1.Pathogenesis Reasoning Chain-of-thought Supervision for Large Language Models: Syndrome Manifestation Recognition and Multidimensional Evaluation in Spleen-stomach Disorders
Shu-Han YANG ; Yu-Xin HU ; Xin-Yu YU ; Yu-Ying TU ; Yi-Chang ZANG ; Pan-Fei LI
Progress in Biochemistry and Biophysics 2026;53(5):1240-1263
ObjectiveThe essence of syndrome manifestation recognition in traditional Chinese medicine (TCM) is to infer the body’s latent pathogenesis state from clinical observational information, rather than to perform simple label matching. However, previous studies have largely modeled this task as syndrome pattern classification within a fixed label space, which does not adequately reflect the cognition process of TCM syndrome differentiation centered on pathogenesis reasoning, and is also insufficient to capture the openness, semantic variability, and cross-disease reusability of syndrome manifestation expression. This study aimed to investigate whether introducing pathogenesis reasoning chain-of-thought (PR-CoT) supervision into large language models (LLMs) could improve the quality and cognitive consistency of syndrome manifestation recognition and support cross-disease transfer. MethodsSyndrome manifestation recognition was formulated as a conditional generation task under the framework of clinical observational information (X)→pathogenesis structure (Z)→syndrome pattern output (Y), where Z serves as an explicit intermediate structural variable linking the clinical evidence and syndrome judgment. Within this framework, a PR-CoT-supervised dataset for syndrome manifestation recognition was constructed based on medical case records of spleen-stomach disorders. After preprocessing, information extraction, manual proofreading, and data cleaning, the dataset comprised 4 800 training cases, 400 development cases, and 400 test cases. Each sample was annotated with a structured PR-CoT consisting of three progressive levels: clinical information summarization, comprehensive pathogenesis analysis, and syndrome pattern output. Supervised fine-tuning was conducted on open-source LLMs, with an end-to-end model serving as the baseline. Qwen3-32B was used as the primary experimental model, and Qwen3-14B as the scale comparison model. A progressive multidimensional evaluation framework was further established, comprising a structural parsing level, a semantic similarity level, and an expert blind review level. At the structural parsing level, syndrome pattern expressions were decomposed into structural elements and evaluated using Precision, Recall, F1 score, and Jaccard similarity. At the semantic similarity level, independent LLMs scored the theoretical proximity between predicted and reference syndrome patterns. At the expert blind review level, three TCM experts independently evaluated model outputs on two dimensions: syndrome differentiation consistency and terminology standardization of syndrome patterns. In addition, zero-shot cross-disease transfer evaluation was conducted on gynecological and heart-system disorder test sets. ResultsAt the structural parsing level, PR-CoT supervision did not lead to a stable improvement in the element-wise overlap of syndrome pattern structural components. Compared with the corresponding baselines, neither Qwen3-32B nor Qwen3-14B showed consistent advantages in structural matching metrics after the introduction of PR-CoT supervision. In contrast, at the semantic similarity level, PR-CoT supervision produced stable positive gains across different model scales and evaluation systems. The average semantic score of Qwen3-32B increased from 6.425 8 in the baseline model to 6.585 0 after PR-CoT supervision, and that of Qwen3-14B increased from 5.870 0 to 5.964 2. At the expert blind review level, the overall score of Qwen3-32B (PR-CoT) was 7.026 0±0.107 7, higher than 6.416 3±0.288 9 for its baseline. In zero-shot cross-disease testing, the PR-CoT model still showed advantages in semantic evaluation and expert evaluation on both gynecological and heart-system disorder test sets, indicating a certain degree of transferability. ConclusionThe benefits of PR-CoT supervision are mainly reflected in TCM semantic consistency and clinical plausibility, rather than in improved hard matching of structural elements. These findings support understanding syndrome manifestation recognition as a process of generating and expressing latent pathogenesis structures, rather than as a classification task within a traditional fixed label space. By introducing pathogenesis reasoning as an explicit intermediate structure into the modeling process and combining it with a progressive multidimensional evaluation framework, this study provides a methodological pathway for intelligent TCM syndrome differentiation that integrates theoretical alignment, interpretability, and multi-level evaluation.
2.Pathogenesis Reasoning Chain-of-thought Supervision for Large Language Models: Syndrome Manifestation Recognition and Multidimensional Evaluation in Spleen-stomach Disorders
Shu-Han YANG ; Yu-Xin HU ; Xin-Yu YU ; Yu-Ying TU ; Yi-Chang ZANG ; Pan-Fei LI
Progress in Biochemistry and Biophysics 2026;53(5):1240-1263
ObjectiveThe essence of syndrome manifestation recognition in traditional Chinese medicine (TCM) is to infer the body’s latent pathogenesis state from clinical observational information, rather than to perform simple label matching. However, previous studies have largely modeled this task as syndrome pattern classification within a fixed label space, which does not adequately reflect the cognition process of TCM syndrome differentiation centered on pathogenesis reasoning, and is also insufficient to capture the openness, semantic variability, and cross-disease reusability of syndrome manifestation expression. This study aimed to investigate whether introducing pathogenesis reasoning chain-of-thought (PR-CoT) supervision into large language models (LLMs) could improve the quality and cognitive consistency of syndrome manifestation recognition and support cross-disease transfer. MethodsSyndrome manifestation recognition was formulated as a conditional generation task under the framework of clinical observational information (X)→pathogenesis structure (Z)→syndrome pattern output (Y), where Z serves as an explicit intermediate structural variable linking the clinical evidence and syndrome judgment. Within this framework, a PR-CoT-supervised dataset for syndrome manifestation recognition was constructed based on medical case records of spleen-stomach disorders. After preprocessing, information extraction, manual proofreading, and data cleaning, the dataset comprised 4 800 training cases, 400 development cases, and 400 test cases. Each sample was annotated with a structured PR-CoT consisting of three progressive levels: clinical information summarization, comprehensive pathogenesis analysis, and syndrome pattern output. Supervised fine-tuning was conducted on open-source LLMs, with an end-to-end model serving as the baseline. Qwen3-32B was used as the primary experimental model, and Qwen3-14B as the scale comparison model. A progressive multidimensional evaluation framework was further established, comprising a structural parsing level, a semantic similarity level, and an expert blind review level. At the structural parsing level, syndrome pattern expressions were decomposed into structural elements and evaluated using Precision, Recall, F1 score, and Jaccard similarity. At the semantic similarity level, independent LLMs scored the theoretical proximity between predicted and reference syndrome patterns. At the expert blind review level, three TCM experts independently evaluated model outputs on two dimensions: syndrome differentiation consistency and terminology standardization of syndrome patterns. In addition, zero-shot cross-disease transfer evaluation was conducted on gynecological and heart-system disorder test sets. ResultsAt the structural parsing level, PR-CoT supervision did not lead to a stable improvement in the element-wise overlap of syndrome pattern structural components. Compared with the corresponding baselines, neither Qwen3-32B nor Qwen3-14B showed consistent advantages in structural matching metrics after the introduction of PR-CoT supervision. In contrast, at the semantic similarity level, PR-CoT supervision produced stable positive gains across different model scales and evaluation systems. The average semantic score of Qwen3-32B increased from 6.425 8 in the baseline model to 6.585 0 after PR-CoT supervision, and that of Qwen3-14B increased from 5.870 0 to 5.964 2. At the expert blind review level, the overall score of Qwen3-32B (PR-CoT) was 7.026 0±0.107 7, higher than 6.416 3±0.288 9 for its baseline. In zero-shot cross-disease testing, the PR-CoT model still showed advantages in semantic evaluation and expert evaluation on both gynecological and heart-system disorder test sets, indicating a certain degree of transferability. ConclusionThe benefits of PR-CoT supervision are mainly reflected in TCM semantic consistency and clinical plausibility, rather than in improved hard matching of structural elements. These findings support understanding syndrome manifestation recognition as a process of generating and expressing latent pathogenesis structures, rather than as a classification task within a traditional fixed label space. By introducing pathogenesis reasoning as an explicit intermediate structure into the modeling process and combining it with a progressive multidimensional evaluation framework, this study provides a methodological pathway for intelligent TCM syndrome differentiation that integrates theoretical alignment, interpretability, and multi-level evaluation.
3.Effects of glycerol ingestion on pure tone audiometry,distortion products otoacoustic emission,and electrocochleography in patients with Ménière disease
Hui PAN ; Linlin WANG ; Cheng LUO ; Meng GONG ; Mengjun WU ; Yi SHU ; Wen XIE ; Hongjun XIAO ; Bo LIU
Journal of Audiology and Speech Pathology 2025;33(4):372-376
Objective To investigate the effects of glycerol ingestion on pure tone audiometry(PTA),distor-tion products otoacoustic emission(DPOAE),and electrocochleography(ECochG)in patients with Ménière disease(MD).Methods Glycerol test was conducted in 50 patients with MD.PTA was performed in four series:before glycerol intake,1,2 and 3 hours after intake.DPOAE and ECochG were performed before glycerol intake and 2 hours after intake.All results were analyzed to assess the effect of glycerol on cochlear function of patients with MD.Results ① 55%of MD patients tested positive in PTA glycerol test,and the positive rate increased gradually after 1-3 hours of glycerin ingestion(P<0.05).For the 33 positive ears,the pure tone threshold decreased the most between 1-2 hours and reached the lowest thresholds at 3 hours.Thresholds at 0.5 kHz,1 kHz,2 kHz dropped the most.② The positive rate of DPOAE glycerol test was 56.67%,with 34 positive ears showing a sig-nificant increase in amplitude between 0.75-2 kHz of f2.③ The positive rate of ECochG glycerin test was 13.64%.The decrease of-SP/AP ratio was not statistically significant before and after ingestion of glycerin(P>0.05).Conclusion Ingestion of glycerin could alter to varying degrees of the results of PTA,DPOAE and ECo-chG,and influence the cochlear function to some extent.
4.Effects of glycerol ingestion on pure tone audiometry,distortion products otoacoustic emission,and electrocochleography in patients with Ménière disease
Hui PAN ; Linlin WANG ; Cheng LUO ; Meng GONG ; Mengjun WU ; Yi SHU ; Wen XIE ; Hongjun XIAO ; Bo LIU
Journal of Audiology and Speech Pathology 2025;33(4):372-376
Objective To investigate the effects of glycerol ingestion on pure tone audiometry(PTA),distor-tion products otoacoustic emission(DPOAE),and electrocochleography(ECochG)in patients with Ménière disease(MD).Methods Glycerol test was conducted in 50 patients with MD.PTA was performed in four series:before glycerol intake,1,2 and 3 hours after intake.DPOAE and ECochG were performed before glycerol intake and 2 hours after intake.All results were analyzed to assess the effect of glycerol on cochlear function of patients with MD.Results ① 55%of MD patients tested positive in PTA glycerol test,and the positive rate increased gradually after 1-3 hours of glycerin ingestion(P<0.05).For the 33 positive ears,the pure tone threshold decreased the most between 1-2 hours and reached the lowest thresholds at 3 hours.Thresholds at 0.5 kHz,1 kHz,2 kHz dropped the most.② The positive rate of DPOAE glycerol test was 56.67%,with 34 positive ears showing a sig-nificant increase in amplitude between 0.75-2 kHz of f2.③ The positive rate of ECochG glycerin test was 13.64%.The decrease of-SP/AP ratio was not statistically significant before and after ingestion of glycerin(P>0.05).Conclusion Ingestion of glycerin could alter to varying degrees of the results of PTA,DPOAE and ECo-chG,and influence the cochlear function to some extent.
5.A case report of premature ovarian insufficiency caused by a novel FANCL mutation(c.1033G>A)and in vitro functional validation
Yi-qing LIU ; Shu-ting REN ; Yun-cheng PAN ; Feng ZHANG ; Xiao-jin ZHANG ; Yan-hua WU
Fudan University Journal of Medical Sciences 2025;52(2):270-276,291
Objective To investigate the characteristics of a novel FANCL mutation identified in a patient with premature ovarian insufficiency(POI)and to explore its potential functional impacts in vitro.Methods A novel FANCL heterozygous mutation c.1033G>A(p.Glu345Lys)was screened in a patient with POI using whole exome sequencing(WES),which was found to be inherited from a mother who had undergone early menopause.The authenticity of the mutation was identified by Sanger sequencing and the conserved nature of the mutation site was predicted by software.Overexpressing FANCL mutant and wildtype plasmids were constructed and transiently transfected into HEK293T cell lines,and the effect of the mutation was detected by qPCR,immunofluorescence and Western blot.Results The mutation site of FANCL was located within the Ring domain of FANCL,which was highly conserved across multiple species.The mutant showed no significant change in mRNA expression level,while the protein expression level was significantly down-regulated.In vitro cellular experiments further revealed that the mutation leads to decreased expression levels by reducing protein stability.Conclusion A FANCL c.1033G>A mutation was found and it may cause disease in the POI patient due to decreased protein stability.
6.Research progress on mechanism of curcumin in treatment of depression
Lin WANG ; Qi-fei PAN ; Wen-juan LONG ; Jia-rong DU ; Zhong-yang HU ; Xin-yao LI ; Yi-shu CHEN ; Dong-dong QIN ; Xiao-man LYU
Chinese Pharmacological Bulletin 2025;41(9):1618-1623
Depression is a prevalent mental and emotional disor-der that often results in significant emotional disturbances,cog-nitive dysfunction,and memory impairments.It is characterized by a high incidence rate,a substantial disability burden,and limited therapeutic efficacy.Currently,the long-term use of medications for the treatment of depression can result in a range of adverse reactions,highlighting the urgent need to explore no-vel approaches that can effectively alleviate depressive symptoms while minimizing side effects.Curcumin,a natural polyphenolic compound derived from the rhizome of turmeric,demonstrates considerable potential in the prevention and treatment of depres-sion,owing to its diverse array of biological activities.In recent years,numerous studies have investigated the use of curcumin for the treatment of depression.This article aims to provide a comprehensive review of the mechanisms of action underlying curcumin's efficacy in treating depression.Specifically,it focu-ses on its ability to improve neurotransmitter imbalances,restore neural plasticity,alleviate neural damage,mitigate dysfunction of the hypothalamic-pituitary-adrenal(HPA)axis,regulate in-flammatory factors and neuroinflammatory signaling pathways,and inhibit oxidative stress.This review is intended to offer in-sights and methodological references for basic research on curcu-min,as well as for the development of novel therapeutic agents for the treatment of depression.
7.A case report of premature ovarian insufficiency caused by a novel FANCL mutation(c.1033G>A)and in vitro functional validation
Yi-qing LIU ; Shu-ting REN ; Yun-cheng PAN ; Feng ZHANG ; Xiao-jin ZHANG ; Yan-hua WU
Fudan University Journal of Medical Sciences 2025;52(2):270-276,291
Objective To investigate the characteristics of a novel FANCL mutation identified in a patient with premature ovarian insufficiency(POI)and to explore its potential functional impacts in vitro.Methods A novel FANCL heterozygous mutation c.1033G>A(p.Glu345Lys)was screened in a patient with POI using whole exome sequencing(WES),which was found to be inherited from a mother who had undergone early menopause.The authenticity of the mutation was identified by Sanger sequencing and the conserved nature of the mutation site was predicted by software.Overexpressing FANCL mutant and wildtype plasmids were constructed and transiently transfected into HEK293T cell lines,and the effect of the mutation was detected by qPCR,immunofluorescence and Western blot.Results The mutation site of FANCL was located within the Ring domain of FANCL,which was highly conserved across multiple species.The mutant showed no significant change in mRNA expression level,while the protein expression level was significantly down-regulated.In vitro cellular experiments further revealed that the mutation leads to decreased expression levels by reducing protein stability.Conclusion A FANCL c.1033G>A mutation was found and it may cause disease in the POI patient due to decreased protein stability.
8.Research progress on mechanism of curcumin in treatment of depression
Lin WANG ; Qi-fei PAN ; Wen-juan LONG ; Jia-rong DU ; Zhong-yang HU ; Xin-yao LI ; Yi-shu CHEN ; Dong-dong QIN ; Xiao-man LYU
Chinese Pharmacological Bulletin 2025;41(9):1618-1623
Depression is a prevalent mental and emotional disor-der that often results in significant emotional disturbances,cog-nitive dysfunction,and memory impairments.It is characterized by a high incidence rate,a substantial disability burden,and limited therapeutic efficacy.Currently,the long-term use of medications for the treatment of depression can result in a range of adverse reactions,highlighting the urgent need to explore no-vel approaches that can effectively alleviate depressive symptoms while minimizing side effects.Curcumin,a natural polyphenolic compound derived from the rhizome of turmeric,demonstrates considerable potential in the prevention and treatment of depres-sion,owing to its diverse array of biological activities.In recent years,numerous studies have investigated the use of curcumin for the treatment of depression.This article aims to provide a comprehensive review of the mechanisms of action underlying curcumin's efficacy in treating depression.Specifically,it focu-ses on its ability to improve neurotransmitter imbalances,restore neural plasticity,alleviate neural damage,mitigate dysfunction of the hypothalamic-pituitary-adrenal(HPA)axis,regulate in-flammatory factors and neuroinflammatory signaling pathways,and inhibit oxidative stress.This review is intended to offer in-sights and methodological references for basic research on curcu-min,as well as for the development of novel therapeutic agents for the treatment of depression.
9.Suggestions for revision of the epilepsy items in the military disability appraisal norms
Shu-Yi QU ; Ze CHEN ; Yuan-Hang PAN ; Ze-Zhi WANG ; Xin-Bo ZHANG ; Yong-Hong LIU
Medical Journal of Chinese People's Liberation Army 2024;49(1):6-9
Epilepsy is a common neurological disease,has the characteristics of recurrent attacks and long-term treatment,thus bringing great pressure to patients and their families.Therefore,it is particularly important to do a good job of disability assessment.In recent years,with the development of the discipline,academic organizations such as the International League Against Epilepsy(ILAE)and China Association Against Epilepsy(CAAE)have successively updated the definition and diagnostic criteria of epilepsy and seizures.However,some items of epilepsy in the current Criteria for Disability Rating of Military Personnel(Trial)issued by People's Liberation Army(PLA)in 2011 can no longer meet the latest guidelines at home and abroad.Therefore,we suggest that the items related to epilepsy in the Criteria for Disability Rating of Military Personnel(Trial)should be revised to ensure that the disability evaluation being completed fairly and successfully.
10.Alpha-Lipoic Acid Induces Adipose Tissue Browning through AMP-Activated Protein Kinase Signaling in Vivo and in Vitro
Shieh-Yang HUANG ; Ming-Ting CHUNG ; Ching-Wen KUNG ; Shu-Ying CHEN ; Yi-Wen CHEN ; Tong PAN ; Pao-Yun CHENG ; Hsin-Hsueh SHEN ; Yen-Mei LEE
Journal of Obesity & Metabolic Syndrome 2024;33(2):177-188
Background:
AMP-activated protein kinase (AMPK) is a key enzyme for cellular energy homeostasis and improves metabolic disorders. Brown and beige adipose tissues exert thermogenesis capacities to dissipate energy in the form of heat. Here, we investigated the beneficial effects of the antioxidant alpha-lipoic acid (ALA) in menopausal obesity and the underlying mechanisms.
Methods:
Female Wistar rats (8 weeks old) were subjected to bilateral ovariectomy (Ovx) and divided into four groups: Sham (n=8), Ovx (n=11), Ovx+ALA2 (n=10), and Ovx+ALA3 (n=6) (ALA 200 and 300 mg/kg/day, respectively; gavage) for 8 weeks. 3T3-L1 cells were used for in vitro study.
Results:
Rats receiving ALA2 and ALA3 treatment showed significantly lower levels of body weight and white adipose tissue (WAT) mass than those of the Ovx group. ALA improved plasma lipid profiles including triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hematoxylin & eosin staining of inguinal WAT showed that ALA treatment reduced Ovx-induced adipocyte size and enhanced uncoupling protein 1 (UCP1) expression. Moreover, plasma levels of irisin were markedly increased in ALA-treated Ovx rats. Protein expression of brown fat-specific markers including UCP1, PRDM16, and CIDEA was downregulated by Ovx but markedly increased by ALA. Phosphorylation of AMPK, its downstream acetyl-CoA carboxylase, and its upstream LKB1 were all significantly increased by ALA treatment. In 3T3-L1 cells, administration of ALA (100 and 250 μM) reduced lipid accumulation and enhanced oxygen consumption and UCP1 protein expression, while inhibition of AMPK by dorsomorphin (5 μM) significantly reversed these effects.
Conclusion
ALA improves estrogen deficiency-induced obesity via browning of WAT through AMPK signaling.

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