The pharmaceutical industry faces challenges in quality digitization for complex multi-stage processes, especially in small-sample systems. Here, an intelligent quality prediction and diagnostic (IQPD) framework was developed and applied to Tong Ren Tang's Niuhuang Qingxin Pills, utilizing four years of data collected from four production units, covering the entire process from raw materials to finished products. In this framework, a novel path-enhanced double ensemble quality prediction model (PeDGAT) is proposed, which combines a graph attention network and path information to encode inter-unit long-range and sequential dependencies. Additionally, the double ensemble strategy enhances model stability in small samples. Compared to global traditional models, PeDGAT achieves state-of-the-art results, with an average improvement of 13.18% and 87.67% in prediction accuracy and stability on three indicators. Additionally, a more in-depth diagnostic model leveraging grey correlation analysis and expert knowledge reduces reliance on large samples, offering a panoramic view of attribute relationships across units and improving process transparency. Finally, the IQPD framework integrates into a Human-Cyber-Physical system, enabling faster decision-making and real-time quality adjustments for Tong Ren Tang's Niuhuang Qingxin Pills, a product with annual sales exceeding 100 million CNY. This facilitates the transition from experience-driven to data-driven manufacturing.

Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

Objective To observe the effects of Ditan Yizhi Decoction on Wnt/β-catenin signaling pathway and mitochondrial autophagy in vascular dementia(VD)rats.Methods Totally 70 male SD rats were randomly selected as the sham-operation group,with only the common carotid artery isolated and not ligated,and the rest of the rats were used to prepare a rat model of VD by the modified bilateral common carotid artery permanent ligature method.The successfully modeled rats were randomly divided into model group,donepezil group,agonist group and Ditan Yizhi Decoction low-,medium-and high-dosage groups and were given corresponding interventions for 4 weeks.Morris water maze experiment was used to assess the learning and memory ability of rats,HE staining and Nissl staining were used to observe the morphology of hippocampal tissue,transmission electron microscopy was used to observe the ultrastructure of hippocampal neuron,Western blot was used to detect the expressions of PINK1,Parkin,p62,Beclin-1,LC3BⅡ/Ⅰ,β-catenin,GSK-3β,p-GSK-3β protein.Results Compared with the sham-operation group,rats in the model group had a prolonged escape latency(P<0.01),a reduced number of crossing platforms(P<0.01);neuronal gaps in the CA1 area of the hippocampus were enlarged,with irregular cell morphology and blurred borders,neuronal solidification,Nissl bodies dissolution and fragmentation,reduced quantity,mitochondrial cristae disorder,and disruption of the structure of the bilayer membrane,with a greater number of autophagosomes in the surroundings;the expressions of PINK1,Parkin,Beclin-1,LC3BⅡ/I,β-catenin,p-GSK-3β/GSK-3β protein were significantly increased(P<0.01),and p62 protein expression was significantly decreased(P<0.01).Compared with the model group,the escape latency of rats in donepezil group,agonist group and Ditan Yizhi Decoction low-,medium-and high-dosage groups were significantly shortened(P<0.01),and the number of crossing platforms significantly increased(P<0.05,P<0.01);the number of neurons in the hippocampal CA1 region increased,with normal morphology and orderly arrangement,Nissl bodies were abundant,and transmission electron microscopy showed that mitochondrial morphology recovered,rupture decreased,and autophagosomes around mitochondria decreased,the protein expressions of PINK1,Parkin,Beclin-1,LC3BⅡ/Ⅰ,β-catenin and p-GSK-3β/GSK-3β in hippocampal tissue were significantly decreased(P<0.01),the protein expression of p62 significantly increased(P<0.05,P<0.01).Conclusion Ditan Yizhi Decoction can improve learning memory ability and neuronal morphology in VD rats,and its mechanism may be related to the activation of Wnt/β-catenin signaling pathway to inhibit mitophagy.

Objective To observe the effects of Ditan Yizhi Decoction on mitochondrial dynamics-mediated glucose metabolism in vascular dementia(VaD)rats based on the ROS/Drp1 axis;To explore its mechanism in treating VaD.Methods Ten male SD rats were randomly selected from 70 as the sham-operation group,and VaD models were prepared using the modified bilateral common carotid artery permanent ligation method for the remaining rats.The successfully modeled rats were randomly divided into model group,positive drug group(donepezil hydrochloride),inhibitor group(Mdivi-1)and Ditan Yizhi Decoction low-,medium-and high-dosage groups(12.86,25.725,51.45 g/kg),and intervened with corresponding method for 4 consecutive weeks.Morris water maze experiment was used to assess the learning memory ability of rats,HE and Nissl staining were used to observe the morphology of hippocampal tissue,transmission electron microscopy was used to observe the mitochondrial ultrastructure of hippocampal neurons,DHE fluorescent probe was used to detect the content of ROS in hippocampal neurons,Western blot was used to detect the expressions of Drp1,p-Drp1,Mfn2,Opa1,HK1,PKM2,GLUT1 and LDHA,the contents of serum IL-1β,IL-6 and TNF-α were detected by ELISA.Results Compared with the sham-operation group,rats in the model group had a prolonged escape latency(P<0.01)and a reduced number of crossing platforms(P<0.01);neuronal gaps in the CA1 region of the hippocampus were enlarged,with irregular cell morphology and blurred borders,neuronal consolidation,lysis and fragmentation of Nissl bodies and reduced number of Nissl bodies,swelling and deformation of mitochondria,disorganization of the cristae,and disruption of the bilayer membrane structure;the content of ROS in CA1 region of the hippocampus was elevated,the protein expressions of Mfn2 and Opa1 significantly decreased(P<0.01),the expressions of p-Drp1,HK1,PKM2,GLUT1,LDHA proteins significantly increased(P<0.01),and serum contents of IL-1β,IL-6 and TNF-α significantly increased(P<0.01).Compared with the model group,the escape latency was significantly shortened in Ditan Yizhi Decoction groups,positive drug group and inhibitor group(P<0.01),and the number of crossing platforms increased(P<0.05,P<0.01);the number of neurons in the hippocampal CA1 region increased,with normal morphology,orderly arrangement,abundant Nissl bodies,recovered mitochondrial morphology,and decreased rupture;the ROS content in hippocampal CA1 region decreased(P<0.01),while the expressions of Mfn2 and Opa1 proteins increased(P<0.01),the expressions of p-Drp1,HK1,PKM2,GLUT1 and LDHA proteins decreased(P<0.01),and the serum contents of IL-1β,IL-6 and TNF-α decreased(P<0.05).Conclusion Ditan Yizhi Decoction can improve cognitive impairment and neuronal morphology in VaD rats,and the mechanism maybe related to regulation of mitochondrial dynamics through the ROS/Drp1 axis,attenuating glycometabolic disorders,and reducing inflammatory response.

Objective To evaluate the influence of the wearing position of dosimeters outside lead aprons on effective dose estimation for interventional radiology workers, analyze the differences between single and double dosimeter methods in effective dose estimation, and provide a reference for the personal dose monitoring of interventional radiology workers. Methods This study employed a combined approach of on-site monitoring and Monte Carlo simulation to evaluate the impact of the wearing position of dosimeters outside lead aprons on effective dose estimation, as well as the differences between effective doses measured using single and double dosimeters. Interventional radiology workers wore dosimeters at three positions: the neck outside the lead collar, the left chest outside the lead apron, and inside the lead apron. Effective doses were estimated using the single and double dosimeter methods specified in GBZ 128-2019 Specifications for individual monitoring of occupational external exposure, and the impact of different wearing positions on the estimation results was compared. Geant4 Monte Carlo simulations were used to model dose distributions at the neck outside the lead collar and at the left chest outside the lead apron for operators performing cardiovascular interventions under tube voltages of 70, 80, 90, and 100 kVp and exposure angles of posteroanterior (PA), anteroposterior (AP), and left anterior oblique 45° (LAO45°) positions. The study assessed the impact of dosimeter wearing position on effective dose estimation. Results Monte Carlo simulations demonstrated that neck doses consistently exceeded left chest doses across different tube voltages and exposure angles, with neck-to-chest dose ratios of 0.80-0.90. Under identical tube voltage conditions, AP showed the highest doses, followed by LAO45°, and PA demonstrated the lowest doses. The single and double dosimeter methods exhibited consistent patterns in effective dose estimation. Single dosimeter method generally yielded higher effective doses with relative deviations of 9.9% to 83%, though these deviations decreased under high tube voltages. Field monitoring data indicated that most interventional radiology workers maintained relative deviations between single and double dosimeter calculations below 6%, with neck-to-chest dose ratios of 0.95-1.1. The estimation patterns remained consistent across both methods, though single dosimeter method showed slightly higher results. Conclusion Under PA, AP, or LAO45°, the doses at the neck consistently exceeded those at the left chest. Therefore, when wearing lead protective equipment, the dosimeter should be properly positioned at the neck outside the lead collar to accurately reflect the radiation doses of surgeons. Some interventional radiology workers improperly positioned the dosimeter (intended at the neck outside the lead collar) at the left chest outside the lead apron, and this may result in an underestimation of the effective dose.

Objective To preliminarily design a wide-energy-spectrum CR-39 solid-state nuclear track individual neutron dosimeter with different energy sections. Methods The thickness of the converter was optimized using the Monte Carlo SRIM program to broaden the energy range of the dosimeter. The self-made wide-energy-spectrum CR-39 individual neutron dosimeter was calibrated using ²⁴¹Am-Be, ²⁵²Cf, and thermal neutron sources to evaluate its dosimetric performance, including linearity, energy response, and neutron energy resolution. Results The linear correlation coefficient of the measurement system exceeded 0.98. The relative deviations of the energy response were 35.0% for blank section and 42.0% for polyethylene section, falling within the range of −50% to + 100% and meeting the monitoring requirements. The detection sensitivity for thermal neutron dose was 67 137.2 tr·cm⁻²·mSv⁻¹, and the detection sensitivity for thermal neutron fluence was 0.98 × 10⁻³ tr·n⁻¹, demonstrating good thermal neutron detection capability. Conclusion The self-made wide-energy-spectrum CR-39 individual neutron dosimeter fundamentally meets the requirements for individual neutron dose monitoring and is suitable for individual neutron dose monitoring in the energy range of thermal neutrons (up to approximately 15 MeV).

Objective To identify the reasons why the monitored personal doses of radiation worker A in an institution exceeded the investigation level in 2023 and 2024, and remind workers to wear personal dosimeters in a standardized manner in scenarios such as work and business trips to ensure the authenticity and reliability of the monitoring data. Methods A thermoluminescence measurement system was used to read the personal dosimeters worn by radiation workers. Investigations were carried out on personnel whose doses exceeded the investigation level described in the “Specifications for individual monitoring of occupational external exposure” (GBZ 128—2019). The reasons for doses exceeding the investigation level were analyzed using additional dosimeters and conducting on-site experiments. Results In 2023 and 2024, radiation worker A recorded a total of 5 personal dose equivalents exceeding the investigation level (1.23 mSv) over a total of 8 monitoring cycles (each lasting 90 days). Following one cycle where the dose exceeded the investigation level, two additional dosimeters (each for a 30-day cycle) were issued to worker A, revealing readings below the investigation level for the 30-day monitoring cycle (0.41 mSv). The reading for the dosimeter was 2-3 μSv per time when passing through an X-ray security scanner, and approximately 2.10 mSv per time when passing through a computed tomography security scanner. Conclusion Within a 90-day monitoring cycle, a single exposure of a personal dosimeter to a computed tomography security scanner can result in a dose exceeding the investigation level. Radiation workers should avoid placing dosimeters in backpacks or suitcases that pass through computed tomography security scanners during business trips, so as to reduce the impact of security scanner irradiation on personal dose monitoring.

Objective:To discuss the effects of bone marrow-derived mesenchymal stem cells(BMSCs)transplantation on mitophagy in the vascular dementia(VaD)rats through reactive oxygen species(ROS)/nuclear factor erythroid 2-related factor 2(Nrf2)signaling,and to clarify its mechanism.Methods:Forty-five male adult SD rats were randomly divided into sham operation group,model group,unloaded group,BMSCs group,and MSCs+ML385(Nrf2 inhibitor)group(combination group),and there were 9 rats in each group.After intraperitoneal anesthesia,the VaD models were established in all groups except sham operation group.Morris water maze test was used to detect the learning and memory abilities of the rats in various groups;HE staining was used to observe the histopathological morphology of brain tissue of the rats in various groups;Nissl staining was used to observe the changes of Nissl bodies in hippocampus region of brain tissue of the rats in various groups;transmission electron microscope was used to observe the ultrastructure of hippocampus region of the rats in various groups;fluorescence probe method was used to detect the ROS levels in hippocampus neurons in various groups;Western blotting method was used to detect the expression levels of Nrf2,heme oxygenase-1(HO-1),PTEN-induced putative kinase 1(PINK1),parkin RBR E3 ubiquitin protein ligase(Parkin),Beclin-1,ubiquitin-binding protein p62(P62),and microtubule-associated protein 1A/1B-light chain 3(LC3-Ⅱ/LC3-Ⅰ)ratio in brain tissue of the rats in various groups.Results:The Morris water maze results showed that compared with sham operation group,the escape latency of the rats in model group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).Compared with model group,the escape latency of the rats in BMSCs group was significantly decreased(P<0.01),while the number of crossing time and residence time were significantly increased(P<0.01).Compared with BMSCs group,the escape latency of the rats in combination group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).The HE staining results showed that hippocampus neurons of the rats in sham operation group were normal in quantity and morphology,with uniform staining and clear structure.Compared with sham operation group,the hippocampus tissue of the rats in model group showed sparse arrangement,disordered structure,reduced neuronal quantity,varied morphology,uneven staining,nuclear pyknosis,and partial neuronal necrosis.Compared with model group,the neuronal damage of the rats in hippocampus regio in BMSCs group was alleviated,with restored morphology and improved neuronal loss.Compared with BMSCs group,the neurons of the rats in hippocampus region in combination group showed irregular morphology,disordered structure,unclear cell boundaries,uneven staining,and nuclear pyknosis.The Nissl staining results showed that the hippocampal neurons in sham operation group were tightly arranged with intact morphology,obvious nucleoli,and abundant darkly stained Nissl bodies.Compared with sham operation group,the neurons in hippocampus region of the rats in model group showed pyknosis,vacuolization,and sparse Nissl bodies.Compared with model group,the BMSCs group showed reduced neuronal pyknosis,relatively intact morphology,and increased Nissl bodies.Compared with BMSCs group,the combination group showed neuronal pyknosis,loss of morphological integrity,and fragmented Nissl bodies.The transmission electron microscope results showed that mitochondria in sham operation group exhibited oval shape with intact double-membrane structure and cristae.Compared with sham operation group,the mitochondria in model group showed swelling,disrupted membranes,broken cristae,and numerous autophagosomes.Compared with model group,the BMSCs group showed improved mitochondrial structure and reduced autophagosomes.Compared with BMSCs group,the combination group showed swollen mitochondria,disrupted membranes,broken cristae,and visible autophagosomes.The fluorescence probe results showed that compared with sham operation group,the ROS levels in the hippocampus neurons in brain tissue of the rats in model group were significantly increased(P<0.01);compared with model group,the ROS levels in hippocampus neurons in brain tissue of the rats in BMSCs group were significantly decreased(P<0.01);compared with BMSCs group,the ROS levels in hippocampus neurons in brain tissue of the rats in combination group were significantly increased(P<0.01).The Western blotting results showed that compared with sham operation group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in model group were significantly decreased(P<0.01);compared with model group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in BMSCs group were significantly increased(P<0.01);compared with BMSCs group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in combination group were significantly decreased(P<0.01);compared with sham operation group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,and LC3-Ⅱ/LC3-Ⅰ ratio of the rats in model group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01);compared with model group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in BMSCs group were significantly decreased(P<0.01),while the expression level of P62 protein was significantly increased(P<0.01);compared with BMSCs group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in combination group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01).Conclusion:BMSCs can alleviate the hippocampal neuronal pathological changes and improve cognitive function in the VaD rats,and its mechanism may be related to the regulation of ROS/Nrf2 signaling pathway to inhibit mitophagy.

Objective:To analyze the intercomparision result of personal dose monitoring and gross alpha/beta detection capability between the disease control and prevention institutions at provincial, municpal and county levels during 2022-2024, in order to provide a reference for radiation detection capability and policy making of these institutions in China.Methods:Data on personal dose monitoring and gross alpha/beta detection, obtanied from the 2022-2024 radiation detection capability intercomparison between the disease control and prevention institutions at different levels, were recorded. Both the qualification rates (including excellence) and excellence rates of all the institutions at all evels from 2022 to 2024 were analyzed using SPSS 22.0.Results:From 2022 to 2024, the number of participating institutions at all levels showed an overall upward trend, increasing from 262 to 430, with particularly notable growth at the municipal level. In the 2024 gross α/β detection capability intercomparison, the non-qualification rate in municipal-level institutions was significantly higher than in county-level institutions ( χ2=10.53, P < 0.05). The qualification rate (including excellence) of the municipal-level gross alpha/beta detection in 2022 and 2024 were lower than in 2023( χ2=29.93, P < 0.01). Among all regions, the 2024 personal dose monitoring intercomparison result showed that the qualification rate (including excellence) in East China was higher than in Southwest and Northwest China ( χ2=15.62, P <0.01). East China also outperformed Northwest China ( χ2=16.21, P <0.01). In the 2022 gross alpha/beta detection capability intercomparison, the qualification rate (including excellent performance) in East China and South China was higher than in Northwest China ( χ2=23.76, 11.22, P<0.01). Overall, East China showed relatively higher qualification rate in intercomparison result of both personal dose monitoring and radiation detection (including excellence), while Northwest China showed lower qualification rates (including excellence). Conclusions:Although the radiation detection capability of disease control and prevention institutions at all levels has improved in recent years, there are still insufficience of detection capabilities at some municipal- and county-level laboratories and even unbalance between different regionas. Policy support should prioritize underdeveloped areas, such as municipal- and county-level institutions and the Northwest, and enhance the technical proficiency and quality management of laboratory personnel.

Objectives:To explore the clinical efficacy and the postoperative recurrence rate of the vertebral"Collapse"lesion resection for treating thoracolumbar spinal metastases compared to separation surgery.Methods:A retrospective study was conducted on 78 patients with thoracolumbar spinal metastases treated at Tianjin University General Hospital from December 2018 to December 2022.There were 42 males(53.8％)and 36 females(46.2％),with a mean age of 61.9±10.6 years(range 34-76 years).The patients were divided into separation surgery group(21 cases)and"Collapse"resection group(57 cases).Two to three weeks after surgery,radiotherapy,chemotherapy or targeted drugs were given according to the type of primary tumor after wound healing.The data on operative time,intraoperative blood loss,drainage volume,Frankel classification for spinal cord injury,and visual analogue scale(VAS)scores for pain preoperatively,7d after operation and at final follow-up,as well as local recurrence rates and perioperative complications were collected.Results:The operative time and intraoperative blood loss in the"Collapse"resection group(328.7±89.2min,782.5±89.2mL)were significantly higher than those in the separation surgery group(243.2±89.2min,585.7±89.2mL)(P＜0.05).There was no statistically significant difference in postoperative drainage volume between the two groups("Collapse"resection group 698.2±230.2mL vs separation surgery group 674.7±180.7mL)(P＞0.05).During follow-up,all the patients in the separation surgery group received stereotactic radiotherapy postoperatively;While 10 patients(21.2％)in the"Collapse"resection group underwent radiotherapy,and the remaining 47(78.8％)patients received targeted,immunological,or chemotherapy as part of comprehensive treatment.The recurrence rate in the separation surgery group was approximately 9.5％(2/21).Among the patients who received"Collapse"resection plus radiotherapy,there was 1 local recurrence,resulting in a recurrence rate of 10％(1/10),while the patients who didn't receive radiotherapy experienced 3 local recurrences,with a recurrence rate of 6.4％(3/47).The overall recurrence rate for patients in the"Collapse"resection group was 7.0％(4/57).There was no statistically significant difference in recurrence rates between the two surgical procedures(P=0.708).In the separation surgery group,postoperative complications included one case of wound infection,one case of wound dehiscence two months after postoperative radiotherapy,and one case of epidural hematoma causing compression.In the group of"Collapse"resection,complications included one case of cerebrospinal fluid leakage with secondary infection and one case of superficial wound infection.VAS scores on 7d postoperatively significantly decreased compared to preoperative scores in both groups(P＜0.05),and there were significant differences in VAS scores at final follow-up compared to preoperative scores(P＜0.05).No statistical difference in VAS scores was observed between the two groups on 7d postoperatively and at final follow-up(P＞0.05).Except for 5 Frankel A-D grade patients with no significant improvement in neurological function,the remaining 73 patients showed no deterioration in neurological function,with varying degrees of recovery of at least 1 grade,yielding an improvement rate of 93.6％(73/78).Conclusions:The vertebral"Collapse"resection for thoracolumbar spinal tumors does not require postoperative radiotherapy,as the tumor recurrence rate is comparable to that of patients treated with separation surgery followed by radiotherapy.