Background Injury poses a serious threat to human health. As global warming continues to intensify, there is an urgent need to explore the impact of temperature changes on injury deaths. However limited research has focused on this issue. Objective To investigate the relationship between daily mean temperature change (Tm) and injury death, as well as to estimate the associated future death burden in Hunan Province. Methods We employed an individual-level, time-stratified case-crossing design to establish a conditional logistic regression model to analyze the exposure-response relationship between daily mean temperature change and injury death in Hunan Province from 2013 to 2018. Consequently, we conducted subgroup analysis of gender, age group, and injury type. Finally, we estimated the excess burden of injury death attributable to temperature changes under a sustainable development path [low emission scenario (SSP1-2.6)], regional competition path [high emission scenario (SSP3-7.0)], or fossil fuel development path [very high emission scenario (SSP5-8.5)]. Results The study collected 155577 injury deaths in Hunan Province. The results indicated that for each 1 ℃ increment in daily mean temperature, the cumulative excess risk (CER) of injury mortality among Hunan residents increased by 0.71% (95%CI: 0.53%, 0.90%). Notably, the CER for intentional injuries (1.06%, 95%CI: 0.51%, 1.61%) was higher than that for unintentional injuries (0.66%, 95%CI: 0.46%, 0.87%). Warmer temperatures were positively associated with CER of mortality due to drowning, falls, transport injuries, assaults, and suicides, while they were negatively associated with mortality due to poisoning. Compared with 2010–2019, for 2090–2099, the excess mortality rate (EMR) due to ambient temperature increase in Hunan Province under the SSP5-8.5 scenario (14.62/100000, 95%CI: 10.81/100000, 18.40/100000) would be higher than that of the SSP3-7.0 scenario (10.28/100000, 95%CI: 7.58/100000, 12.97/100000) and the SSP1-2.6 scenario (3.35/100000, 95%CI: 2.46/100000, 4.23/100000); the EMR would be around 2.5 times among men (20.64/100000, 95%CI: 14.44/100000, 26.8/100000) than that among women (8.33/100000, 95%CI: 3.98/100000, 12.6/100000). Among unintentional injuries, the leading contributors to EMR would be drowning (4.46/100000), falls (3.96/100000), and transport injuries (2.96/100000). And among intentional injuries, the EMR for suicide (2.08/100000) would be higher than that for assault (0.47/100000). Conclusion Climate warming will increase the total burden of injury-related deaths among residents in Hunan Province, especially in the absence of effective mitigation strategies and measures. It is necessary to strengthen the prevention and control of severe injuries closely related to temperature changes, such as drowning, falls, traffic, and suicides injuries, in order to reduce injury deaths associated with climate change.

Protein arginine methyltransferase 5 (PRMT5) exhibits elevated expression levels in a variety of cancers and has emerged as a critical target for cancer therapy in recent years. However, first-generation PRMT5 inhibitors have exhibited inadequate selectivity, leading to significant hematological toxicity, thus limiting their clinical utility. The second-generation PRMT5 inhibitors have shown marked improvement in safety and efficacy by selectively targeting MTAP-null tumor cells without impacting normal cells. This review systematically summarizes the biological and functional roles of PRMT5 in MTAP-deficient tumor cells, and comprehensively analyzes the research and development process, molecular binding mechanisms, and the latest advancements in clinical trials of the five second-generation PRMT5 inhibitors currently under investigation, aiming to provide valuable insights for further in-depth studies in this field.

Objective To explore the risk factors for obstetric septic shock.Methods The clinical data of 122 obstetric sepsis patients from Jan.2013 to Apr.2025 were retrospectively analyzed.The patients were assigned to shock group(n=26)or non-shock group(n=96)based on whether they progressed to septic shock.Variables including age,body mass index,multiple pregnancy,sequential organ failure assessment(SOFA)score,organ dysfunction status,white blood cell count(WBC),neutrophil count(NEU),neutrophil ratio,platelet count,procalcitonin,C-reactive protein,lactate(Lac),and D-dimer were recorded.Multivariate logistic regression analysis was used to identify the independent risk factors for obstetric septic shock.The predictive efficacy of these factors was evaluated using receiver operating characteristic(ROC)curve analysis.Results The proportions of patients aged≥35 years,and those with respiratory,cardiac,or central nervous system dysfunction,were significantly higher in the shock group than in the non-shock group,and the SOFA score,WBC,NEU,neutrophil ratio and Lac level were significantly higher in the shock group(all P＜0.05).Multivariate logistic regression analysis showed that increased NEU(odds ratio[OR]=1.093,95%confidence interval[CI]1.022-1.169,P=0.010)and age≥35 years(OR=3.433,95%CI 1.112-10.602,P=0.032)were independent risk factors for obstetric septic shock.ROC curve analysis showed that NEU had predictive value for obstetric septic shock(area under curve=0.741,95%CI 0.634-0.848),with an optimal cut-offvalue of 17.17×109/L.Conclusion Increased NEU and age≥35 years are independent risk factors for obstetric septic shock.NEU has predictive value for the development of obstetric septic shock and may serve as an important indicator for clinical assessment and timely treatment.

This study aims to investigate the medication rules of patented traditional Chinese medi-cine(TCM)compound formulas and molecular mechanisms of core drugs for treating sepsis using data mining and network pharmacology approaches.In the present study,we first searched the PubMed database,Web of Science database,and the China National Knowledge Infrastructure(CNKI)since the establishment of the library to April 30,2024 for the relevant literature on the treatment of sepsis by traditional Chinese medicine.The prescriptions were then statistically ana-lyzed for drug frequency and association analysis to obtain the core drugs.Then we screened the ef-fective active ingredients of the core drugs by TCMSP and other database platforms,obtained sep-sis-related genes in GeneCards and other databases,and statistically intersected targets,and predic-ted the mechanism of action of the core TCMs by subjecting the intersected targets to PPI analy-sis,GO function and KEGG pathway enrichment analysis.Finally,the relationship between key tar-gets and herbal components was examined in reverse by molecular docking method.The results showed that 64 compound formulas were obtained,with a total of 150 Chinese medicines,which were mostly sweet in taste,cold in nature,and belonged to the spleen,stomach and intestinal me-ridians.According to the association rules,the core drugs were identified as"mirabilite-peach ker-nel-rheum officinale".There were 79 intersecting targets between the core drugs and sepsis,with core targets such as IL-1β,EGFR and SRC.MAPK,TNF,IL-17 and other signaling pathways are involved to mediate inflammatory responses,apoptosis and other biological processes to exert ther-apeutic effects on sepsis.The molecular docking results indicated that the docking activity of the key targets with the main components of the drug,and sennoside E_qt has the lowest binding ener-gy and the best docking activity with SRC.In conclusion,this study showed that the prescription of Chinese medicine for sepsis is mostly based on tonifying the spleen and clearing heat.The mecha-nism of action of the core drug"mirabilite-peach kernel-rheum officinale"in the treatment of sep-sis is multilevel and multifaceted,which provides a certain theoretical basis for the treatment of sepsis by traditional Chinese medicine.

[Objective]To explore the correlation between general anesthesia and mild cognitive impairment in older adults so as to provide new ideas for early prevention and timely intervention of mild cognitive impairment(MCI).[Methods]Based on the baseline survey of the Hubei memory and aging cohort study(2018-2023),the participants completed a thorough neuropsychological assessment and physical examination,and self-reported a history of general anesthesia and surgery.The association of general anesthesia and MCI in the elderly was analyzed using the logistic regression model.In addition,the stratification and interaction analysis of anesthesia history,anesthesia number and physical intellectual exercise were conducted separately.[Results]A total of 5 069 older adults aged 65 and above were included in this study,including 3 692 city dwellers and 1 377 rural people,among whom were 2 584 women(51%).Out of the 1 472 participants with history of general anesthesia,249 people(17.4%)had MCI.After controlling for confounding factors,there was a 39.6%increased risk of MCI in older adults who underwent general anesthesia[OR=1.396,95%CI(1.169,1.668),P<0.001],suggesting that general anesthesia may be an independent influence on MCI.For the older adults who had one general anesthesia[OR=1.235,95%CI(1.001,1.523),P=0.049],two general anesthesia[OR=1.779,95%CI(1.292,2.450),P<0.001],and three OR more general anesthesia[OR=2.395,95%CI(1.589,3.610),P<0.001],their risks of MCI were increased by 23.5%,77.9%,and 139.5%,respectively.Compared with the older adults without a history of general anesthesia who did not exercise,the risk of developing MCI was significantly negatively correlated with the exercise group,cognitive exercise group,and combined exercise and cognitive exercise groups(all P<0.001).The risk of developing MCI in the exercise group was 60.2%of that in the no exercise group[OR=0.602,95%CI(0.456,0.795)],the risk in the cognitive exercise group was 42.4%of that in the no exercise group[OR=0.424,95%CI(0.294,0.613)],and the risk in the combined exercise and cognitive exercise group was 27.0%of that in the no exercise group[OR=0.270,95%CI(0.208,0.353)].In the older adults with a history of general anesthesia,compared with the no exercise group,the risk of developing MCI was significantly negatively correlated with the cognitive exercise group and the combined exercise and cognitive exercise group(all P<0.05).The risk of developing MCI in the cognitive exercise group was 47.7%of that in the no exercise group[OR=0.477,95%CI(0.256,0.892)],the risk in the combined exercise and cognitive exercise group was 34.5%of that in the no exercise group[OR=0.345,95%CI(0.220,0.540)],while the risk in the exercise-only group did not show a significant difference.[Conclusion]The risk of MCI increased significantly in older adults with a history of general anesthesia,and this risk increased with the times of anesthesia.Physical and mental exercise reduces the risk of MCI.it is recommended that older adults with a history of anesthesia incorporate physical and mental exercise into their daily lives to prevent mild cognitive impairment.

This study aims to investigate the medication rules of patented traditional Chinese medi-cine(TCM)compound formulas and molecular mechanisms of core drugs for treating sepsis using data mining and network pharmacology approaches.In the present study,we first searched the PubMed database,Web of Science database,and the China National Knowledge Infrastructure(CNKI)since the establishment of the library to April 30,2024 for the relevant literature on the treatment of sepsis by traditional Chinese medicine.The prescriptions were then statistically ana-lyzed for drug frequency and association analysis to obtain the core drugs.Then we screened the ef-fective active ingredients of the core drugs by TCMSP and other database platforms,obtained sep-sis-related genes in GeneCards and other databases,and statistically intersected targets,and predic-ted the mechanism of action of the core TCMs by subjecting the intersected targets to PPI analy-sis,GO function and KEGG pathway enrichment analysis.Finally,the relationship between key tar-gets and herbal components was examined in reverse by molecular docking method.The results showed that 64 compound formulas were obtained,with a total of 150 Chinese medicines,which were mostly sweet in taste,cold in nature,and belonged to the spleen,stomach and intestinal me-ridians.According to the association rules,the core drugs were identified as"mirabilite-peach ker-nel-rheum officinale".There were 79 intersecting targets between the core drugs and sepsis,with core targets such as IL-1β,EGFR and SRC.MAPK,TNF,IL-17 and other signaling pathways are involved to mediate inflammatory responses,apoptosis and other biological processes to exert ther-apeutic effects on sepsis.The molecular docking results indicated that the docking activity of the key targets with the main components of the drug,and sennoside E_qt has the lowest binding ener-gy and the best docking activity with SRC.In conclusion,this study showed that the prescription of Chinese medicine for sepsis is mostly based on tonifying the spleen and clearing heat.The mecha-nism of action of the core drug"mirabilite-peach kernel-rheum officinale"in the treatment of sep-sis is multilevel and multifaceted,which provides a certain theoretical basis for the treatment of sepsis by traditional Chinese medicine.

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca²⁺ imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.
Humans ; Amyotrophic Lateral Sclerosis/therapy* ; Animals ; Axons/metabolism* ; Mitochondria/metabolism* ; Motor Neurons/pathology*

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC₅₀ = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Objective:To evaluate psychometric properties of infertility related stress assessment instruments and the methodological quality of research.Methods:Research on the psychometric property evaluation of infertility related stress assessment instruments was electronically searched on China National Knowledge Infrastructure, China Biology medicine disc, WanFang Data, VIP, PubMed, Web of Science, Embase, Scopus, and CINHAL. The search period was from database establishment to November 1, 2023. Two researchers independently screened literature and extracted data, evaluated the included assessment tools using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) guideline, and formed recommendations.Results:A total of 20 studies were included, including 8 assessment instruments of the Fertility Problem Stress Inventory, Infertility Distress Scale, Fertility Problem Inventory, Fertility Problem Inventory-Short Form, Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scales, Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scales-Short Form, Infertility-Related Stress Scale, and the Symptom and Stress Inventory for Infertility. The content validity of assessment instrument was not reported or uncertain, and the quality of evidence for the assessment tools was moderate, all of which were B-level recommendations.Conclusions:The Fertility Problem Inventory, Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scales, Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scales-Short Form and the Infertility-Related Stress Scale can be temporarily recommended for use, but the psychometric property of each tool still needs to be fully verified. Clinical medical and nursing staff need to choose appropriate assessment instruments based on actual situation.