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.

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.

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 evaluate the dosimetric effect of three-dimensional(3D)printed headrests made of different materials in radiotherapy for head and neck tumor,and to evaluate whether the existence of customized 3D-printed headrest can be neglected during planning phase by comparing differences in target area doses,homogeneity index(HI),conformity index(CI),monitor units(MU),and organ-at-risk(OAR)dose.Methods Ten patients with head and neck tumors,including 5 cases with nasopharyngeal carcinoma and 5 with other head and neck tumors,were enrolled.The headrest contours were outlined using Monaco treatment planning system,and with the same calculation parameters,treatment plans were generated for scenarios without a headrest,with a standard headrest,and with 3D-printed headrests made of 10%filled polylactic acid and thermoplastic polyurethane.The target area doses,OAR dose,MU,and other results were recorded and subjected to statistical analysis.Results No significant differences were observed among the 4 groups(ignoring headrest,standard headrest,3D-printed headrests with 10%filled polylactic acid and thermoplastic polyurethane)in parameters such as D95,D5,Dmean,HI,CI,MU,and OAR dose(the maximum dose to the spinal cord)(P>0.05).Considering the presence of the headrest,significant differences were found in CI for nasopharyngeal carcinoma and other head and neck tumors(P<0.05).Conclusion During the planning phase,the existence of customized 3D-printed headrest can be ignored,but it should be noted that the presence of a headrest may reduce the MU in radiotherapy plans.When considering the headrest,the average CI of patients with other head and neck tumors is significantly higher than that with nasopharyngeal carcinoma.

Objective:To evaluate the efficacies of intravenous immunoglobulin (IVIG) in the clearance of Bovine Kobu (BK) virus and treatment of BK virus nephropathy (BKVN) in kidney transplantation recipients.Methods:From March 1, 2018 to March 31, 2022, the relevant clinical data were retrospectively reviewed for 13 kidney transplantation recipients with histologically proven BKVN on a full course of IVIG. The changes of serum creatinine and glomerular filtration rate (GFR) were compared before and after Month 1/3/6/12. Univariate Cox regression analysis was performed for examining the overall risk factors of BK virus clearance failure.Results:kidney transplantation (12 cases) and combined pancreatorenal transplantation (1 case) were performed. Among them, 9/13 patients were pathologically classified as stage A (early changes without tubular necrosis) and another 4 cases as stage B (active nephropathy with viral tubular necrosis). After IVIG dosing, all patients with BK virus in blood turned negative. Urinary BK virus DNA load of 7 patients with BK virus declined by 10 3 copies/ml, and 6 patients with BK virus in urine turned negative. Blood BK viral DNA load, urinary BK viral DNA load, GFR and serum creatinine before IVIG were 26 100 (1 000, 254 000) copies /ml and 1 450 (438, 7 480) ×10 6 copies /ml, (35. 36±14. 57) ml/min and (208. 50±66. 89) μmol/L, respectively, after 12 months of use of IVIG were 0、0(0, 0. 58) ×10 6 copies/ml、(46. 05±13. 00) ml/min and(175. 38±50. 64) μmol/L, the differences were statistically significant ( P=0. 012, 0. 027, 0. 046 and 0. 039) . Univariate Cox regression analysis showed that the overall risk factor for viral clearance failure was high initial viral load ( HR=0. 780, 95% CI: 0. 64-0. 98, P=0. 032) , concurrent transplanted kidney rejection ( HR=0. 847, 95% CI: 0. 52-0. 93, P=0. 013) and higher BKVN grade ( HR=0. 426, 95% CI: 0. 22-0. 81 , P=0. 010) were the overall risk factors for urinary BK virus clearance failure. No major adverse events occurred. Conclusions:IVIG may achieve a high efficacy of BK virus clearance. IVIG is effective in the treatment of BKVN. The graft renal function was stable or improved after treatment.