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Abstract Background Amotivation is regarded as a core negative symptom in patients with schizophrenia. There are currently no objective methods for assessing and measuring amotivation in the scientific literature, only a trend towards assessing motivation using effort-orientated, decision-making tasks. However, it remains inconclusive as to whether cognitive effort-avoidance in patients with schizophrenia can reflect their amotivation. Therefore, this study aimed to find out whether cognitive effort-avoidance in patients with schizophrenia can reflect their amotivation. Methods In total, 28 patients with schizophrenia and 27 healthy controls were selected as participants. The demand selection task (DST) was adapted according to the feedback-based Guilty Knowledge Test (GKT) delayed response paradigm, which was combined with the mean amplitude of contingent negative variation (CNV), considered as the criterion of motivation. Results Our results showed that: (1) patients with schizophrenia showed a lower CNV amplitude for the target stimuli compared to the probe stimuli, whereas the control group showed the opposite trend (P

ObjectiveGasdermin D (GSDMD), controlling pyroptosis in cells, has multiple physiological functions. The diagnostic role of GSDMD in pleural effusion (PE) remains unknown.MethodsSandwich ELISA kits that we developed were applied to measure the level of GSDMD for 335 patients with a definite cause of PE, including transudative PE, tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). The diagnostic accuracy of Light’s criteria vs. the new marker GSDMD was performed. Clinical follow-up of 40 cases of PPE was conducted and divided into efficacy and non-efficacy groups according to the therapeutic outcome. Nucleated cells (NCs) in PE were isolated and further infected with bacteria to verify the cell source of GSDMD.ResultsThe diagnostic accuracy of GSDMD for the diagnosis of PE were 96% (sensitivity) and 94% (specificity). The receiver operating characteristic (ROC) curve indicated that GSDMD can be an efficient biomarker for the differential diagnosis of transudative PE and other groups (all AUC > 0.973). Noteworthily, the highest AUC belonged to tuberculosis diagnosis of 0.990, and the cut-off value was 18.40 ng/mL. Moreover, the same cut-off value of PPE and MPE was 9.35 ng/mL. The combination of GSDMD, adenosine deaminase (ADA), and lactate dehydrogenase (LDH) will further improve the diagnostic efficiency especially between TPE and PPE (AUC = 0.968). The AUC of GSDMD change at day 4, which could predict the therapeutic effect at an early stage, was 0.945 (P < 0.0001). Interestingly, bacterial infection experiments further confirm that the pleural fluid GSDMD was expressed and secreted mainly by the NCs.ConclusionGSDMD and its combination are candidates as a potentially novel biomarker not only to separate PEs early and effectively, but also monitor disease progression.

Objective To explore the therapeutic mechanism of cordycepin for acute kidney injury （AKI） based upon gene chips in gene expression omnibus （GEO） database, network pharmacology, molecular docking and in vitro experiments. Methods Targeted genes of AKI were obtained from two databases, GEO （GSE87025） and GeneCards. Cordycepin-related targets were retrieved from three databases of TargetNet, BATMAN and GeneCards. The common targets of AKI and cordycepin were screened by taking the intersection of two sets. Molecular docking was performed for cordycepin and key targets after gene ontology （GO） annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. Cell experiments were performed for control, hypoxia/reoxygenation and hypoxia/reoxygenation+cordycepin groups for experimental verifications of the relevant targets. Results There were 12 common targets of AKI and cordycepin. GO functional annotation results indicated that these targets participated predominantly in negative regulation of apoptotic signaling pathway and necroptosis process. KEGG enrichment analysis results showed that they played some roles in signaling pathways of Toll-like receptor, necroptosis, nucleotide-binding oligomerization domain （NOD）-like receptor, nuclear factor-κB （NF-kB）, tumor necrosis factor （TNF） and cell apoptosis, etc. Optimal binding energy between cordycepin and receptor interacting protein kinase 1 （RIPK1） in molecular docking was -7.1, denoting potent binding activity. Western blot indicated that cordycepin down-regulated the expressions of RIPK1, bcl-2 associated x protein （Bax） and caspase 3 and up-regulated B cell lymphoma/lewkmia-2（Bcl-2）. Cell immunofluorescence results revealed that cordycepin down-regulated the expression of RIPK1. Conclusion Cordycepin may alleviate hypoxia/reoxygenation-induced renal tubular epithelial cell injury through regulating RIPK1-mediated apoptosis. Thus it achieves the therapeutic efficacy for AKI.

Abstract Objective To assess the infiltration characteristics of tumour-associated macrophages (TAMs) in buccal mucosa carcinoma (BMC) and the correlation of these features with clinicopathological factors. Materials and methods Immunohistochemistry was used to detect the expression of TAM-related markers (CD68, CD163, CD206), CD8+ T cell markers, PD-L1, and epidermal growth factor receptor (EGFR) in 46 patients with mucosal cancer after radical surgery. In addition, the correlation between TAM infiltration and clinical characteristics, PD-L1 expression, and EGFR expression was analysed. Results A high infiltration level of M2-polarized (CD206+) TAMs and M2-polarized (CD163+) TAMs was more common in stage T3–T4, N+, III–IV patients than in other patient groups (P

The present study focused on the action mechanism of S. pneumoniae (Sp) in inducing autophagy in human alveolar epithelial cells. Sp, a gram-positive extracellular bacterium, activates autophagy with considerably increased microtuble-associated protein light chain 3 (LC3) punctation in A549 cells. The accumulation of typical autophagosomes and conjugation of LC3 to phosphatidylethanolamine were observed in Sp-infected cells as an indication of autophagy. Using the pneumolysin (PLY) mutant, we successfully demonstrated that PLY is involved in initiating autophagy without affecting the expression levels of PI3K-III and Beclin1. PLY-mediated autophagy depends on the inhibition of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Furthermore, Sp could also lead to the reactive oxygen species (ROS) hypergeneration in A549 cells. Taken together, Sp infection-induced autophagy is PLY-mediated through ROS hypergeneration and mTOR inhibition. PI3K-I and rapamycin (autophagy inducers) enhanced bacterial clearance, whereas wortmannin (autophagy inhibitor) and acetylcysteine (ROS inhibitor) reduced intracellular bacteria clearance. Thus, Sp-induced autophagy represents a host-protective mechanism, providing new insight into the pathogenesis of respiratory tract Sp infection.

IntroductionAmdizalisib (HMPL-689) is an ATP-competitive PI3Kδ inhibitor currently under investigation for treating Hodgkin’s lymphoma. This study aimed to evaluate the metabolism, excretion, pharmacokinetics, and safety profile of amdizalisib in healthy human subjects to support its clinical application.MethodsThis Phase I clinical trial included six healthy Chinese male volunteers who received a single oral dose of 30 mg/100 µCi [14C]amdizalisib suspension. Blood, urine, and fecal samples were collected to analyze pharmacokinetics, metabolic pathways, and excretion patterns.ResultsAmdizalisib was rapidly absorbed, with a median Tmax of 2.5 h. The Cmax of 244 ± 48.9 ng/mL, and AUC0-t was 1870 ± 474 h ng/mL after a single oral dose. The blood-to-plasma total radioactivity ratio ranged from 0.561 to 0.645, indicating no significant affinity of [14C]amdizalisib and its metabolites to blood cells and the radioactive material is mainly distributed in plasma. Excretion was primarily via feces and urine, with 62.08% ± 3.00% and 37.15% ± 2.84% of the dose recovered, respectively, and over 94% of the drug excreted within 96 h. The parent drug was the main radioactive component in plasma (51.45% of total radioactivity). Additionally, 11 metabolites were identified, and the metabolic pathways include oxidation on the benzene or pyrimidine rings and conjugation with cysteine or glucuronic acid. The major metabolites in plasma were the di-oxidized and hydrogenated product (M424) and the mono-oxidized product (M406-2), accounting for 16.67% and 20.91%, respectively. Both of them are also the major radioactive components in urine and feces, among of which M424 accounted for 21.01% and 14.26%, M406-2 accounted for 8.08% and 11.30%, of the administered dose in urine and feces, respectively. In addition, the di-oxidized and methylated product (M436) was one of the major metabolites in feces accounting for 17.7% of the administered dose. Few of the parent drug was found in urine and feces, suggesting primary metabolized in the liver. No serious adverse events or drug-related deaths occured, with diarrhea as the most common adverse event.DiscussionThese findings demonstrate that amdizalisib is rapidly absorbed, extensively metabolized, and primarily excreted via feces and urine, supporting its continued development as a potential therapeutic for Hodgkin's lymphoma.Systematic Review Registration:https://www.chinadrugtrials.org.cn/, identifier CTR20212448.

In this study, we established a method for the determination of three metabolic regulators including clomiphene, trimetazidine and meldonium in foods by pass-through solid phase extraction combined with ultra-high performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS). The samples were extracted with 5% formic acid in acetonitrile, and the extract was purified on a pass-through solid phase extraction column and chromatographically separated on an amide column (3.0 mm × 100 mm, 1.7 μm). The separated analytes were detected in the multiple reaction monitoring (MRM) mode, and quantitated by an internal standard method. Good linearity was observed for clomiphene and trimetazidine within the concentration range of 1.0-40.0 ng/mL, and 5.0-200.0 ng/mL for meldonium. The average recoveries for spiked samples ranged from 81.3% to 100.7%, and the relative standard deviations (RSD) were between 0.3% and 6.1% (n = 6). The developed method was simple, rapid and practical with low matrix interferences, and was generally suitable for the determination of clomiphene, trimetazidine and meldonium in foods, which could provide effective technical support for the assurance of food safety for sports events.

Hemorrhagic shock is a common acute and critical disease caused by trauma in clinic. In particular, local tissue hypoperfusion and cell hypoxia caused by renal ischemia and hypoxia can easily lead to acute kidney injury. In clinical practice, safer, practical, and effective resuscitation methods for patients with hemorrhagic shock are constantly explored to achieve the purpose of better protection of the kidney, such as the applications from colloidal crystal liquid to hypertonic fluid, from normal-pressure resuscitation to low-pressure resuscitation, from correcting blood pressure to restoring oxygen supply to tissue cells, from maintaining hemodynamic stability to inhibiting apoptosis, and from vasoactive drugs to Chinese traditional medicines to enzyme inhibitors. This article reviews the research progress of kidney protection for patients with hemorrhagic shock in recent years.

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A–C (1–3), and three meroterpenoids containing an orthoester group, talaroterpenoids D–F (6–8), together with five known compounds (4–5 and 9–11), were isolated from the marine-derived fungus Talaromyces aurantiacus. Their chemical structures were elucidated through 1D, 2D NMR, HRESIMS, J-based configuration analysis (JBCA), computational ECD calculations, and single-crystal X-ray diffraction analysis. Compounds 1 and 2 contain an unusual 6,20-γ-lactone-bridged scaffold. Compounds 10 and 11 presented inhibitory effects on NO release in lipopolysaccharide (LPS)-induced BV-2 cells with IC50 values of 11.47 and 11.32 μM, respectively. Talaroterpenoid C (3) showed moderate antifungal activity against A. alternata and P. theae Steyaert.

Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.

Background Data from open label follow-up were merely 5 years for secukinumab as second line treatment. Real world evidence from European and Korean cohort revealed retention rate up to 4 years. No data from China has been published. We aim to evauate the longterm retention rate of secukinumab in axial spondyloarthritis (axSpA) and its predisposing factors in Chinese patients. Methods Patients were recruited from retrospective medical records of two tertiary hospitals in China from January 2020 and March 2024. Patients were diagnosed with 2009 ASAS classification criteria. The retention rate of secukinumab was estimated using the Kaplan-Meier method, and the log-rank test was used to compare the retention curves of the two cohorts. Results In total, medical records of prescription for secukinumab and relevant clinical information from 445 patients were identified. The mean age was 34 (29[Formula: see text]41) years with male gender of 77.30% and HLA-B27 posititivy of 88.54% in our cohort. Mean disease duration was 8 (5[Formula: see text]13) years with relatively shorter duration in biologics naive compared with biologics experienced patients (7 (3[Formula: see text]12) vs. 9 (6[Formula: see text]14) years, p¡0.05). The secukinumab treatment period was 3-42 months, with majority of 150mg dosage. 16 patients (3.60%) initiated with 300mg loading dose. Smoking status and other clinical characteristics including concomitant treatment and comorbility were not significant between the two groups. Overall retention rate of our cohort during follow-up at 12-month, 24-month and 36-month was 0.750, 0.686 and 0.641, respectively. In subgroup analysis, biologics experience contributed to lower retention rate (Figure 1) and higher dose (300mg) treatment resulted in better retention rate (Figure 2). Discontinuation occurred in 35 patients mainly due to fertility demand. Switching because of inefficient response occurred in 58 patients. Adalimumab (n=24) was the preferred choice, followed by etanercept (n=16)., other DMARDs or NSAIDs (n=13) and JAKi (n=5). Conclusion Secukinumab had a good performance of retention in patients with axSpA from China, especially in those with higher dosage and without biologics experience.

Using intelligent optimization algorithms to retrieve atmospheric duct parameters by monitoring automatic identification system (AIS) signals at sea is a new passive remote sensing technology for atmospheric ducts. To thoroughly compare and analyze the inversion results of different intelligent optimization algorithms and optimize the parameters of the algorithms, this study considered a simulated atmospheric duct environment for atmospheric duct inversion using the genetic, simulated annealing, and particle swarm optimization (PSO) algorithms. The results indicated that the PSO algorithm exhibited the best inversion performance. The inversion results of the simulated annealing particle swarm optimization (SAPSO) and PSO algorithms under different inversion parameters were further statistically analyzed, and the atmospheric duct parameters were obtained from measured AIS signals based on the SAPSO algorithm. The inversion results verified the effectiveness of the proposed algorithm, and they continuously improved with additional calculations in the inversion algorithm. However, the changing trend gradually slowed. Therefore, in practical applications, the inversion time consumption should be balanced with the inversion effect to optimize the inversion parameters.

Low-altitude atmospheric ducts are abnormal atmospheric phenomena in the troposphere, impacting the operation of microwave or ultrashort wave radio systems. Therefore, the real-time acquisition of low-altitude atmospheric duct parameters is essential to ensure the successful operation of radio systems. Remote sensing methods based on deep learning are, presently, the most important tools to infer duct parameters. In a traditional deep learning loss function, different duct parameters adopt the same weight coefficient. This study establishes a weight loss function and proposes a method for determining the weight coefficient based on the extended Fourier amplitude sensitivity test method. Based on Global Navigation Satellite System (GNSS) occultation signals, the cooperative inversion model of atmospheric duct parameters is established. Test results show that our proposed loss function was feasible, effective, and yielded a higher inversion accuracy than the traditional loss function.