ObjectiveTo screen key genes associated with neuroblastoma （NB） diagnosis and prognosis using the Gene Expression Omnibus （GEO） database， and to investigate the expression and clinical significance of nucleoporin 93 （NUP93） in NB tissues. MethodsNB gene chip data （GSE73517， GSE49710， GSE19274） were retrieved from the GEO database. Differentially expressed genes （DEGs） commonly upregulated in high-risk groups were screened. The R2 database was then used to assess the prognostic value of DEGs that were commonly upregulated in the MYCN amplification group. Finally， NUP93 expression levels in the tissues from 60 NB， 25 ganglioneuroblastoma （GNB）， and 26 ganglioneuroma （GN） cases were measured by immunohistochemistry . ResultsTwenty-five DEGs were identified as commonly upregulated in high-risk groups. Among these， 10 genes （SIVA1， NUP93， STIP1， LSM4， RAI14， MYOZ3， KNTC1， TNFRSF10B， TACC3 and CEP152） showed significantly higher expression in MYCN-amplified subgroups （P＜0.05）. Survival analysis revealed that high NUP93 expression was associated with shorter overall survival （HR = 4.0， 95% CI： 3.0，5.3， P = 1.80 × 10⁻³⁴）. Immunohistochemistry results revealed that NUP93 expression in NB tissues was significantly higher than in GNB and GN tissues （P＜0.001）. NUP93 expression was positively correlated with high mitosis-karyorrhexis index （MKI； P=0.040）， poor differentiation （P＜0.001）， and MYCN expression （r_s = 0.793， P ＜0.001）. ConclusionsHigh expression of NUP93 is associated with high MKI and poor differentiation， and predicts unfavorable prognosis in patients with NB， suggesting it may promote tumor progression by regulating MYCN. NUP93 has the potential to be a novel diagnostic biomarker and therapeutic target for NB.

Bloodstream infections(BSIs) are associated with high morbidity and mortality. The widespread emergence of antimicrobial resistance has significantly increased the complexity of treating BSIs, making the development of precise antimicrobial treatment strategies based on positive blood culture results a critical clinical challenge. Additionally, it is imperative to systematically correct traditional misconceptions to optimize treatment outcomes and alleviate the pressure of antimicrobial selection. This article provides an in-depth exposition across the following dimensions, including bloodstream infection diagnosis, infection source identification, antimicrobial treatment regimen formulation, etc., to optimize the diagnostic and therapeutic process for patients with positive blood culture results.

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr ^-/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680^+/+) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680^+/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680^+/+ mice.
Animals ; Prefrontal Cortex/metabolism* ; Basolateral Nuclear Complex/metabolism* ; Mice ; Anxiety/metabolism* ; Nerve Tissue Proteins/genetics* ; Male ; Gene Knock-In Techniques ; Pyramidal Cells/physiology* ; Mice, Transgenic ; Neural Pathways/physiopathology* ; Mice, Inbred C57BL ; Microfilament Proteins

Stem-leaf saponins from Panax notoginseng (SLSP) comprise numerous PPD-type saponins with diverse pharmacological properties; however, their role in Parkinson's disease (PD), characterized by microglia-mediated neuroinflammation, remains unclear. This study evaluated the effects of SLSP on suppressing microglia-driven neuroinflammation in experimental PD models, including the 1-methyl-4-phenylpyridinium (MPTP)-induced mouse model and lipopolysaccharide (LPS)-stimulated BV-2 microglia. Our findings revealed that SLSP mitigated behavioral impairments and excessive microglial activation in models of PD, including MPTP-treated mice. Additionally, SLSP inhibited the upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) and attenuated the phosphorylation of PI3K, protein kinase B (AKT), nuclear factor-κB (NFκB), and inhibitor of NFκB protein α (IκBα) both in vivo and in vitro. Moreover, SLSP suppressed the production of inflammatory markers such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in LPS-stimulated BV-2 cells. Notably, the P2Y2R agonist partially reversed the inhibitory effects of SLSP in LPS-treated BV-2 cells. These results suggest that SLSP inhibit microglia-mediated neuroinflammation in experimental PD models, likely through the P2Y2R/PI3K/AKT/NFκB signaling pathway. These novel findings indicate that SLSP may offer therapeutic potential for PD by attenuating microglia-mediated neuroinflammation.
Animals ; Panax notoginseng/chemistry* ; Saponins/pharmacology* ; Microglia/immunology* ; Mice ; NF-kappa B/immunology* ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/immunology* ; Phosphatidylinositol 3-Kinases/genetics* ; Male ; Parkinson Disease/immunology* ; Mice, Inbred C57BL ; Disease Models, Animal ; Plant Leaves/chemistry* ; Neuroinflammatory Diseases/drug therapy* ; Humans

Mercury (Hg)-contaminated soil poses a significant threat to the environment and human health. Hg-resistant microorganisms have the ability to survive under the stress of inorganic and organic Hg and effectively reduce Hg levels and toxicity. Compared to physical and chemical remediation methods, microbial remediation technologies have garnered increasing attention in recent years due to their lower cost, remarkable efficacy, and minimal environmental impact. This paper systematically elucidates the molecular mechanisms of Hg resistance in microbes, with a focus on their potential applications in phytoremediation of Hg-contaminated soils through plant-microbe interactions. Furthermore, it highlights the critical role of microbes in enhancing the effectiveness of transgenic plants for Hg remediation, aiming to provide a theoretical foundation and scientific basis for the bioremediation of Hg-contaminated soils.
Mercury/toxicity* ; Biodegradation, Environmental ; Soil Pollutants/isolation & purification* ; Soil Microbiology ; Plants, Genetically Modified/metabolism* ; Bacteria/genetics*

Hemoglobin A1c (HbA1c) has a unique structure that makes monoclonal antibody (mAb) preparation challenging. This study aims to develop a method for preparing HbA1c mAbs and establish a fluorescent immunochromatographic assay (FICA) for rapid detection of HbA1c. Three glycosylated peptides were synthesized and used to prepare complete antigens, which were identified by dot enzyme-linked immunosorbent assay (Dot-ELISA) and ultraviolet absorption spectroscopy. The complete antigens and natural HbA1c were used for cross-immunization of mice, and the optimal complete antigen was selected. The mouse with the highest serum titer was chosen for mAb preparation. The purity and specificity of the mAbs were verified, and a FICA method was developed. The optimal complete antigen, with a titer of 1:512 000, was successfully prepared and selected. Fusion with splenocytes resulted in four specific HbA1c antibodies (purity > 90%). The best antibody exhibited a binding constant (Ka) of 1.67×10¹⁰ L/mol with the antigen. Based on this antibody, a FICA method was successfully established, capable of producing results within 15 min. The method demonstrated a good linear range (3%-13% HbA1c, y=0.071 3x+0.005 6, R²=0.993 7), recovery rates of 98%-102%, precision < 10.00%, and no nonspecific reactions. Clinical testing of 210 samples showed positive agreement of 96.36%, negative agreement of 97.00%, and overall agreement of 96.68%. The receiver operating characteristic (ROC) curve analysis yielded an area under curve (AUC) of 0.980 9 [95% confidence interval (CI): 0.961 0-1.000 0], with high consistency verified in multicenter studies. We successfully developed a key technique for preparing HbA1c monoclonal antibodies and established a FICA method for rapid detection of HbA1c. It will provide an efficient and convenient detection method for the early diagnosis and long-term management of diabetes and its complications.
Antibodies, Monoclonal/biosynthesis* ; Animals ; Mice ; Glycated Hemoglobin/immunology* ; Mice, Inbred BALB C ; Humans ; Antibody Specificity ; Chromatography, Affinity/methods* ; Enzyme-Linked Immunosorbent Assay/methods* ; Female

  Objective  To establish a prediction model for non-curative resection in patients with early gastric cancer (EGC) who underwent endoscopic submucosal dissection (ESD), and to evaluate its predictive value.  Methods  Clinical data of EGC patients in the Second Hospital & Clinical Medical School, Lanzhou University from January 2014 to July 2023 were retrospectively collected. According to the postoperative pathological results of ESD, the patients were divided into curative resection group and non-curative resection group. Multifactorial Logistic regression analysis was used to screen the risk factors for non-curative resection after ESD surgery and establish a prediction model, and the model was evaluated using receiver operating characteristic(ROC) curves, calibration curves and clinical decision curve analysis.  Results  A total of 479 EGC patients who underwent ESD were included, with 60 cases in the non-curative resection group and 419 cases in the curative resection group. The results of multifactorial Logistic regression analysis showed that the lesion diameter > 2 cm (OR=3.017, 95% CI: 1.483-6.136, P=0.002), flat lesion morphology (OR=2.712, 95% CI: 0.774-9.497, P=0.043), undifferentiated/mixed histologic type (OR= 4.199, 95% CI: 1.621-10.872, P=0.003), and submucosal infiltration (OR=30.329, 95% CI: 13.059-70.436, P < 0.001) were independent risk factors for non-curative resection after ESD in EGC patients. The area under the curve of ROC validated within the column-line graph prediction model constructed accordingly was 0.867 (95% CI: 0.811-0.923), the calibration curve showed that the model had good calibration, and decision curve analysis showed the model had a good clinical usefulness.  Conclusions  The prediction model constructed based on lesion diameter, lesion morphology, histologic type, and depth of mucosal infiltration has good differentiation, calibration, and clinical utility. This model is expected to assist in the early clinical screening of the population at high risk for noncurative resection after ESD in patients with EGC, and to provide a basis for the development of optimal clinical decisions.

Background Results of genetic testing for antipsychotic drugs can guide the rational use of drugs in clinical practice and help improve the clinical symptoms of patients with schizophrenia.However,there is currently limited evidence in China regarding the impact of genetic testing results on medication adherence,social function and drug side effects of antipsychotic drug treatment.Objective To explore the improvement of clinical symptoms,medication adherence and social function in patients with schizophrenia under the guidance of antipsychotic drug gene testing results and examine the safety of drug treatment,so as to provide references for ifor precise treatment of schizophrenia patients.Methods Patients with acute schizophrenia who received hospitalization at Dazhou Minkang Hospital from July 2019 to August 2021 as well as met the diagnostic criteria of the International Classification of Diseases,tenth edition(ICD-10)were selected as research subjects(n=144).Based on random number table,subjects were divided into study group and control group,with 72 cases in each group.Control group received drug treatment based on the doctor's clinical experience,while study group received drug treatment based on the results of gene testing for antipsychotic drug.Both treatments lasted for 12 weeks.At baseline as well as 2,4,8 and 12 weeks after treatment,Positive and Negative Syndrome Scale(PANSS),8-item Morisky Medication Adherence Scale(MMAS-8),Social Functional Rating Scale(SFRS)and Treatment Emergent Symptom Scale(TESS)were adopted for assessment.Result Time effect and group effect of the reducing rate of PANSS,MMAS-8 and SFRS scores in the groups were statistically significant(Ftime=95.251,6.650,14.101,Fgroup=38.055,58.175,128.221,P<0.01).The interaction effect of the reduction rates of MMAS-8 scores in two groups was statistically significant(Finteraction=5.837,P<0.01).The group effect and interaction effect of the severity scores of drug side effects and patient pain scores in two groups were statistically significant(Fgroup=7.553,81.533,Finteraction=8.693,9.322,P<0.01).Conclusion In terms of improving clinical symptom relief,medication adherence,social function and drug side effects,medication for patients with schizophrenia guided by genetic testing of antipsychotic drugs may be more effective than that relying on medication based on clinical experience.