Human lactate dehydrogenase A (LDHA) is an NADH-dependent oxidoreductase that catalyzes the conversion of pyruvate to lactate, playing a crucial role in the aerobic glycolysis of tumor cells. Additionally, LDHA is responsible for catalyzing the conversion of glyoxylate to oxalate in the liver, excessive accumulation of which leads to hyperoxaluria. Representative LDHA inhibitors reported to date include GNE-140, NCATS-SM1441, and CHK-336. In this study, NCATS-SM1441 was used as the lead compound. Based on the analysis of its cocrystal binding mode with LDH, the key carboxythiazole and aromatic pharmacophores were retained, while the original substituted pyrazole linker was replaced with urea linker moieties to simplify the structure. As a result, nine urea derivatives were designed and synthesized. Subsequently, on the basis of structure-activity relationship and molecular docking studies, nine target triazole compounds were further designed. Ultimately, triazole compound 25 was found to exhibit the most potent LDHA inhibitory activity (IC50 = 1.59 μmol/L) in vitro. Molecular dynamics simulations were employed to analyze the interactions between compound 25 and key amino acid residues. Finally, the prediction of physicochemical properties and the evaluation of cell viability were performed for compound 25. The study provides an experimental basis for future development of novel LDHA inhibitors with improved drugability.

Objective: To explore the distribution characteristics and influencing factors of adverse reactions in whole blood donation in Jinan, Shandong, so as to provide evidence for the prevention and control of such adverse reactions in this region. Methods: A retrospective analysis was conducted on whole blood donors and adverse reaction cases in Jinan during 2023. To explore influencing factors of adverse reactions, univariate and multivariate logistic regression analyses were used to examine the relationships between adverse reactions and factors such as gender, age, donation organization mode, donation frequency, donation volume, time slot, and health examination results. Results: A total of 122 961 whole blood donations were recorded in Jinan in 2023. Donation-related adverse reactions occurred in 2 054 cases, with an incidence rate of 1.67%. Univariate analysis revealed significant differences in the incidence of adverse reactions across donor characteristics: the rate was higher in females (2.35%, 921/39 192) than in males (1.35%, 1 133/83 769), donors aged 18-25 years had the highest incidence (3.48%, 1 799/51 733), the incidence in group donations (3.13%, 1,737/55 534) was significantly higher than in individual donations (0.47%, 317/67 427), and insufficient blood collection was closely associated with adverse reactions (all P<0.001). Multivariate logistic regression analysis identified group donation, female gender, and a pulse rate of 81-99 beats per minute as risk factors for adverse reactions (all P<0.001), while systolic blood pressure of 116-139 mmHg and diastolic blood pressure of 76-89 mmHg were protective factors (all P<0.05). Compared to younger and lower-weight donor groups, older and higher-weight donors had a significantly lower risk of adverse reactions (all P<0.05). Donors giving 400 mL had a higher risk than those giving 200 mL (P<0.001). In addition, compared with the donation time slot of 7:00-8:59, the risk of adverse reactions was significantly higher during 9:00-16:59, with the time slot of 13:00-14:59 showing the most prominent risk (all P<0.05). However, no statistically significant difference was observed between the time slot of 17:00-20:59 and that of 7:00-8:59 (P>0.05). The primary clinical manifestation of adverse reactions was donation-related vasovagal reaction, with mental tension being the leading precipitating factor, accounting for 69.08% (1 419/2 054) of cases. Conclusion: The occurrence of adverse reactions in whole blood donation in the Jinan is influenced by multiple factors, including donor demographic characteristics, donation organization mode, physiological indicators, and time of donation. It is recommended to enhance the identification and intervention for high-risk groups, and optimize donation processes and service models to reduce the incidence of adverse reactions, thereby ensuring donor safety and blood quality.

ObjectiveThe Golgi apparatus serves as a central hub in the eukaryotic secretory pathway, responsible for the processing, sorting, and trafficking of proteins and lipids. In mammalian cells, the Golgi typically forms a perinuclear ribbon-like structure composed of laterally connected cisternae stacks.The maintenance of Golgi ribbon structure depends on the balance of membrane flux across multiple intracellular trafficking pathways, yet the specific contributions of distinct trafficking branches to Golgi macroscopic morphology remain elusive. In mammalian cells, the Golgi ribbon is typically organized as a perinuclear, laterally connected structure composed of stacked cisternae, and its integrity is highly dynamic and sensitive to perturbations in membrane trafficking. This study aims to elucidate the role of coat protein complex I (COPI)-mediated retrograde transport in maintaining the Golgi ribbon and to dissect the functional relationship between the transmembrane cargo receptors LEPROT/LEPROTL1 (LEPROTs) and the COPI adaptor GOLPH3. MethodsUsing siRNA interference and gene-deficient cell lines, we selectively perturbed COPI- or adaptor protein complex 1 (AP-1)-mediated trafficking pathways in HeLa cells. To quantitatively evaluate Golgi morphology, we employed a “Golgi Angle”-based measurement to assess its circumferential distribution around the nucleus. The spatial distribution of the Golgi ribbon was quantitatively analyzed using confocal microscopy, while Golgi ultrastructure and vesicle density were examined via transmission electron microscopy. Additionally, the subcellular distribution of COPI components was assessed by immunofluorescence co-localization. ResultsSelective inhibition of COPI retrograde transport significantly induced the circumferential extension of the Golgi ribbon around the nucleus, whereas blocking AP-1-mediated anterograde transport resulted in Golgi compaction, indicating opposing roles. These results suggest that different trafficking branches downstream of ARF1 exert distinct and even antagonistic effects on Golgi morphology. LEPROTs-deficient cells exhibited a Golgi extension phenotype highly consistent with COPI impairment. Furthermore, knockdown of GOLPH3 in a LEPROTs double-knockout background produced a significant additive effect on Golgi extension, suggesting that LEPROTs and GOLPH3 play non-redundant roles in regulating COPI-related trafficking processes. Mechanistically, loss of either LEPROTs or GOLPH3 led to the aberrant accumulation of COPI components at endoplasmic reticulum exit sites, accompanied by a reduction in COPI-like vesicles around the Golgi. This redistribution indicates a defect in COPI recycling between the ER-Golgi interface and the Golgi apparatus. Ultrastructural analysis revealed that Golgi cisternae in defective cells became shorter and thicker while maintaining a stable number of stacks. In parallel, the density of Golgi-associated vesicles was markedly decreased, further supporting an impairment in COPI vesicle formation or budding processes. ConclusionThis study demonstrates that active COPI retrograde transport is a critical factor in restricting the over-connection of the Golgi ribbon and maintaining its compactness. Rather than causing fragmentation, partial disruption of COPI function leads to a distinct morphological outcome characterized by Golgi ribbon extension at the light microscopy level and cisternal remodeling at the ultrastructural level. LEPROTs and GOLPH3 cooperatively promote the recycling and vesiculation of COPI components, thereby imposing a structural constraint on the Golgi periphery. Our findings support a model in which multiple adaptor proteins act in parallel to sustain efficient COPI cycling, thereby maintaining Golgi structural homeostasis. These findings provide new cell biological evidence for the membrane trafficking basis of Golgi morphological homeostasis.

psychiatric disorders （PD） and neurological disorders （ND） are currently major public health issues. The "four jiao （焦） and eight systems" theory categorizes them respectively into "spirit-system diseases" and "marrow-system diseases"， collectively attributing to "top jiao diseases". In the prevention and treatment of these diseases， deficiencies still exist in treating only the physical form while neglecting the spirit， or treating only the spirit while neglecting the physical form， lacking theoretical basis that integrates both form and spirit. Accordingly， the theory of spirit collaterals is proposed， aiming to expand the scope of collateral disease theory based on the concept of the unity of form and spirit， thereby providing a reference for the differentiation and treatment of top jiao diseases. By clarifying the relationships between concepts such as spirit， collaterals， marrow， brain spirit， the five spirit organs， brain orifices， clear orifices and spirit collaterals， and combining modern medical research on neurovascular units and neurovascular bundles， the connotations of spirit collaterals are elucidated from the perspectives of traditional Chinese medicine （TCM） and western medicine. It is also demonstrated that spirit collaterals takes top jiao as its center， spreads throughout the body， and possesses the attributes of qi collaterals， blood collaterals， and fluid collaterals， achieving the unity of physical structure and functional regulation. Based on the spirit collaterals theory， the core pathogenesis of top jiao diseases is proposed as collateral stasis and failure of spirit mechanism， with an evolutionary pattern of "collateral stagnation-collateral stasis-collateral block". In the clinical differentiation and treatment of top jiao diseases， unblocking and regulating the spirit collaterals is taken as the core therapeutic method. Basic formulas are formulated respectively for spirit-system diseases and marrow-system diseases， and a modification strategy is formed that takes into account the three collaterals， regulates qi and treats the spirit， and performs precise treatment according to the disease location.

Objective To evaluate the clinical outcomes of sutureless aortic valve replacement (SU-AVR) and transcatheter aortic valve implantation (TAVI) for aortic valve disease. Methods We conducted a computer-based search of databases including CNKI, WanFang Database, VIP, Chinese Biology Medicine disc, PubMed, The Cochrane Library, Embase and Web of Science from the inception of the databases to March 2024. Two reviewers independently screened articles, extracted data and used the Newcastle-Ottawa Scale to evaluate the quality of the included studies. Meta-analysis was performed using Stata 18.0 software. Results The included 17 propensity score matching studies involved with 6 630 patients, including 3 319 patients in the SU-AVR group and 3 311 patients in the TAVI group. The SU-AVR group had lower mortality than the TAVI group at 1-year [RR=0.58, 95%CI(0.38, 0.87), P=0.009], 2-year [RR=0.61, 95%CI(0.43, 0.85), P=0.004] and 5-year [RR=0.63, 95%CI(0.50, 0.79), P<0.001]. The SU-AVR group had a significantly lower rate of new permanent pacemaker implantation (PPI) [RR=0.75, 95%CI(0.58, 0.98), P=0.037], moderate-to-severe paravalvular leak [RR=0.20, 95%CI(0.12, 0.32), P<0.001], myocardial infarction [RR=0.30, 95%CI (0.11, 0.80), P=0.017], more-than-mild residual aortic regurgitation [RR=0.29, 95%CI(0.17, 0.48), P<0.001]. In addition, the SU-AVR group had a higher postoperative mean aortic gradient [SMD=0.39, 95%CI (0.17, 0.62), P<0.001] than the TAVI group. Conclusion The early and mid-term clinical outcomes of SU-AVR are superior to TAVI.

Objective To evaluate the safety and efficacy of a new domestic ultra-high frequency bipolar radiofrequency ablation device. Methods Six fresh cadaveric lumbar spine specimens were used as experimental subjects, and a novel domestic ultra-high frequency bipolar radiofrequency ablation device was employed for nucleus pulposus ablation and annulus fibrosus cauterization. Nucleus pulposus ablation: a total of 18 intervertebral discs from L₁ to L₄ were selected and randomly divided into six groups. Radiofrequency electrodes were inserted into the intervertebral discs through the lateral aspect of the intervertebral foramen, and the ablation was performed at power outputs of 50 W, 75 W, and 100 W for 1 min and 2 min, respectively. The ablation of the nucleus pulposus was observed, and the ablation range was recorded. Annulus fibrosus cauterization: a total of 12 intervertebral discs from L₄ to S₁ were divided into three groups based on cauterization duration of 3 s, 10 s, or 15 s. In a water bath maintained at a constant 37 °C, cauterization was performed at power outputs of 20 W, 30 W, and 40 W, respectively. After hard tissue sectioning and hematoxylin and eosin (HE) staining, the depth of cauterization and the carbonization of surrounding soft tissues were observed. Results No obvious vaporization cavity was observed in the nucleus pulposus at a power of 50 W for either 1 or 2 min. The 100 W–2 min group achieved the largest ablation area ([7.471±0.365] mm², P＜0.001). The temperature elevation at all four annulus fibrosus sites remained below 0.5℃ throughout the ablation process. The cauterization depth in the 20 W group was significantly lower than that in both the 30 W and 40 W groups across all time conditions (P＜0.01), whereas no statistically significant difference was observed between the latter two. In 20 W group, the cauterization depth at 3 s was significantly lower than that of the 10 s and 15 s groups (P＜0.01). No significant intra-group differences were found among subgroups with different cauterization durations in the 30 W and 40 W groups. An effective cauterization depth was already achieved at 30 W for 3 s. Conclusions Ex vivo experiments have shown that the new domestic bipolar radiofrequency ablation device possesses excellent ablation efficacy and safety parameters. For nucleus pulposus ablation, it is recommended to use 100 W for 2 min, while for annulus fibrosus cauterization and shaping, 30 W for 3 s is suggested. Its clinical application value remains to be further verified through in vivo studies.

BACKGROUND:Neuregulin 1 has been shown to be characterized in cell proliferation,differentiation,and vascular growth.Human amniotic mesenchymal stem cells are important seed cells in the field of tissue engineering,and have been shown to be involved in tissue repair and regeneration. OBJECTIVE:To construct human amniotic mesenchymal stem cells overexpressing neuregulin 1 and investigate their proliferation and migration abilities,as well as their effects on wound healing. METHODS:(1)Human amniotic mesenchymal stem cells were in vitro isolated and cultured and identified.(2)A lentivirus overexpressing neuregulin 1 was constructed.Human amniotic mesenchymal stem cells were divided into empty group,neuregulin 1 group,and control group,and transfected with empty lentivirus and lentivirus overexpressing neuregulin 1,or not transfected,respectively.(3)Edu assay was used to detect the proliferation ability of the cells of each group,and Transwell assay was used to detect the migration ability of the cells.(4)The C57 BL/6 mouse trauma models were constructed and randomly divided into control group,empty group,neuregulin 1 group,with 8 mice in each group.Human amniotic mesenchymal stem cells transfected with empty lentivirus or lentivirus overexpressing neuregulin-1 were uniformly injected with 1 mL at multiple local wound sites.The control group was injected with an equal amount of saline.(5)The healing of the trauma was observed at 1,7,and 14 days after model establishment.Histological changes of the healing of the trauma were observed by hematoxylin-eosin staining.The expression of CD31 on the trauma was observed by immunohistochemistry. RESULTS AND CONCLUSION:(1)Human amniotic mesenchymal stem cells overexpressing neuregulin-1 were successfully constructed.The mRNA and protein expression of intracellular neuregulin 1 was significantly up-regulated compared with the empty group(P<0.05).(2)The overexpression of neuregulin 1 promoted the migratory ability(P<0.01)and proliferative ability of human amniotic mesenchymal stem cells(P<0.05).(3)Human amniotic mesenchymal stem cells overexpressing neuregulin 1 promoted wound healing in mice(P<0.05)and wound angiogenesis(P<0.05).The results showed that overexpression of neuregulin 1 resulted in an increase in the proliferative and migratory capacities of human amniotic mesenchymal stem cells,significantly promoting wound healing and angiogenesis.

To summarise the clinical experience of treating insomnia with the method of resolving depression， regulating the middle， and tranquilising mind. It is believed that the key to the pathogenesis of insomnia lies in qi depression， disharmony of qi pivot， and disharmony of qi and blood， and the core treatment is to resolve depression， regulating the middle， and tranquilising mind. The self-prescribed Jieyu Anmian Formula （解郁安眠方） could be used as the basic treatment， then modified according to the performance of the patient and syndromes. For syndrome of liver depression restricting spleen， the treatment should soothe liver and invigorate spleen， resolve depression and regulate the middle； for syndrome of liver depression and phlegm coagulation， the treatment should resolve depression and phlegm， support the earth and free the wood； for syndrome of liver depression transforming into fire， the treatment should soothe liver and clear fire， resolve depression and dysphoria； for syndrome of qi stagnation and blood stasis， the treatment should activate blood and regulate the middle， resolve depression and tranquilise mind.

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Bone grafting is a primary method for treating bone defects. Among various graft materials, xenogeneic bone substitutes are widely used in clinical practice due to their abundant sources, convenient processing and storage, and avoidance of secondary surgeries. With the advancement of domestic production and the limitations of imported products, an increasing number of bone filling or grafting substitute materials isentering clinical trials. Relevant experts have drafted this consensus to enhance the management of medical device clinical trials, protect the rights of participants, and ensure the scientific and effective execution of trials. It summarizes clinical experience in aspects, such as design principles, participant inclusion/exclusion criteria, observation periods, efficacy evaluation metrics, safety assessment indicators, and quality control, to provide guidance for professionals in the field.
Humans ; Bone Substitutes/therapeutic use* ; Randomized Controlled Trials as Topic/methods* ; Consensus ; Bone Transplantation ; Research Design