香蕉枯萎病菌内源报告基因Foc4carS的鉴定及其应用

香蕉枯萎病是由尖孢镰刀菌古巴转化型(Fusarium oxysporum f. sp. cubense, Foc)引起的香蕉毁灭性土传病害,其中4号生理小种(Foc4)能感染几乎所有的香蕉品系,危害最严重。carS基因通过调控下游car结构基因参与调控镰刀菌类胡萝卜素的生物合成,本研究克隆鉴定了Foc4carS基因(FOIG_05085),Foc4carS蛋白具有典型的RING-finger蛋白结构域。利用分割标记法(Split-marker PCR)获得Foc4carS基因的融合片段,同时构建含有Foc4carS基因sgRNA591序列的pUC-fFuCas9-HTBNLS-hph-Foc4carS基因编辑载体,通过PEG介导的原生质体转化获得该基因的敲除突变体、回补突变体以及基因编辑敲除体,并对敲除和回补突变体的生物学特性和致病力进行分析。结果显示:ΔFoc4carS突变体的菌落直径、产孢量和致病力等生物学表型与野生菌株Foc4无显著差异,而ΔFoc4carS突变体菌落颜色呈深橙色,Foc4carS基因的缺失影响了次生代谢产物类胡萝卜素的生物合成;基因编辑的ΔFoc4carS(HDR)突变体不论是再生筛选板还是继代后的PDA平板,其菌落均出现典型的深橙色,表明Foc4carS可作为内源报告基因,在香蕉枯萎菌Foc4中进行基因质粒型CRISPR/Cas9编辑可行。

基于Partial New Causality的因果脑网络情绪识别

为了研究情绪产生过程中脑区以及通道之间的因果作用,在部分格兰杰与新型因果关系的基础上,提出一种用于研究时间序列之间因果关系的部分新型因果关系(PNC)方法。在不同情绪下选取脑区内的8个通道,用PNC计算脑区内通道之间的因果连接关系,根据连接关系构建因果网络;对因果网络中节点的信息流向和介数属性进行分析,将PNC因果网络和Granger因果网络节点之间的因果连接视为一种特征送入SVM中训练分类。实验结果表明,基于PNC因果网络和Granger因果网络的平均识别精度分别为76.4%和68.5%,PNC可用于计算时间序列之间的因果关系。

BCMA CAR-T治疗复发/难治性多发性骨髓瘤患者的长期疗效和影响因素分析

目的:评价靶向B细胞成熟抗原(B cell maturation antigen,BCMA)嵌合抗原受体T细胞(chimeric antigen receptor-T cell,CAR-T)治疗复发/难治性多发性骨髓瘤(relapsed/refractory multiple myeloma,R/R MM)的长期疗效和安全性。方法:回顾性分析2018年7月至2023年7月在南昌大学第一附属医院接受BCMA CAR-T细胞治疗20例R/R MM患者的临床资料,随访日期截至2023年12月31日。应用Kaplan-Meier生存分析评估患者总生存(overall survival,OS)率和无进展生存(progression-free survival,PFS)率,并统计相关不良反应。结果:20例R/R MM患者,既往中位治疗线数为3(2~6)线,客观缓解率(objective response rate,ORR)为75%,完全缓解(complete response,CR)率为50%;中位随访时间29个月,中位PFS为26个月。10例CR的患者中,5例在末次随访时仍处于缓解状态,缓解持续时间最短为6个月,最长48个月。亚组分析中,髓外浸润、17p缺失遗传学异常和肿瘤高负荷患者PFS显著更差(P<0.05)。细胞因子释放综合征(cytokine release syndrome,CRS)是CAR-T细胞治疗最常见的不良反应,发生率为90%,3~4级CRS的发生率为35%;远期不良反应少,未发生CAR-T细胞治疗相关死亡。结论:BCMA CAR-T细胞是当前R/R MM治疗的有效方案,不良反应可控。髓外浸润和肿瘤高负荷的患者治疗有效,但持久反应欠佳,如何进一步巩固和维持患者的疗效,值得进一步设计前瞻性的临床研究并探究其差异性。

预后营养指数联合CAR、Alb对腹膜透析患者远期预后的预测价值

目的 评估预后营养指数(PNI)联合C反应蛋白/白蛋白比值(CAR)、血清白蛋白(Alb)对腹膜透析(PD)患者远期预后的预测价值。方法 分析纳入2019年1月至2024年1月在自贡市第一人民医院肾病内科接受PD治疗的终末期肾病患者102例,根据5年随访期间PD患者生存结局分为死亡组(n=33)和生存组(n=69)。采用单因素及多因素Logistic回归分析影响PD患者远期预后的独立危险因素。绘制受试者工作特征(ROC)曲线评估PNI联合CAR、Alb对PD患者生存结局的预测价值。结果 与生存组相比,死亡组患者合并糖尿病、心血管疾病及腹膜炎并发症的比例较高,差异有统计学意义(χ^(2)=0.947,4.846,5.840);肾小球滤过率(eGFR)、PNI、Alb水平降低,差异有统计学意义(t=9.495,6.068,5.422);血清肌酐(SCR)、尿酸(UA)及CAR水平升高,差异有统计学意义(t=5.369,4.581,5.048),差异均有统计学意义(P<0.05)。Logistic回归分析显示,患者合并糖尿病、心血管疾病、CAR是PD患者死亡的独立危险因素(P<0.05),eGFR、PNI、Alb是PD患者死亡的独立保护因素(P<0.05)。ROC曲线分析显示,PNI、CAR、Alb联合预测的曲线下面积分别为0.928,显著高于单独预测(P<0.05)。结论 PNI、Alb水平降低及CAR升高是PD患者死亡的独立影响因素,三者均可为PD患者长期预后生存结局提供参考,且联合预测价值更高。

儿童CD19 CAR-T细胞治疗相关B细胞再生障碍的临床意义和对策

急性B系淋巴细胞白血病(B-ALL)患儿在CD 19 CAR-T细胞治疗后普遍发生B细胞再生障碍(BCA),BCA持续的时间长短对患者的免疫状态及预后会产生影响。对BCA的充分认识有助于临床医师科学、规范、合理地选择治疗策略,减少CAR-T治疗后白血病患儿的感染机会,提高生活质量,改善预后。

碧根果致敏原Car i 1的分离纯化及表征鉴定

目的分离纯化碧根果致敏原Car i 1,并对其结构进行表征鉴定。方法以新鲜碧根果果仁为原料,通过粉碎、脱脂、浸提、粗分级、凝胶过滤层析,对碧根果致敏原蛋白Car i 1进行分离纯化。结合十二烷基硫酸钠-聚丙烯酰胺凝胶电泳、液相色谱-串联质谱法和免疫印迹法3种方法对Cari1进行鉴定,并通过圆二色谱仪与紫外分光光度计表征其二、三级结构。结果本方法纯化获得碧根果致敏原Cari1,单轮制备量可达5 mg以上,且纯度大于95%,蛋白质高级结构未被破坏,能够被全部3名碧根果过敏患者的血清准确识别。结论该纯化方法技术路线简单、设备要求低且单次制备量高,总得率可达65%,操作便捷,为碧根果致敏原Car i 1的相关研究奠定了物质基础。

Immune cell signatures and causal association with irritable bowel syndrome:A mendelian randomization study

BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(IBS).Prior studies linking immune inflammation with IBS have been inconsistent.To further elucidate this relationship,we conducted a Mendelian randomization(MR)analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS.Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.AIM To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS.We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.METHODS We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS.By utilizing genetic data from public databases,we examined the causal associations between 731 immune cell markers,encompassing median fluorescence intensity,relative cell abundance,absolute cell count,and morphological parameters,with IBS susceptibility.Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.RESULTS Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes.However,our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes(P<0.05).Nine immune phenotypes demonstrated a protective effect against IBS[inverse variance weighting(IVW)<0.05,odd ratio(OR)<1],while 21 others were associated with an increased risk of IBS onset(IVW≥0.05,OR≥1).CONCLUSION Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS,providing valuable insights into the pathophysiology of the condition.These results pave the way for the development of more precise biomarkers and targeted therapies for IBS.Furthermore,this research enriches our comprehension of immune cell roles in IBS pathogenesis,offering a foundation for more effective,personalized treatment approaches.These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

Causal role of immune cells in obstructive sleep apnea hypopnea syndrome:Mendelian randomization study

BACKGROUND Despite being one of the most prevalent sleep disorders,obstructive sleep apnea hypoventilation syndrome(OSAHS)has limited information on its immunologic foundation.The immunological underpinnings of certain major psychiatric diseases have been uncovered in recent years thanks to the extensive use of genome-wide association studies(GWAS)and genotyping techniques using highdensity genetic markers(e.g.,SNP or CNVs).But this tactic hasn't yet been applied to OSAHS.Using a Mendelian randomization analysis,we analyzed the causal link between immune cells and the illness in order to comprehend the immunological bases of OSAHS.AIM To investigate the immune cells'association with OSAHS via genetic methods,guiding future clinical research.METHODS A comprehensive two-sample mendelian randomization study was conducted to investigate the causal relationship between immune cell characteristics and OSAHS.Summary statistics for each immune cell feature were obtained from the GWAS catalog.Information on 731 immune cell properties,such as morphologic parameters,median fluorescence intensity,absolute cellular,and relative cellular,was compiled using publicly available genetic databases.The results'robustness,heterogeneity,and horizontal pleiotropy were confirmed using extensive sensitivity examination.RESULTS Following false discovery rate(FDR)correction,no statistically significant effect of OSAHS on immunophenotypes was observed.However,two lymphocyte subsets were found to have a significant association with the risk of OSAHS:Basophil%CD33dim HLA DR-CD66b-(OR=1.03,95%CI=1.01-1.03,P<0.001);CD38 on IgD+CD24-B cell(OR=1.04,95%CI=1.02-1.04,P=0.019).CONCLUSION This study shows a strong link between immune cells and OSAHS through a gene approach,thus offering direction for potential future medical research.

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of the EGFR signaling pathway

The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

系统性红斑狼疮CAR T细胞治疗疗效预测及安全性评估的潜在生物标志物

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种复杂的自身免疫疾病,传统治疗在部分重度和难治性患者中效果有限。近期研究显示,嵌合抗原受体(chimeric antigen receptor,CAR)T细胞疗法在SLE治疗中展现出了具有前景的疗效。生物标志物在精准评估治疗效果和安全性方面至关重要,CAR T细胞治疗与安全性评估标志物包括传统标志物和与CAR T细胞疗法相关的标志物。传统的SLE病情监测标志物,仍可用于CAR T细胞治疗基线随访和病情监测,如血清抗双链DNA、抗单链DNA和抗核小体等自身抗体的滴度下降,血清补体水平恢复正常,以及尿蛋白/肌酐比值的改善,均提示病情得到有效控制。CAR T细胞疗效监测标志物分为B细胞和T细胞标志物。输注后,B细胞数量下降,B细胞表型以初始B细胞为主,记忆B细胞和浆母细胞的比例显著降低,表明治疗取得了疗效。输注前,初始T细胞(CD45RA+CD27+)和中央记忆型T细胞(CD45RA-CD62L+CD27+)的高比例则提示更强的抗肿瘤效应;患者的CAR T细胞表达与早期记忆分化相关的转录因子,如T细胞因子7和淋巴增强子结合因子1,提示这些患者对CAR T细胞疗法更为敏感。输注后,CD25、CD69和CD137等T细胞激活标志物,以及CD57、PD-1和Tim-3等耗竭标志物的高表达,提示T细胞的杀伤能力受到限制。CAR T细胞治疗安全性标志物不仅包括CAR T细胞分泌的效应细胞因子(如白细胞介素-2和IFN-γ),还包括单核细胞和巨噬细胞产生的细胞因子(如IL-1和IL-8),其水平可用于评估CAR T细胞疗法最常见的毒副反应[细胞因子释放综合征(cytokine release syndrome,CRS)和免疫效应细胞相关神经毒性综合征(immune effector cell-associated neurotoxicity syndrome,ICANS)]。高水平的血清巨噬细胞炎性蛋白1α对于预测CAR T细胞治疗后发生严重CRS和ICANS的风险具有较高的价值。此外,基线血小板计数和中性粒细胞绝对值可预测血液毒性,由IL-8、IFN-γ和IL-1β组成的感染相关预测模型,能够有效预测患者输注后出现严重感染的风险。CAR受体结构设计、清除淋巴细胞的化疗方式,患者曾接受的治疗选择及自身免疫状态等都会影响CAR T细胞治疗的疗效及安全性。在当前及未来将开启的相关临床研究中,应纳入全面、规范的检测和评估体系,为CAR T细胞疗法在SLE等自身免疫疾病的应用,提供比较标准。

CAR-T疗法安全性控制技术专利现状

CAR-T疗法属于先进细胞治疗手段,自问世以来,因其在肿瘤治疗中发挥的卓越的治疗效果而备受关注,但由于受制于临床治疗过程的各种毒副作用,这一疗法的广泛推广仍然还有很长的路要走。本文从解决CAR-T疗法毒副作用的关键技术——安全性控制出发,分析了该领域相关专利的技术发展路线,以期为我国创新主体在该领域的研发及产业化提供专利信息支持。

衰老细胞清除策略与CAR细胞疗法在抗衰老治疗中的应用

人类寿命逐渐延长,世界各国老年人口的数量和占比持续上升,但健康寿命却并未同步增长,衰老仍然是肿瘤、心血管疾病、阿尔茨海默病等疾病的主要风险因素。如何防治衰老相关疾病,延长老年人的健康寿命,仍亟待研究人员解决。细胞衰老是衰老的12大标志之一,存在于机体的整体衰老过程,可以说机体衰老的本质是组成机体的细胞的衰老,而通过转基因技术、基因重编程技术、使用新型抗衰老药物如senomorphic和senolytic等方法清除衰老细胞,已经成为目前延缓衰老、治疗衰老相关疾病、延长人类健康寿命的重要策略。免疫衰老是机体衰老的一部分,而免疫细胞是人体中最易、最先发生老化的细胞群体,针对免疫系统的抗衰老治疗例如抗体治疗、CAR细胞疗法、NK细胞疗法等是近年衰老研究的热点,研究认为,免疫疗法具有极高的临床抗衰老潜力。本文从细胞衰老和免疫衰老的特征入手,进而总结了目前衰老的非靶向干预方法和靶向衰老细胞清除的干预方法及其优缺点,并重点综述了靶向衰老细胞的免疫治疗清除策略。本文旨在阐明新兴衰老细胞清除方法的发展及局限,为防治衰老相关疾病、延长健康寿命提供新的临床应用策略。

SII联合CAR对小细胞肺癌预后的预测价值

目的分析全身免疫炎症指数(SII)联合C反应蛋白/白蛋白比值(CAR)对小细胞肺癌(SCLC)预后的预测价值。方法回顾性选择本院256例SCLC患者,根据末次随访情况分为死亡组218例和存活组38例。收集两组患者入院时的临床资料,采用多因素Cox回归分析法分析SCLC患者全因死亡的独立危险因素,采用Kaplan-Meier法绘制生存曲线,采用ROC评估SII联合CAR预测SCLC死亡的临床效能。结果存活组与死亡组红细胞分布宽度、中性粒细胞/淋巴细胞比值(NLR)、SII、CAR、D-二聚体、TNM分期比较,差异均有显著性(P<0.05)。低SII组、低CAR组3年生存率分别高于高SII组、高CAR组(P<0.05)。多因素Cox回归分析结果显示,NLR>3.5、SII>766×109个/L、CAR>0.52、TNMⅣ期是SCLC患者全因死亡的独立危险因素。ROC分析显示,SII联合CAR预测SCLC患者全因死亡的AUC高于NLR联合CAR,预测性能最优。结论SII联合CAR对SCLC患者预后具有较好的预测能力。

PXR/CAR-代谢酶/转运体解毒系统的功能及研究进展

目的综述孕烷X受体(PXR)和组成型雄甾烷受体(CAR)-代谢酶/转运体解毒系统的功能和研究进展。方法从肝脏代谢酶、肝肾转运体、PXR/CAR介导的药物解毒等多方面对PXR/CAR-代谢酶/转运体解毒系统及其在药物解毒方面的研究进展进行论述。结果与结论药物作为人体外源性物质,可能存在一定毒副作用,使用不当或毒性较强的药物易造成机体损伤。药物代谢酶和转运体是决定药物体内过程及暴露量的两大核心因素,在药物毒性与解毒方面扮演重要角色。随着对PXR和CAR研究的不断深入,发现其对药物解毒相关的代谢酶和转运体发挥核心调控作用,共同构成了机体最重要的防御解毒系统—PXR/CAR-代谢酶/转运体解毒系统。

Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

生酮饮食疗法对孤独症患儿症状及ATEC和CARS评分的改善效果

目的 探讨生酮饮食疗法对孤独症患儿症状及孤独症治疗评估量表(ATEC)和及儿童孤独症评定量表(CARS)评分的改善效果。方法 回顾性选取2021年7月至2022年7月收治的78例ASD患儿为研究对象,根据不同治疗方案将其分为对照组和治疗组,每组39例,对照组接受ASD特殊教育及日常训练+普通饮食,治疗组接受ASD特殊教育及日常训练+生酮饮食,均连续治疗6个月,比较2组《自闭症儿童心理教育评核(第三版)》(C-PEP-3)评分、孤独症治疗评估量表(ATEC)评分、儿童孤独症评定量表(CARS)评分及孤独症行为量表(ABC)评分。结果 治疗后,2组C-PEP-3各维度评分及总分均显著上升,且治疗组高于对照组(P<0.05);治疗后,2组ATEC各维度(表达/语言沟通、社交能力、感知/认知能力及健康/生理/行为)评分均显著下降,且治疗组低于对照组(P<0.05);治疗后,2组CARS和ABC评分均显著下降,且治疗组低于对照组(P<0.05);治疗后,研究组就寝习惯不良、睡眠焦虑、睡眠持续时间不规律、白天嗜睡、夜醒、入睡潜伏期延长及CSHQ总分均显著低于对照组(P<0.05)。结论 生酮饮食疗法可有效控制孤独症患儿临床症状,改善其认知及异常行为,降低其疾病程度,提高其睡眠质量,值得临床推广。

Causal temporal graph attention network for fault diagnosis of chemical processes

Fault detection and diagnosis(FDD)plays a significant role in ensuring the safety and stability of chemical processes.With the development of artificial intelligence(AI)and big data technologies,data-driven approaches with excellent performance are widely used for FDD in chemical processes.However,improved predictive accuracy has often been achieved through increased model complexity,which turns models into black-box methods and causes uncertainty regarding their decisions.In this study,a causal temporal graph attention network(CTGAN)is proposed for fault diagnosis of chemical processes.A chemical causal graph is built by causal inference to represent the propagation path of faults.The attention mechanism and chemical causal graph were combined to help us notice the key variables relating to fault fluctuations.Experiments in the Tennessee Eastman(TE)process and the green ammonia(GA)process showed that CTGAN achieved high performance and good explainability.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

TCAS-PINN:Physics-informed neural networks with a novel temporal causality-based adaptive sampling method

Physics-informed neural networks(PINNs)have become an attractive machine learning framework for obtaining solutions to partial differential equations(PDEs).PINNs embed initial,boundary,and PDE constraints into the loss function.The performance of PINNs is generally affected by both training and sampling.Specifically,training methods focus on how to overcome the training difficulties caused by the special PDE residual loss of PINNs,and sampling methods are concerned with the location and distribution of the sampling points upon which evaluations of PDE residual loss are accomplished.However,a common problem among these original PINNs is that they omit special temporal information utilization during the training or sampling stages when dealing with an important PDE category,namely,time-dependent PDEs,where temporal information plays a key role in the algorithms used.There is one method,called Causal PINN,that considers temporal causality at the training level but not special temporal utilization at the sampling level.Incorporating temporal knowledge into sampling remains to be studied.To fill this gap,we propose a novel temporal causality-based adaptive sampling method that dynamically determines the sampling ratio according to both PDE residual and temporal causality.By designing a sampling ratio determined by both residual loss and temporal causality to control the number and location of sampled points in each temporal sub-domain,we provide a practical solution by incorporating temporal information into sampling.Numerical experiments of several nonlinear time-dependent PDEs,including the Cahn–Hilliard,Korteweg–de Vries,Allen–Cahn and wave equations,show that our proposed sampling method can improve the performance.We demonstrate that using such a relatively simple sampling method can improve prediction performance by up to two orders of magnitude compared with the results from other methods,especially when points are limited.

Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis

BACKGROUND Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention.However,it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis.AIM To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization(MR)study.METHODS Data on 731 immunocyte phenotypes were obtained from genome-wide assoc-iation studies.Liver cirrhosis data were derived from the Finn Gen dataset,which included 214403 individuals of European ancestry.We used inverse variable weighting as the primary analysis method to assess the causal relationship.Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy.RESULTS The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis[P<0.05,odds ratio(OR)>1]and that 9 immu-nocyte phenotypes were negatively correlated with liver cirrhosis(P<0.05,OR<1).Liver cirrhosis was positively linked to 9 immune cell phenotypes(P<0.05,OR>1)and negatively linked to 10 immune cell phenotypes(P<0.05;OR<1).None of these associations showed heterogeneity or horizontally pleiotropy(P>0.05).CONCLUSION This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis.These findings offer new directions for the treatment of liver cirrhosis.