Tfu_0875N249W/L163H/E217L exhibited the highest specific activity (320% of wild-type Tfu_0875), the greatest catalytic efficiency (kcat/KM = 1.00 min−1mM−1), the highest succinyl-CoA specificity (KM = 0.59 mM, 28.1% of Tfu_0875) and dramatically reduced substrate binding energy (−30.25 kcal mol−1 v.s. −15.94 kcal mol−1). A structural comparison between Tfu_0875N249W/L163H/E217L and the wild type Tfu_0875 revealed that the increased interaction between the enzyme and succinyl-CoA was the primary reason for the enhanced enzyme activity. This interaction facilitated rapid substrate anchoring and stabilization. Furthermore, a reduced binding pocket volume improved substrate specificity by enhancing the complementarity between the binding pocket and the substrate in stereo conformation. Finally, our rationally designed mutant, Tfu_0875N249W/L163H/E217L, increased the adipic acid titer by 1.35-fold compared to the wild type Tfu_0875 in shake flask. The demonstrated enzymatic methods provide a promising enzyme variant for the adipic acid production. The above effective substrate binding pocket engineering strategy can be beneficial for the production of other industrially competitive biobased chemicals when be applied to other thiolases.

Color vision, which is mediated by cone photoreceptors in vertebrates, is essential for perceiving the external environment. Bisphenol A (BPA) and its substitute bisphenol S (BPS) have been widely used worldwide, while the evaluation of their safety, especially the newly discovered visual toxicity mechanism caused by them in recent years, has not been clearly explored. In the present study, we investigated the effects of BPA treatment (1, 10, and 100 μg/L) on cone cell development and function to evaluate visual toxicity. We also compared the mechanisms of color deficiency induced by BPA and BPS at the same concentrations. The results indicated that BPA (10 and 100 μg/L) caused the abnormal proliferation (increased number of cone cells), morphological abnormalities (increased height of cone cells), mosaic pattern disorder, and depressed expression of key genes related to the photo-transduction pathway, and impaired the light perception ability of both red and UV cones ultimately. Similar to the BPA exposure group, BPS (1, 10, and 100 μg/L) exposure resulted in structural damage and mosaic arrays disorder of red and UV cone photoreceptors. In contrast to BPA exposure, BPS exposure resulted in significant activation of key genes involved in the phototransduction pathway. Our data indicate that both BPS and BPA exposure can interfere with the development of cone cells, and two types of compounds disturb the transduction of photon signals within cone cells in different ways, which further impaired the retinal spectral sensitivity to the light signal. This study clarifies the root cause for color vision impairment induced by BPA from the perspective of cone-mediated color vision. It also clarified that the BPA and its substitute BPS may not be entirely safe at the single-cell level.

Excessive lipid accumulation promotes the occurrence and progression of hepatocellular carcinoma (HCC), accompanied by high levels of fatty acid synthetase (FASN) and more active lipogenesis. Heat shock protein 90 (Hsp90) acts as a chaperone to maintain the stability and activity of the client proteins. Studies have revealed that Hsp90 regulates the lipid metabolism of HCC, but the effect of Hsp90 on FASN still remains unknown. This study aims to discover the mechanism of Hsp90 inhibition on lipid accumulation and investigate the different effects of Hsp90 N-terminal domain inhibitor STA9090 and C-terminal domain inhibitor novobiocin on FASN protein stability and transcription pathway in HCC. We found that HCC cells tended to store lipids, which could be disrupted by Hsp90 inhibitors in vivo and in vitro. High levels of Hsp90α and FASN in tumor tissue had correlation with poor prognosis of HCC patients, and Hsp90α interacted with FASN to maintain its protein stability. Furthermore, N-terminal domain of Hsp90α was essential for process of sterol regulatory element binding protein 1 to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α to upregulate FASN transcription via liver X receptor α/sterol regulatory element binding protein 1 axis. Our data reveal that Hsp90α promotes lipid accumulation by increasing the protein stability and FASN mRNA transcription, and can be alleviated by Hsp90 inhibitors, which provides a theoretical basis for Hsp90-targeted therapy on lipid metabolism in HCC.

Acute kidney injury remains a serious condition with a high mortality risk. In the absence of any new drugs, renal replacement therapy (RRT) is the most important treatment option. Randomized controlled trials have concluded that in critically ill patients without an emergency indication for RRT, a watchful waiting strategy is safe; however, further delays in RRT did not seem to confer any benefit, rather was associated with potential harm. During this process, balancing the risks of complications due to an unnecessary intervention with the risk of not correcting a potentially life-threatening complication remains a challenge. Dynamic renal function assessment, especially dynamic assessment of renal demand-capacity matching, combined with renal biomarkers such as neutrophil gelatinase-associated lipocalin and furosemide stress test, is helpful to identify which patients and when the patients may benefit from RRT.

Despite the widespread use of R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL), the therapeutic efficacy for this disease remains suboptimal, primarily due to the heterogeneity of refractory and/or relapsed diseases. To address this challenge, optimization of DLBCL treatment regimens has focused on the strategy of combining an additional drug “X” with R-CHOP to enhance efficacy. However, the failure of R-CHOP combined with the BTK inhibitor ibrutinib in treating ABC-type DLBCL patients has raised significant concerns regarding ibrutinib resistance. While some studies suggest that venetoclax may synergize with ibrutinib to kill ibrutinib-resistant cells, the underlying mechanisms remain unclear. Our study aimed to validate the enhanced tumor-suppressive effect of combining ibrutinib with venetoclax against ibrutinib-resistant cells and elucidate its potential mechanisms. Our experimental results demonstrated that ibrutinib-resistant cells exhibited significant cytotoxicity to the combination therapy of ibrutinib and venetoclax, inducing cell apoptosis through activation of the mitochondrial pathway and inhibition of aerobic respiration. Furthermore, we validated the inhibitory effect of this combination therapy on tumor growth in in vivo models. Therefore, our study proposes that the combination therapy of ibrutinib and venetoclax is a promising treatment strategy that can be applied in clinical practice for ABC-type DLBCL, offering a new solution to overcome the urgent challenge of ibrutinib resistance.

20CrMnTi steel is widely used in the gear manufacturing field of engineering machinery. The addition of Ti element to steel can effectively improve its low-temperature impact toughness and enhance its mechanical properties. However, during the smelting process of 20CrMnTi, large-sized TiN inclusions are inevitably formed in the steel, which affects its service performance improvement. This paper focuses on the directional modification behaviors of TiN inclusions in 20CrMnTi gear steel by rare earth Ce under deoxygenation conditions of Si–Ca–Ba alloy. The results show that under the deoxygenation conditions of Si–Ca–Ba alone, there are composite inclusions in 20CrMnTi steel with CaAl12O19 as the core and TiN wrapped around the periphery, all of which have sizes greater than 2 μm. This type of inclusion is square or diamond shaped, and the addition of Si–Ca–Ba deoxygenation alone has poor TiN modification effect on gear steel 20CrMnTi. Adding Ce element can effectively improve the nucleation core of inclusions. The CeAlO3–TiN and (CaAl12O19–Ba–Ce)–TiN composite inclusions are formed, and the TiN inclusions are modified in terms of morphology and size. The average size of inclusions decreases from 4.1 to 3.0 μm, which prevented the excessive growth of pure TiN inclusions to some extent.

20CrMnTi gear steel has high low-temperature impact toughness and is widely used in the manufacturing of engineering machinery such as automotive transmission gears. The sizes and distributions of TiN inclusions have a significant impact on the service performances of 20CrMnTi gear steel. Controlling the growth behaviors and size distributions of TiN inclusions are the foundation for stable, high-quality, and efficient production of 20CrMnTi gear steel. This paper uses experimental and computational methods to study the effects of different ratios of Al–Ce composite deoxidizers on the modification behaviors of TiN inclusions in 20CrMnTi steel. The results show that the TiN inclusions in 20CrMnTi steel without Al–Ce composite deoxidizer are square in shape, with a size of approximately 4 μm. After Al–Ce composite deoxidation, a composite phase inclusion is formed in the steel, which has contracted edges and corners. The center is the nucleation core composed of elements such as Ce, Al, O, etc. The elements of Ti and N are wrapped around the periphery of the composite inclusion, reducing its size to 2 μm. When the ratio of Al and Ce in the Al–Ce composite deoxidizer is 7:3, the number of TiN inclusions in steel is the highest, accounting for 51.7% of the total amount of titanium inclusions. The average diameter of inclusions in the modified steel decreases to 2.4 μm. When the ratio of Al and Ce elements is 8:2 and 7:3, the final deoxygenation product is CeAlO3, which is more conducive to the modification of TiN inclusions in 20CrMnTi steel.

Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. Results: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; p < 0.001), DNMT3A mutations (HR = 3.01 [1.57, 5.78]; p < 0.001), FLT3-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; p < 0.001) and DDX11 mutations (HR = 4.38 [2.38, 8.04]; p < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; p < 0.001; HR = 2.99 [1.60, 5.62]; p < 0.001; HR = 4.20 [1.87, 9.40]; p < 0.001; and HR = 4.22, 95% CI [1.99, 8.95], p < 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. Conclusions: We identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML.

A novel screening platform based on an Fe3O4@C@PDA-Ni2+@COX-2 ligand fishing combination with high-performance liquid chromatography–mass spectrometry was first designed, synthesized, and employed to screen and identify COX-2 inhibitors from Panax notoginseng leaves. The obtained magnetic nanoparticles exhibit outstanding preconcentration ability that allows for controlling the enzyme orientation to avoid enzyme active site blocking, conformational changes, or denaturing during immobilization. The as-prepared Fe3O4@C@PDA-Ni2+@COX-2 composite was carefully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectrometry (FT-IR), Xray powder diffraction (XRD), thermal gravimetric analyzer (TGA), vibrating sample magnetometer (VSM), and Zeta potential analysis. The analytical parameters influencing the magnetic solid-phase fishing efficiency were optimized by univariate and multivariate methods (Box–Behnken design) by testing a positive control and celecoxib with active and inactive COX-2. Under the optimized ligand fishing conditions, twelve potential COX-2 inhibitors were screened and characterized in Panax notoginseng leaves. The results indicate that the proposed method provides a simple, feasible, selective, and effective platform for the efficient screening and identification of active compounds from Chinese herbal medicine. It has guiding significance for the synthesis and development of novel anti-inflammatory drugs, and provides a reference for the efficient discovery of anti-inflammatory drugs or lead compounds from the complex system of Chinese herbal medicine.

Abstract Background In the ICU ward, septic cirrhotic patients are susceptible to suffering from sepsis-associated encephalopathy and/or hepatic encephalopathy, which are two common neurological complications in such patients. However, the mutual pathogenesis between sepsis-associated and hepatic encephalopathies remains unclear. We aimed to identify the mutual hub genes, explore effective diagnostic biomarkers and therapeutic targets for the two common encephalopathies and provide novel, promising insights into the clinical management of such septic cirrhotic patients. Methods The precious human post-mortem cerebral tissues were deprived of the GSE135838, GSE57193, and GSE41919 datasets, downloaded from the Gene Expression Omnibus database. Furthermore, we identified differentially expressed genes and screened hub genes with weighted gene co-expression network analysis. The hub genes were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analyses, and protein-protein interaction networks were constructed. Receiver operating characteristic curves and correlation analyses were set up for the hub genes. Finally, we explored principal and common signaling pathways by using Gene Set Enrichment Analysis and the association between the hub genes and immune cell subtype distribution by using CIBERSORT algorithm. Results We identified seven hub genes—GPR4, SOCS3, BAG3, ZFP36, CDKN1A, ADAMTS9, and GADD45B—by using differentially expressed gene analysis and weighted gene co-expression network analysis method. The AUCs of these genes were all greater than 0.7 in the receiver operating characteristic curves analysis. The Gene Set Enrichment Analysis results demonstrated that mutual signaling pathways were mainly enriched in hypoxia and inflammatory response. CIBERSORT indicated that these seven hub genes were closely related to innate and adaptive immune cells. Conclusions We identified seven hub genes with promising diagnostic value and therapeutic targets in septic cirrhotic patients with sepsis-associated encephalopathy and/or hepatic encephalopathy. Hypoxia, inflammatory, and immunoreaction responses may share the common downstream pathways of the two common encephalopathies, for which earlier recognition and timely intervention are crucial for management of such septic cirrhotic patients in ICU.

The backscatter characteristics of ocean surfaces are of great importance in active marine remote-sensing fields. This paper presents the high spatial and temporal resolution dual co-polarized (VV and HH) and cross-polarized (HV) Ka-band sea-surface backscattering measurements taken from the Yellow Sea research platform at incidence angles ranging from 30° to 50° and in the wind speed range from 5.8 to 8.6 m/s. The experimental results show that the backscattering coefficient in HH polarization is close to (or even surpassing) that in VV polarization within a wind speed range of 7.1 to 8.6 m/s for Ka band under high resolution at medium incidence angles (30°–50°). Further analysis of the 10-ms short-time observation samples found that the sea surface echoes in VV polarization are more sensitive to wave motions, exhibiting more complex scattering characteristics such as multi-peaks and reducing scattering energy, especially at high wind speeds and large incident angles. The Doppler velocity analysis also confirms that rapid ocean wave changes can be detected within a short observation period, especially in VV polarization. The research in this article not only demonstrates the high spatial and temporal resolution capabilities of Ka-band radar for ocean surface observation but also reveals its great potential in interpreting and inversing rapidly evolving marine phenomena.

Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient’s liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.

Background: Patients with leukemia rely on social and family support. This study aimed to explore the knowledge, attitude, and practice (KAP) toward leukemia among family members of patients with leukemia and the general population in southeast China. Methods: A cross-sectional study was conducted in September 2022 in southeast China (Anhui Province). The KAP scores and demographic data were assessed by questionnaire and analyzed by multivariable logistic regression and structural equation modeling. Results: A total of 760 valid questionnaires were collected, including 117 (15.39%) answered by family members of patients with leukemia. The mean knowledge (8.30 ± 2.79 vs. 8.72 ± 2.56, P = 0.103), attitude (52.17 ± 5.52 vs. 52.27 ± 5.53, P = 0.862), and practice (8.06 ± 2.00 vs. 8.18 ± 2.05, P = 0.547) scores were comparable among family members and the general population. Higher knowledge scores [OR = 1.18 (1.10, 1.27), P

A NHC-catalyzed hypervalent iodine reagents and transition-metal free redox-neutral dearomatization of phenols is reported. This protocol provides an efficient access for highly congested quaternatry carbon centers construction. It also features operationally simplicity, mild reaction conditions and good functional group tolerance. Moreover, the reported procedure can be easily emplified to 1 ​g scale. Mechanism study reveals the dearomative transformation possibly undergoes a single electron transfer process with NHC radical cation as a reactive intermediate.

Abstract Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, with a high morbidity and mortality rate. Exogenous vitamin C supplementation is a potential therapeutic option for the treatment of multi-organ dysfunction in sepsis due to the significantly lower levels of vitamin C in the circulating blood of sepsis patients compared to healthy subjects and the importance of vitamin C in many of the physiological processes of sepsis. Vitamin C may influence the function of numerous organs and systems, including the heart, lungs, kidneys, brain, and immune defences, by reducing oxidative stress, inhibiting inflammatory factor surges, regulating the synthesis of various mediators and hormones, and enhancing immune cell function. With the development of multiple clinical randomized controlled trials, the outcomes of vitamin C treatment for critically ill patients have been discussed anew. This review's objectives are to provide an overview of how vitamin C affects various organ functions in sepsis and to illustrate how it affects each organ. Understanding the pharmacological mechanism of vitamin C and the organ damage caused by sepsis may help to clarify the conditions and clinical applications of vitamin C.

We describe animal-to-human transmission of SARS-CoV-2 in a zoo setting in Indiana, USA. A vaccinated African lion with physical limitations requiring hand feeding tested positive for SARS-CoV-2 after onset of respiratory signs. Zoo employees were screened, monitored prospectively for onset of symptoms, then rescreened as indicated; results were confirmed by using reverse transcription PCR and whole-genome virus sequencing when possible. Traceback investigation narrowed the source of infection to 1 of 6 persons. Three exposed employees subsequently had onset of symptoms, 2 with viral genomes identical to the lion’s. Forward contact tracing investigation confirmed probable lion-to-human transmission. Close contact with large cats is a risk factor for bidirectional zoonotic SARS-CoV-2 transmission that should be considered when occupational health and biosecurity practices at zoos are designed and implemented. SARS-CoV-2 rapid testing and detection methods for big cats and other susceptible animals should be developed and validated to enable timely implementation of One Health investigations.

BackgroundLiver hepatocellular carcinoma (LIHC) is a prevalent form of primary liver cancer. Research has demonstrated the contribution of tumor stem cells in facilitating tumor recurrence, metastasis, and treatment resistance. Despite this, there remains a lack of established cancer stem cells (CSCs)-associated genes signatures for effectively predicting the prognosis and guiding the treatment strategies for patients diagnosed with LIHC.MethodsThe single-cell RNA sequencing (scRNA-seq) and bulk RNA transcriptome data were obtained based on public datasets and computerized firstly using CytoTRACE package and One Class Linear Regression (OCLR) algorithm to evaluate stemness level, respectively. Then, we explored the association of stemness indicators (CytoTRACE score and stemness index, mRNAsi) with survival outcomes and clinical characteristics by combining clinical information and survival analyses. Subsequently, weighted co-expression network analysis (WGCNA) and Cox were applied to assess mRNAsi-related genes in bulk LIHC data and construct a prognostic model for LIHC patients. Single-sample gene-set enrichment analysis (ssGSEA), Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) analysis were employed for immune infiltration assessment. Finally, the potential immunotherapeutic response was predicted by the Tumor Immune Dysfunction and Exclusion (TIDE), and the tumor mutation burden (TMB). Additionally, pRRophetic package was applied to evaluate the sensitivity of high and low-risk groups to common chemotherapeutic drugs.ResultsA total of four genes (including STIP1, H2AFZ, BRIX1, and TUBB) associated with stemness score (CytoTRACE score and mRNAsi) were identified and constructed a risk model that could predict prognosis in LIHC patients. It was observed that high stemness cells occurred predominantly in the late stages of LIHC and that poor overall survival in LIHC patients was also associated with high mRNAsi scores. In addition, pathway analysis confirmed the biological uniqueness of the two risk groups. Personalized treatment predictions suggest that patients with a low risk benefited more from immunotherapy, while those with a high risk group may be conducive to chemotherapeutic drugs.ConclusionThe current study developed a novel prognostic risk signature with genes related to CSCs, which provides novel ideas for the diagnosis, prognosis and treatment of LIHC.

The multiple etiological characteristics of acute kidney injury (AKI) have brought great challenges to its clinical diagnosis and treatment. Renal injury in critically ill patients always indicates hemodynamic injury. The Critical Care UltraSound Guided (CCUSG)-A(KI)BCDE protocol developed by the Chinese Critical Ultrasound Study Group (CCUSG), respectively, includes A(KI) diagnosis and risk assessment and uses B-mode ultrasound, Color doppler ultrasound, spectral Doppler ultrasound, and contrast Enhanced ultrasound to obtain the hemodynamic characteristics of the kidney so that the pathophysiological mechanism of the occurrence and progression of AKI can be captured and the prognosis of AKI can be predicted combined with other clinical information; therefore, the corresponding intervention and treatment strategies can be formulated to achieve targeted, protocolized, and individualized therapy.

Objective To explore the relationship between body mass index (BMI) and health-related physical fitness among late adolescent college students, and to provide evidence for adolescent health promotion. MethodsThe data on 30523 first-year college students of Guangxi Normal University were collected from the National Student Physical Fitness Surveillance conducted annually from 2017 to 2021 for examining the association between body mass index (BMI) and health-related physical fitness among the students. Results The mean BMI for all the students aged 18.3 ± 0.3 years was 20.46 ± 2.89 (21.51 ± 3.47 for 7407 males, 20.13 ± 2.59 for 23116 females). Of the male students, 71.8%, 9.1%, 13.3%, and 5.8% were assessed as having normal weight (BMI > 17.8 and < 24.0), underweight (BMI ≤ 17.8), overweight (BMI ≥ 24.0 and < 28.0), and obesity (BMI ≥ 28.0); of the female students, 85.8%, 7.0%, 5.8%, and 1.4% were having normal weight (BMI > 17.1 and < 24.0), underweight (BMI ≤ 17.1), overweight, and obesity; while for all the students, those proportions were 82.4%, 7.5%, 7.6%, and 2.5%, respectively. The physical fitness index (PFI) of the male students with underweight (0.006 ± 2.719), overweight (– 1.823 ± 2.995) or obesity (– 4.621 ± 3.268) were significantly lower than that of the students with normal weight (0.708 ± 2.946) (all P < 0.01); the PFI of the female students with overweight (– 1.677 ± 2.944) or obesity (– 3.787 ± 3.425) were significantly lower than that of the students with normal weight (0.177 ± 2.974) (both P < 0.01). There exists a quadratic curve relationship between PFI and BMI for the students, with the maximum PFI values of 0.845 and 0.215 corresponding to the BMI of 18.0 and 17.3 for the male and female students. The results of binary logistic regression analysis showed that compared to those with normal weight, the underweight, overweight, and obese students were at an increased risk of having low PFI, with the odds ratios (95% confidence interval) of 1.82 (1.49 – 2.22), 5.20 (4.09 – 6.61), and 16.81 (9.21 – 30.68) for the males and 1.21 (1.07 – 1.36), 3.10 (2.59 – 3.70), and 8.13 (4.76 – 13.91) , respectively. ConclusionIn late adolescent college students, maintaining a normal BMI is the basis for ensuring physical fitness; both underweight and overweight could exert an adverse effect on health-related physical fitness and the adverse effect of overweight and obesity are much stronger.

In recent years, China attaches great importance to the prevention and treatment of rare diseases. As one of the representative diseases of rare diseases, management of Hemophilia has made great progress in China. From 1986 to 1989, the National Hemophilia Cooperative Group conducted China's hemophilia epidemiological survey according to the unified method and standard, and the results showed that the prevalence of hemophilia was 2.73/100 000, and there was no statistical difference in prevalence among different regions. In 2014, Meta-analysis showed that the prevalence of hemophilia in China was 2.8/100 000, and in 2018, based on the data of the urban population of Tianjin, the local prevalence of hemophilia was estimated to be 3.09/100 000. With the comprehensive promotion of the construction of hemophilia hierarchical diagnosis and treatment system, China requires that hospitals applying for hemophilia comprehensive management centers and diagnosis and treatment centers must be able to independently carry out screening tests and confirmatory tests related to hemophilia diagnosis. For diagnosis of hemophilia, most laboratories in China usually adopt the one-stage method (coagulation method) based on the activated partial thromboplastin time (APTT) for the determination of coagulation factor activity, but it should be noted that more than two activity detection methods are required for some special types of hemophilia. The types of each mutation in the F8 gene of patients in China are similar to those reported in international data, and the mutations in the F9 gene of our patients are mainly single base point mutations, with no mutation hotspots found. As of June 2023, a total of more than 40 000 cases with inherited bleeding disorders registered in 261 centers in China (including hemophilia), through the National Hemophilia Registration System. The history of hemophilia treatment in China has been explored through inadequate on-demand and low-dose prophylaxis, and is now moving towards higher-dose prophylaxis and individualized prophylaxis with higher efficacy. Based on the above registry data and literature, this report comprehensively summarizes the progress of basic and clinical research and medical protection in the field of hemophilia in China, and analyzes the shortcomings for further improvement of hemophilia diagnosis and treatment in China.

Abstract Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278–16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

Abstract Purpose The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85–90%, with a 10–15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. Methods We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher’s exact test for categorical variables. Results A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P

Abstract Background Classical swine fever and porcine reproductive and respiratory syndrome have seriously affected the development of the swine breeding industry in China. Vaccine immunization remains the main way to prevent these infections. The aim of this study was to establish an optimized protocol for vaccine immunization against classical swine fever virus (CSFV) and porcine reproductive and respiratory syndrome virus (PRRSV). Methods Blood samples were collected from the anterior vena cava of pigs after immunization, and blood indices, secreted levels of specific antibodies and neutralizing antibodies associated with humoral immunity, the proliferation capacity of T lymphocytes as a measure of cellular immunity, and secreted levels of IFN-γ and TNF-α were determined. Results The results showed that simultaneous immunization against CSFV and PRRSV infections induced strong and specific humoral and T-cellular immune responses, high levels of cytokine IFN-γ secretion and delayed secretion of cytokine TNF-α. Moreover, significantly higher lymphocyte percentages and red blood cell and leukocyte counts were found in the group simultaneously immunized against CSFV and PRRSV. However, no statistically significant differences were observed in hemoglobin values, neutrophil counts, and median cell percentages among the S + PRRS, PRRS-S, and S-PRRS groups. Conclusion This study demonstrated that simultaneous immunization against CSFV and PRRSV had the advantages of inducing a rapid, enhanced, and long-lasting immune response. These findings provide a theoretical basis for the establishment of a reasonable and optimized vaccine immunization protocol against CSFV and PRRSV in combination with a variety of other vaccine inoculations.

Background: Several prognostic biomarkers have been validated for acute myeloid leukemia (AML), a heterogeneous hematopoietic malignancy. However, the factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in real-world patients with AML have not been well defined. Methods: This study examined clinical and mutational data of 246 patients with newly diagnosed AML who received the traditional “3 ​+ ​7” regimen in PLA General Hospital from January 2008 to August 2020. Factors associated with CIR and LFS in patients newly diagnosed with AML were analyzed using next-generation sequencing. Results: Additional sex combs-like 1 (ASXL1) and Serine/arginine-rich splicing factor 2 (SRSF2) mutations were found to be associated with an increased risk of CIR and a reduced LFS in univariate analysis, while only SRSF2 mutations were associated with these factors in the multivariate analysis. Hyperleukocytosis maintained an independent effect on LFS in the multivariate analysis. Hematopoietic stem cell transplantation conferred a significant prognostic benefit on both CIR and LFS in our cohort. Furthermore, we validated the risk classification of patients with AML receiving traditional induction regimens across a broad age range. Based on next-generation sequencing results, we concluded that SRSF2 mutations were predictive of an increased risk of relapse, inferior LFS rates, and non-relapse mortality in patients with newly diagnosed AML. Conclusion: These findings indicate that patients with SRSF2 mutations might not benefit from the conventional “3 ​+ ​7” regimen. Our results may help in developing molecular stratification strategies and could guide treatment decisions for patients with newly diagnosed AML.

Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.

BackgroundMethotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported.MethodsHere, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center.ResultsWe discovered all gene polymorphisms were in the Hardy–Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II–IV aGvHD (HR = 2.604, p = 0.039).ConclusionIn summary, our findings prove that the host’s genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis.

The half-logistic (HL) distribution is a widely considered statistical model for studying lifetime phenomena arising in science, engineering, finance, and biomedical sciences. One of its weaknesses is that it has a decreasing probability density function and an increasing hazard rate function only. Due to that, researchers have been modifying the HL distribution to have more functional ability. This article provides an extensive overview of the HL distribution and its generalization (or extensions). The recent advancements regarding the HL distribution have led to numerous results in modern theory and statistical computing techniques across science and engineering. This work extended the body of literature in a summarized way to clarify some of the states of knowledge, potentials, and important roles played by the HL distribution and related models in probability theory and statistical studies in various areas and applications. In particular, at least sixty-seven flexible extensions of the HL distribution have been proposed in the past few years. We give a brief introduction to these distributions, emphasizing model parameters, properties derived, and the estimation method. Conclusively, there is no doubt that this summary could create a consensus between various related results in both theory and applications of the HL-related models to develop an interest in future studies.

This study investigates the foundational elements that contribute to effective emergency management in urban settings, with a particular focus on experiences from Chinese municipalities. Drawing on resource dependence theory and attention allocation theory, this research develops an analytical framework encompassing four pivotal factors: environmental resources, information sharing, social participation, and leadership attention allocation. Utilizing Qualitative Comparative Analysis (QCA), we examine these factors across sixteen critical incidents of urban accidents and disaster responses in China. Our findings reveal that a high degree of leadership attention allocation is an essential prerequisite for municipal governments to exhibit robust emergency management capabilities during crises. Furthermore, two primary pathways affecting emergency management capacity were identified: the “resource–leadership attention type” and the “social participation–resource coordination type”. These findings contribute to a nuanced understanding of the complexities of emergency management and enlighten the local governments to take some effective measures to enhance emergency management capacities to mitigate disaster losses.

In order to optimize the nuclear material accounting of spent fuel reprocessing facilities and find the main factors of the material unaccounted for (MUF), a numerical simulation model based on nuclear material accounting perspective is built, which includes the front-end process, PUREX process, uranium and plutonium back-end and MUF calculations. The material flow rate in the model can be changed easily by changing different process parameters to simulate different production scale. The simulated material measurement error comprising of random and system errors are simulated by normal distributed random variables and constant numbers respectively, which have the similar randomness and statistical features with the actual measurement uncertainty. When the model measurements are set to different random and system errors, the corresponding square error distribution and improvement direction can be obtained, by which a better measurements precision combination satisfying the uncertainty requirement can be found. The final results show that the system error of the 1AF measurement is the main source of the MUF.

Purpose: To evaluate the accuracy of intraoral scanners by comparing the marginal fit of 70 all-ceramic crowns fabricated from both conventional impressions and intraoral scans. Materials and Methods: A total of 70 posterior teeth requiring single-crown restorations randomly underwent either intraoral scanning or conventional impression-taking, followed by laboratory scanning of the casts in a parallel-group randomized controlled trial (RCT). Subsequently, 70 monolithic all-ceramic crowns were CAD/CAM fabricated; only the impression technique differed. The marginal fit, internal fit, adjustment time required for insertion and occlusal contacts, and visual analog scale (VAS) scores assessing dentists' satisfaction with the crowns were clinically evaluated by a calibrated examiner who was blinded to the groups. Data were analyzed using independent samples t test and likelihood-ratio test or Fisher exact test. All tests were performed with α = .05. Results: The mean marginal fit with intraoral scanning (57.94 ± 22.51 µm) was better than with diagnostic cast scanning (82.98 ± 21.72 µm). The difference was statistically significant (P = .000). The differences in internal fit, adjustment time for crown insertion and occlusal contacts, and VAS scores were also significant, and the secondary outcomes were in favor of intraoral scanning. Conclusions: Within the limitations of this clinical trial, CAD/CAM--fabricated single-tooth restorations in the posterior region produced with an intraoral scanning technique using TRIOS were found to be a more accurate, efficient alternative to restorations based on conventional impressions in combination with the laboratory scanning technique. [ABSTRACT FROM AUTHOR]