Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

Francisella philomiragia(F.philomiragia)infection is a rare infectious disease.This article repor-ted one case of bloodstream infection of F.philomiragia.Relevant literatures from at home and abroad were sys-tematically reviewed,and clinical characteristics of infected patients were summarized and analyzed.The research found that people with chronic granulomatous disease,drowning,blood system diseases,diabetes,kidney trans-plantation,rheumatism,alcoholism,and other immunocompromised or immune barrier damaged people are suscep-tible to F.philomiragia.Salt water exposure is a risk factor.The combined anti-infection scheme based on amino-glycosides,fluoroquinolones and doxycycline can improve the success rate of treatment.

In recent years,the development of acupuncture and moxibustion(shortened as acup-moxibustion)has flourished.With the verification of clinical efficacy of acup-moxibustion,its basic research has gradually drawn the attention of the practitioners accordingly.But how to scientifically perform the basic research of acup-moxibustion and to serve the clinic effectively has become a major problem for the contemporary Chinese medicine practitioners.By analyzing the characteristics of acup-moxibustion-related research projects funded by the National Natural Science Foundation of China,this paper outlined the current status of domestic research of acup-moxibustion,and proposed four suggestions after analyzing the problems and weaknesses of acup-moxibustion basic research in China:①the clinical evidence-based system in the current acup-moxibustion should be further constructed and the basic research should be focused on the area of advantages;② the key problems of acup-moxibustion basic research should be clarified,and the proportion of original researches should be increased;③ the integration of production,teaching and research of acup-moxibustion should be enhanced to adapt to the era of big science;④ the funding system and its polity and structure needed to be reformed.This study will help to increase the discipline ranking of acup-moxibustion,enhance its high-quality development,and promote its internationalization.

Perimenopause is a vulnerable stage for emotional disorders such as anxiety and depression,which is the result of a combination of bio-psycho-social factors,and it seriously affect the quality of life of perimenopausal women.Therefore,finding safe and effective treatments is one of the urgent problems in modern medicine.This paper summarises the etiology and treatment of emotional disorder in perimenopause in Chinese and western medicine,and on this basis,this paper discusses the clinical diagnostic and treatment strategies and research ideas of acupuncture in treating emotional disorder in perimenopause,thus providing a new idea for the prevention and treatment of emotional disorder in perimenopause.

Objective:To investigate the effects of Curcumol on the malignant biological characteristics of acute myeloid leukemia (AML)cells and its molecular mechanism,and to provide theoretical and experimental evidence for the anti-leukemia treatment of traditional Chinese medicine.Methods:After the AML cell lines HL-60 and KG-1 cells were treated different concentrations of with Curcumol.The proliferation activity of cells was detected by CCK-8 method,and the expression changes of apoptotic proteins and PI3 K/AKT signaling pathway proteins were detected by Western blot. Real-time quantitative fluorescence polymerase chain reaction (RT-qPCR ) was used to detect the expression of Caspase family mRNA.Results:Curcumol could inhibit the proliferation and induce apoptosis of HL-60 and KG-1 cells,promote apoptosis by up-regulating the expression of Bax and down-regulating the expression of Bcl-2 protein (P<0.05).When Curcumol interferes with HL-60 and KG-1 cells,it can also induce programmed cell death of AML by inhibiting PI3 K/AKT signaling pathway.In addition,after the intervention of Curcumol,the expression of Caspase 3,Caspase 6,Caspase 8 and Caspase 9 were up-regulated in HL-60 cells (P<0.05 ),the expression of Caspase 3,Caspase 8 and Caspase 9 were significantly up-regulated in KG-1 cells (P<0.01),while the expression of Caspase 6 was weakly affected (P<0.05 ),but low concentration of Curcumol (<60 μg/ml)had no effect on the expression of Caspase 6 in KG-1 cells (P>0.05).Conclusion:Curcumol may mediate the programmed death of AML cells by inhibiting the PI3K/AKT signaling pathway,affecting the expression of Bcl-2 family proteins,and promoting the activation of core members of Caspase family,so as to play an anti-leukemia role.

Hip fracture in the elderly is characterized by high incidence, high disability rate, and high mortality and has been recognized as a public health issue threatening their health. Surgery is the preferred choice for the treatment of elderly patients with hip fracture. However, lower extremity deep venous thrombosis (DVT) has an extremely high incidence rate during the perioperative period, and may significantly increase the risk of patients′ death once it progresses to pulmonary embolism. In response to this issue, the clinical guidelines and expert consensuses all emphasize active application of comprehensive preventive measures, including basic prevention, physical prevention, and pharmacological prevention. In this prevention system, basic prevention is the basis of physical and pharmacological prevention. However,there is a lack of unified and definite recommendations for basic preventive measures in clinical practice. To this end, the Orthopedic Nursing Professional Committee of the Chinese Nursing Association and Nursing Department of the Orthopedic Branch of the China International Exchange and Promotive Association for Medical and Health Care organized relevant nursing experts to formulate Expert consensus on perioperative basic prevention for lower extremity deep venous thrombosis in elderly patients with hip fracture ( version 2024) . A total of 10 recommendations were proposed, aiming to standardize the basic preventive measures for lower extremity DVT in elderly patients with hip fractures during the perioperative period and promote their subsequent rehabilitation.

Ashi points play a significant role in the clinical localization and qualitative diagnosis of acupuncture, as well as in selecting acupoints along the meridians and applying tonifying or reducing techniques. This paper introduces the theoretical basis and existing technical methods of objectification of ashi point diagnosis and treatment. It proposes that using sensory quantitative testing to determine the temperature and tenderness thresholds of ashi points could help to identify the pathological characteristics of "cold" "heat" "deficiency" or "excess" of ashi points. In addition, the possibility of objectification of ashi point diagnosis-treatment plan is explored from three perspectives, precision of selection of ashi point therapy, objectification of effect evaluation of ashi point analgesia, and differentiation of the studies on ashi point analgesic mechanism, aiming to provide new research ideas for the modernization of traditional Chinese acupuncture.
Acupuncture Therapy ; Meridians ; Acupuncture Points ; Acupuncture ; Analgesia

OBJECTIVES: To explore the risk factors for hemorrhagic cystitis (HC) in children with β-thalassemia major (TM) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A retrospective analysis was conducted on clinical data of 247 children with TM who underwent allo-HSCT at Shenzhen Children's Hospital from January 2021 to November 2022. The children were divided into an HC group (91 cases) and a non-HC group (156 cases) based on whether HC occurred after operation. Multivariable logistic regression analysis was used to explore the risk factors for HC, and the receiver operating characteristic curve was used to analyze the predictive efficacy of related factors for HC. RESULTS: Among the 247 TM patients who underwent allo-HSCT, the incidence of HC was 36.8% (91/247). Univariate analysis showed age, incompatible blood types between donors and recipients, occurrence of acute graft-versus-host disease (aGVHD), positive urine BK virus deoxyribonucleic acid (BKV-DNA), and ≥2 viral infections were associated with the development of HC after allo-HSCT (P<0.05). Multivariable analysis revealed that incompatible blood types between donors and recipients (OR=3.171, 95%CI: 1.538-6.539), occurrence of aGVHD (OR=2.581, 95%CI: 1.125-5.918), and positive urine BKV-DNA (OR=21.878, 95%CI: 9.633-49.687) were independent risk factors for HC in children with TM who underwent allo-HSCT. The receiver operating characteristic curve analysis showed that positive urine BKV-DNA alone or in combination with two other risk factors (occurrence of aGVHD, incompatible blood types between donors and recipients) had a certain accuracy in predicting the development of HC after allo-HSCT (area under the curve >0.8, P<0.05). CONCLUSIONS Incompatible blood types between donors and recipients, occurrence of aGVHD, and positive urine BKV-DNA are risk factors for HC after allo-HSCT in children with TM. Regular monitoring of urine BKV-DNA has a positive significance for early diagnosis and treatment of HC.
Humans ; Child ; Retrospective Studies ; beta-Thalassemia/therapy* ; Cystitis/epidemiology* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Risk Factors ; Hemorrhage/etiology* ; Graft vs Host Disease/complications* ; DNA ; Polyomavirus Infections/epidemiology*