Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

OBJECTIVE To investigate the effects of subanesthetic dose of esketamine on postoperative anxiety and recovery in patients undergoing laparoscopic cholecystectomy. METHODS A total of 200 patients scheduled for laparoscopic cholecystectomy at Suzhou Ninth Hospital Affiliated to Soochow University from January 2023 to December 2024 were randomly assigned to control group （n＝100） and observation group （n＝100）. One minute before the initiation of anesthesia， patients in the control group received intravenous injections of Propofol emulsion injection， Sufentanil citrate injection， and Succinylcholine chloride injection. On this basis， patients in the observation group received an intravenous injection of Esketamine hydrochloride injection. The anxiety status of patients in both groups was compared， along with their general intraoperative conditions （including sufentanil dosage， duration of pneumoperitoneum， operative time， anesthesia time， and extubation time）， postoperative recovery， incidence of adverse reactions， and the need for dezocine rescue analgesia. Heart rate and mean arterial pressure， entropy index （state entropy and response entropy）， inflammatory marker levels [interleukin-6 （IL-6） and C-reactive protein （CRP）]， numerical rating scale （NRS） for pain intensity were compared between the two groups at different time points. RESULTS No significant differences were found between the two groups in pneumoperitoneum duration， operative time， anesthesia time，extubation time， incidence of postoperative dry mouth， entropy index or length of stay in the post-anesthesia care unit （P＞0.05）. Compared with the control group， the observation group showed significantly lower postoperative STAI-S scores， reduced intraoperative sufentanil consumption， decreased incidence of postoperative nausea， vomiting， and shivering， the need for dezocine rescue analgesia， as well as lower plasma IL-6 and CRP levels at 24 h after surgery， and NRS （P＜0.05）. The heart rate and mean arterial pressure of patients in the observation group at the start of surgery， end of surgery， and during extubation were all significantly higher than those in the control group （P＜0.05）. CONCLUSIONS Subanesthetic dose of esketamine can effectively alleviate postoperative anxiety， reduce intraoperative opioid consumption， suppress postoperative inflammatory response， relieve postoperative pain， and promote recovery in patients undergoing laparoscopic cholecystectomy.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

The application of nutritional support in critically ill patients has gained widespread recognition due to its significant benefits for intestinal function and related immune systems.Patients with Acute Respiratory Distress Syndrome(ARDS)are particularly susceptible to intestinal dysbiosis and dysfunction,which can facilitate the translocation of pathogenic bacteria into the lungs via the"gut-lung"axis.This process activates the immune system,exacerbating lung injury and worsening patient outcomes.Therefore,restoring the stability of the intestinal environment and normalizing immune function in ARDS patients is of critical importance.This article reviews the role of nutritional support in modulating intestinal mucosal barrier function and immune response in ARDS patients through the gut-lung immune axis,while also exploring the mechanistic effects of specific nutritional components in this context.

Objective To develop and validate a fast Monte Carlo(MC)-based patient-specific quality assurance(PSQA)tool using the treatment log files that is suitable to be used in the online adaptive radiotherapy for pencil beam scanning proton therapy(PBSPT-ART).Methods The proposed tool first used the delivery log file of a PBSPT plan to reversely reconstruct the PBSPT(rPBSPT)plan,and then used an in-house developed graphic processing unit(GPU)-accelerated virtual particle MC(VPMC)dose engine to calculate the dose distribution of the rPBSPT plan.The rPBSPT dose calculated by VPMC was then compared to the rPBSPT dose calculated by another independent MC dose engine(MCsquare),using 3D gamma analysis to verify the accuracy of VPMC calculation.As a demonstration of the feasibility of developed log file-based PSQA,the VPMC calculated dose of the rPBSPT plan was compared to the pre-delivery second check dose of the corresponding PBSPT plan calculated by MCsquare,using 3D gamma analysis.3D gamma analysis employes a criterion of 2 mm/2%/10%.Twenty patients with different disease sites were representatively selected to validate the efficiency and accuracy of the tool.Results The average calculation time of a rPBSPT plan by VPMC was(5.88±4.00)s in the accuracy verification.Compared to MCsquare,the passing rate of the 3D gamma analysis was 99.47%±0.72%.In the proposed PSQA tool demonstration,the passing rate of comparing the VPMC calculated rPBSPT dose to MCsquare calculated second check dose of the corresponding PBSPT plan was 98.91%±0.92%.Conclusion The accuracy and efficiency of the tool can meet the requirements of PSQA in the online PBSPT-ART workflow.

With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.

Objective To investigate the influence of helical tomographic radiotherapy plans with different combinations of lead gate width,pitch and algorithms on threading effects.Methods A target model was established with a Cheese Phantom used as the simulated human body,then three lead gate widths(1.0,2.5,and 5.0 cm),six screw pitches(0.143,0.172,0.215,0.287,0.430,and 0.500)and two computational grids(Fine algorithm and Normal algorithm)were respectively combined for designing the helical tomography radiotherapy plans.The radiotherapy plans with a pitch of 0.143,0.172,0.215,0.287 or 0.430 were enrolled into an experimental group,and the plans with a pitch of 0.500 were divided into a control group.The dosimetric parameters including maximum dose(Dmax),minimum dose(Dmin)and mean dose(Dmean)of the target area PTV1 and PTV2 were evaluated by the dose volume histogram(DVH).The dose homogeneity index(HI)of the target area was calculated,and the single rotation time and total treatment time of each plan were recorded and counted.SPSS 27.0 software was used for statistical analysis.Results No significant threading effect appeared regardless of the pitch value when the lead gate width was 1.0 cm.The threading effects in the experimental group were weaker than those in the control group when the lead gate width was 2.5 or 5.0 cm.The threading effect gradually rose with the pitch increased when the lead gate width was 5.0 cm.The most significant difference was found between the threading effect in case of the screw pitch being 0.500 and that with the screw pitch being 0.143,with the differenes being statistically obvious(P<0.05).The lead gate width had significant effects on the Dmax,Dmin,Dmean and HI of PTV1 and PTV2.When the lead gate width was 5.0 cm,high HI value and uneven dose distribution were detected and lowered screw pitch weakened the threading effect.The single rotation time first remained constant and then increased with the screw pitch was enlarged,with the changing points occurring in case of the screw pitches of 0.287 and 0.430.With a certain lead gate width,the treatment time for plans was shortened with the decrease of the pitches in case of the pritches lower than 0.287,and tended to be constant after the screw pitches reached 0.287.The changes of the computational grid had no significant effects on the results of radiotherapy plans when the lead gate width and screw pitch were kept constant.Conclusion When designing a spiral tomotherapy plan with conventional doses,a lead gate width of 1.0 or 2.5 cm and a screw pitch of 0.287 or 0.430 should be selected in order to minimize the threading effect while ensuring the efficiency of plan implementation.[Chinese Medical Equipment Journal,2025,46(8):58-66]

Objective To evaluate the efficacy and safety of transcatheter aortic valve implantation(TAVI)for the treatment of primary aortic valve regurgitation(NAVR)and to compare the difference in the choice of prosthetic valve size and the difference in complications with aortic stenosis(AS).Methods According to the definition of Valve Academic Research Consortium(VARC-3),143 patients with NAVR/AS treated with TAVI and patients with NAVR treated with surgical aortic valve replacement(SAVR)at Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,China,from March 2019 to September 2024 were selected,and clinical data on baseline,perioperative,and primary endpoint events were were retrospectively collected and compared.Results Forty-three patients with NAVR were treated with TAVI,with a device success rate of 86.0％and a surgical success rate of 95.3％.Subgroup comparisons:(1)NAVR-TAVI group than NAVR-SAVR group:patients in the TAVI group had a significantly shorter operative time than those in the SAVR group(P＜0.001);complete left bundle branch block was more likely to occur after TAVI(P=0.042),and complete right bundle branch block was more likely to occur after SAVR(P=0.044).SAVR postoperatively The incidence of congestive heart failure was higher(P=0.013),and the mortality rate was significantly higher in the SAVR group than in the TAVI group(P=0.019).(2)NAVR-TAVI group than AS-TAVI group:the differences in access selection,THV size[28(22,34)mm vs.24(22,32)mm,P=0.044]and proportion of THV overdiameter[14％(7％,20％)vs.7％(3％,11％),P＜0.001]were statistically significant.patients in AS and NAVR groups had 1 case of permanent pacing after TAVI treatment.In the AS and NAVR groups,there was 1 case of permanent pacemaker implantation after TAVI.2 patients in the AS group were converted to surgical treatment,and 6 patients died.Conclusions The use of"off-label"(transfemoral)and"on-label"(transapical)TAVI devices(both from domestic sources)is safer than SAVR for the treatment of NAVR,especially in elderly and high-risk patients.Compared with patients with AS treated with TAVI,larger diameter annulas are usually selected for NAVR,with higher rates of valve migration,but overall safety and efficacy are comparable to AS.