IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-06 DOI: 10.1016/j.gene.2025.149934

Xin Lin , Zi-yan Xu , Li-jun Xie , Juan Zhu , Hong-ping Yu , Ruo-li Wang , Yi-jia Luo , Jing Zou , Jian-hui Zhang , Qian Chen , Peng-fei Wang , Dan-dan Ruan , Yan-feng Zhou , Li Chen , Fang-meng Huang , Mei-zhu Gao , Li Zhang , Yun-fei Li , Zhu-ting Fang , Jue Wang , Jie-wei Luo

Type A insulin resistance syndrome (TAIRS) is a rare autosomal dominant disorder associated with variants in the Insulin Receptor (INSR) gene. It is characterized by insulin resistance, hyperandrogenism, and acanthosis nigricans. The severity of the condition may be influenced by homozygosity or heterozygosity, with some female patients being misdiagnosed with polycystic ovary syndrome (PCOS). A 13-year-old female proband from a family was identified with hyperinsulinemia, hyperandrogenism, acanthosis nigricans, hirsutism, acne, oligomenorrhea, and masculinization. Exome sequencing and Sanger sequencing confirmed that the proband was a carrier of the INSR (NM_000208.2): c.3734 T > A(p.V1245E) variant. This variant is not listed in the Human Gene Mutation Database (HGMD) or ClinVar. The novel variant was predicted to be deleterious by the bioinformatic tools SIFT, MutationTaster, and Condel. According to the American College of Medical Genetics and Genomics (ACMG) criteria, it was evaluated as PM6, PM2_Supporting, and PP3, and classified as uncertain significance. The variant was not detected in the proband’s parents or other family members, all of whom lacked the associated clinical phenotypes. The p.V1245E variant was found to be a de novo variant. SWISS-MODEL analysis suggested that the p.V1245E variant induces structural changes in the three-dimensional configuration of the INSR protein, potentially impairing its normal function. RT-qPCR revealed a significant reduction in INSR mRNA expression in the proband. In a 293 T cell model transfected with lentivirus carrying the p.V1245E variant, both Western blotting and RT-qPCR demonstrated decreased INSR mRNA and protein expression, while immunofluorescence showed reduced INSR protein levels with altered localization. Therefore, the ACMG evaluation (PS2, PS3, PM2_Supporting, PP3) was further upgraded to pathogenic. In conclusion, this de novo variant represents the pathogenic variant responsible for TAIRS in this family, expanding the variant spectrum of the INSR gene.

A型胰岛素抵抗综合征（TAIRS）是一种罕见的常染色体显性遗传病，与胰岛素受体（INSR）基因变异有关。它的特点是胰岛素抵抗、雄激素过多和黑棘皮病。多囊卵巢综合征的严重程度可能受纯合性或杂合性的影响，一些女性患者被误诊为多囊卵巢综合征（PCOS）。来自一个家庭的13岁女性先证被鉴定为高胰岛素血症、高雄激素症、黑棘皮病、多毛症、痤疮、少月经和男性化。外显子组测序和Sanger测序证实先证者为INSR （NM_000208.2）的携带者：c.3734 T > a (p。V1245E)变异。这种变异没有在人类基因突变数据库（HGMD）或ClinVar中列出。通过生物信息学工具SIFT、MutationTaster和Condel预测该新变异是有害的。根据美国医学遗传学和基因组学学会（ACMG）的标准，评估为PM6、pm2_support和PP3，并归类为不确定意义。该变异未在先证者的父母或其他家庭成员中检测到，他们都缺乏相关的临床表型。p.V1245E改型被发现是一个全新的改型。SWISS-MODEL分析表明，p.V1245E变异诱导了INSR蛋白三维构型的结构变化，潜在地损害了其正常功能。RT-qPCR显示先证者中INSR mRNA表达显著降低。在携带p.V1245E变异体的慢病毒转染293 T细胞模型中，Western blotting和RT-qPCR均显示INSR mRNA和蛋白表达降低，而免疫荧光显示INSR蛋白水平降低，定位改变。因此，ACMG评价（PS2、PS3、pm2_support、PP3）进一步升级为致病性。总之，这一新生变异代表了该家族中导致TAIRS的致病变异，扩大了INSR基因的变异谱。

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引用次数: 0

Bioinformatics applications in pharmacogenomics: towards personalized medicine 生物信息学在药物基因组学中的应用：走向个性化医疗

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-04 DOI: 10.1016/j.gene.2025.149935

Nabil Zaid , Lamyaa Benchikhi , Banacer Himmi , Hassan Ghazal

Pharmacogenomics investigates how genetic variation influences individual responses to drug therapy and aims to optimize treatment outcomes through personalized approaches. Bioinformatics plays a foundational role in this field, enabling the processing, annotation, and interpretation of complex genomic and multi-omics datasets. This review explores the current landscape of bioinformatics in pharmacogenomics, including key databases, variant analysis tools, and artificial intelligence-driven predictive models. It also discusses the integration of multi-omics data, real-world clinical applications, and the regulatory and ethical frameworks supporting clinical implementation. Finally, the role of pharmacogenomics in drug discovery and development is highlighted, illustrating how genetic insights contribute to target identification, trial design, and drug repurposing. Together, these components form the computational backbone of precision medicine and are essential for translating genomic knowledge into actionable, patient-centered care.

药物基因组学研究遗传变异如何影响个体对药物治疗的反应，旨在通过个性化方法优化治疗结果。生物信息学在这一领域起着基础作用，使复杂的基因组和多组学数据集的处理、注释和解释成为可能。本文综述了药物基因组学中生物信息学的现状，包括关键数据库、变异分析工具和人工智能驱动的预测模型。它还讨论了多组学数据的集成，现实世界的临床应用，以及支持临床实施的监管和伦理框架。最后，强调了药物基因组学在药物发现和开发中的作用，说明了遗传见解如何有助于目标识别，试验设计和药物再利用。这些组成部分共同构成了精准医疗的计算支柱，对于将基因组知识转化为可操作的、以患者为中心的护理至关重要。

引用次数: 0

TRPV4-mediated mechanotransduction of matrix stiffness in the pathogenesis, progression, and malignant transformation of oral submucous fibrosis trpv4介导的基质刚度在口腔黏膜下纤维化的发病、进展和恶性转化中的机械转导。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-04 DOI: 10.1016/j.gene.2025.149936

Sampurna Raha, Rajiv S. Desai, Shivani P. Bansal, Pankaj M. Shirsat, Pooja S. Prasad

Oral Submucous Fibrosis (OSF) is a long-standing, scarring, inflammatory, potentially malignant disorder induced by areca nut. The transient receptor potential vanilloid 4 (TRPV4), a cation channel permeable to Ca²⁺, in the TRPV family, is implicated in wound healing, fibrotic changes and malignancy, but its role as a mechanosensor for matrix-stiffness and stress in OSF and its malignant transformation to oral squamous cell carcinoma (OSCC) remains unexplored. The current research sought to investigate the probable involvement of TRPV4 in the onset different OSF stages and its progression to malignancy by immunohistochemistry. Primary antibodies targeting TRPV4 were applied to formalin-fixed paraffin-embedded blocks from ten cases for each category: (a) Stage-1 OSF, (b) Stage 2 OSF, (c) Stage 3 OSF, (d) Stage 4 OSF, (e) OSCC + OSF, and (vi) OSCC − OSF. Additionally, buccal mucosa tissues from ten healthy individuals (NOM) were utilized as control. Mean epithelial quick scores of TRPV4 in NOM, Stages 1–4 OSF, and OSCC with and without OSF were 1.2, 2.5, 3.9, 4.5, 4.6, 5.8, and 6.2, while connective tissue scores were 1.5, 3.5, 4.1, 4.7, 5.3, 5.9, and 6.5, respectively. TRPV4 expression was upregulated in Stages 3 OSF and 4 OSF and OSCC in the presence or absence of OSF compared to NOM and Stage 1 and 2 OSF. This study evaluates the unpaved role of TRPV4 in OSF, mediated by various canonical pathways, contributing to its development by increasing matrix-stiffness and rigidity, which further upregulates TRPV4 expression, ultimately facilitating carcinogenesis.

口腔黏膜下纤维化（OSF）是由槟榔引起的一种长期存在的、疤痕性的、炎症性的、潜在的恶性疾病。TRPV家族中的瞬时受体电位香兰素4 （TRPV4）是一种可渗透到Ca2+的阳离子通道，与伤口愈合、纤维化改变和恶性肿瘤有关，但其作为OSF基质刚度和应力的机械传感器及其向口腔鳞状细胞癌（OSCC）的恶性转化的作用仍未被探索。本研究试图通过免疫组织化学方法探讨TRPV4在OSF不同阶段的发病及其向恶性发展中的可能参与。将靶向TRPV4的一抗应用于10例福尔马林固定石蜡包埋块中，每个类别：(a) 1期OSF， (b) 2期OSF， (c) 3期OSF， (d) 4期OSF， (e) OSCC + OSF, (vi) OSCC - OSF。另外，以10名健康个体（NOM）的口腔黏膜组织作为对照。TRPV4在NOM、1-4期OSF和有无OSF的OSCC中的平均上皮快速评分分别为1.2、2.5、3.9、4.5、4.6、5.8和6.2，结缔组织评分分别为1.5、3.5、4.1、4.7、5.3、5.9和6.5。与NOM和第1、2期OSF相比，无论OSF存在与否，TRPV4在第3期OSF和第4期OSF和OSCC中的表达均上调。本研究评估了TRPV4在OSF中的非铺平作用，通过多种典型途径介导，通过增加基质刚度和刚性来促进其发展，从而进一步上调TRPV4的表达，最终促进癌变。

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引用次数: 0

CRISPR 2.0: Expanding the genome engineering Toolbox for epigenetics, RNA editing, and molecular diagnostics CRISPR 2.0：扩展基因组工程工具箱，用于表观遗传学、RNA编辑和分子诊断。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-04 DOI: 10.1016/j.gene.2025.149938

Khushboo Pradhan , Sindhu Anoop

Non-canonical CRISPR systems adaptation has led to genome editing through nucleases, and the development of transcriptional and epigenetic regulation, transcriptome editing, and molecular diagnostics has resulted in a diversified set of tools—CRISPR 2.0. In this review, the author summarizes the mechanisms and recent engineering advances of (i) dCas9-based epigenetic effectors, (ii) RNA-targeting Cas13 systems and engineered RNA editors, (iii) DNA base editors and prime editors, and (iv) CRISPR-powered diagnostic platforms and their translational readiness. There is a critical comparison of the various approaches (e.g., RNAi/ASO versus Cas13-based methods; base editing versus prime editing) along with practical translational considerations such as delivery technologies, safety (off-target/edit windows, mosaicism), and regulatory pathways which are evaluated. Three concise case studies refer to map laboratory evidence to clinical or near-clinical outcomes and the ethical and governance discussion is widened to include global access, intellectual property and equity in deployment. Finally, the authors classify technologies according to their level of readiness — diagnostics and some ex-vivo therapeutic approaches are already in or very close to clinical use, chosen in-vivo editing methods are undergoing early trials, and AI-assisted nuclease design is still mostly theoretical but is getting better fast. This comprehensive viewpoint is intended to help researchers and physicians understand which CRISPR tools are most likely to be translated soon and where more validation is required.

非规范CRISPR系统的适应导致了通过核酸酶进行基因组编辑，转录和表观遗传调控、转录组编辑和分子诊断的发展导致了一套多样化的工具——CRISPR 2.0。在这篇综述中，作者总结了(i)基于dcas9的表观遗传效应物的机制和最近的工程进展，（ii） RNA靶向Cas13系统和工程化RNA编辑器，（iii） DNA碱基编辑器和引物编辑器，以及（iv） crispr驱动的诊断平台及其翻译准备。对各种方法（例如，RNAi/ASO与基于cas13的方法；碱基编辑与初始编辑）以及实际翻译考虑因素（如传递技术、安全性（脱靶/编辑窗口、镶嵌）和评估的调控途径）进行了关键的比较。三个简明的案例研究涉及将实验室证据映射到临床或近临床结果，并扩大了伦理和治理讨论，包括全球获取、知识产权和部署的公平性。最后，作者根据技术的准备程度对技术进行了分类——诊断和一些离体治疗方法已经进入或非常接近临床应用，选定的体内编辑方法正在进行早期试验，人工智能辅助核酸酶设计仍然主要是理论上的，但正在快速发展。这一全面的观点旨在帮助研究人员和医生了解哪些CRISPR工具最有可能很快被翻译，哪些需要更多的验证。

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引用次数: 0

Downregulation of Syncytin-2 expression in preeclamptic placentas is associated with DNA hypermethylation of the downstream CpG-rich region Syncytin-2在子痫前期胎盘中的表达下调与下游富含cpg区域的DNA超甲基化有关。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-03 DOI: 10.1016/j.gene.2025.149932

Chun Feng , Teng Zhang , Yuan Li , Yuyun Long , Qian Meng , Shi-Wen Jiang

Syncytin-2 is an endogenous retroviral envelope protein constitutively expressed in human placental trophoblasts. As a membrane glycoprotein, Syncytin-2 together with Syncytin-1 mediates the fusion of mononucleated cytotrophoblasts to form multinucleated syncytiotrophoblasts. Syncytiotrophoblasts constitute the fetal-maternal interface important for fetal-maternal exchange, barrier and endocrine functions of the placenta. Besides the fusogenic function, Syncytin-2 also possesses an immunosuppressive activity. In this study, the results of quantitative PCR indicated that Syncytin-2 expression was downregulated in third-trimester preeclamptic placentas, which is consistent with the result of previous studies. Importantly, the results of Combined Bisulfite Restriction Assay (COBRA) suggested hypermethylation of the downstream CpG-rich region, but not the promoter/exon1/intron1 and exon2 CpG- rich regions of SYN-2 gene in third-trimester preeclamptic placentas. Subsequent bisulfite conversion and PCR amplification, cloning and sequencing of the downstream CpG- rich region confirmed hypermethylation of the 4 CpGs in this region in preeclamptic placentas. Moreover, treatment of human choriocarcinoma BeWo cells with DNMT inhibitor ADC (5-aza-deoxycytidine) resulted in a dose-responsive demethylation of the downstream CpG-rich region and an increased SYN-2 mRNA level. Thus, the hypermethylation of the downstream CpG-rich region closely correlated with the downregulation of Syncytin-2 expression in preeclamptic placentas. These new findings underscore the significance of epigenetic alterations in preeclamptic placentas, and facilitate a better understanding on the pathological mechanism of preeclampsia.

Syncytin-2是一种内源性逆转录病毒包膜蛋白，在人胎盘滋养细胞中组成性表达。Syncytin-2作为一种膜糖蛋白，与Syncytin-1一起介导单核细胞滋养细胞融合形成多核细胞滋养细胞。合体滋养细胞是母胎交换、屏障和胎盘内分泌功能的重要界面。除了促融合功能外，Syncytin-2还具有免疫抑制活性。本研究中，定量PCR结果显示Syncytin-2在妊娠晚期子痫前期胎盘中表达下调，这与以往研究结果一致。重要的是，联合亚硫酸氢盐限制性测定（COBRA）的结果表明，在妊娠晚期子痫前期胎盘中，SYN-2基因的下游富含CpG区域发生了高甲基化，但启动子/外显子/内含子1和外显子2富含CpG区域并未发生高甲基化。随后亚硫酸转化、PCR扩增、下游富含CpG区域的克隆和测序证实了子痫前期胎盘中该区域的4个CpGs的高甲基化。此外，用DNMT抑制剂ADC（5-偶氮-脱氧胞苷）治疗人绒毛膜癌BeWo细胞导致下游富含cpg区域的剂量反应性去甲基化和SYN-2 mRNA水平升高。由此可见，子痫前期胎盘中下游富含cpg区域的高甲基化与Syncytin-2表达下调密切相关。这些新发现强调了子痫前期胎盘表观遗传改变的重要性，并有助于更好地了解子痫前期的病理机制。

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引用次数: 0

Reference genes for quantitative real-time polymerase chain reaction in in vitro non-alcoholic fatty liver disease 体外非酒精性脂肪肝定量实时聚合酶链反应的内参基因

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-12-02 DOI: 10.1016/j.gene.2025.149931

Jingzhi Chen , Xingmi Chen , Ying Liu , Chunming Lyu , Ming Xu , Yang Yang

Background

In metabolic dysfunction-associated fatty liver disease (MAFLD) research, reference genes for qPCR are crucial but often unvalidated.

Methods

RNA-seq was performed in control and free fatty acid (FFA) treated AML12 cells, and the candidates for reference gene were selected by previous literatures and filtered by dual-index ranking via normalization of coefficient variation and Log₂FoldChange in the RNA-seq library. qPCR data was further analyzed via NormFinder, BestKeeper, geNorm, ΔCt and RefFinder to assess reference gene expression stability.

Results

FFA treated cells showed a significantly increased lipid droplet accumulation. RNA-seq dual-index ranking and RefFinder identified that Ywhaz was the most stable reference gene.

Conclusion

Our finding revealed that Ywhaz is the most stable reference gene for qPCR in the AML12 cell model of FFA-induced MAFLD, and provided a reliable procedure for screening reference genes.

背景：在代谢功能障碍相关脂肪性肝病（MAFLD）的研究中，qPCR的内参基因是至关重要的，但往往未经验证。方法：对照AML12细胞和游离脂肪酸（FFA）处理AML12细胞进行RNA-seq，参考前人文献筛选出内参基因候选基因，通过系数变异归一化和RNA-seq文库Log2FoldChange双指标排序筛选。通过NormFinder、BestKeeper、geNorm、ΔCt和RefFinder对qPCR数据进行进一步分析，评估内参基因表达的稳定性。结果：FFA处理后的细胞脂滴积累明显增加。RNA-seq双指数排序和RefFinder鉴定Ywhaz是最稳定的内参基因。结论：Ywhaz是ffa诱导的MAFLD AML12细胞模型中最稳定的qPCR内参基因，为筛选内参基因提供了可靠的方法。

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引用次数: 0

A novel frameshift variant in PURA syndrome: role of NMD pathway in disease mechanism PURA综合征中一种新的移码变异：NMD通路在疾病机制中的作用。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-29 DOI: 10.1016/j.gene.2025.149930

Huiqin Yang, Xihui Zhou

Background

PURA syndrome is a rare genetic disorder characterized by obvious hypotonia, feeding difficulties, apnea, and drowsiness, which is caused by variants in the Purine Rich Element Binding Protein A (PURA) on chromosome 5q31.2-q31.3, and is inherited in an autosomal dominant manner. This condition presents challenges for early diagnosis and effective treatment. This study investigates its pathogenic mechanisms and potential therapeutic strategies.

Methods

Peripheral blood samples were collected from a Chinese newborn with severe hypotonia and his parents. Whole-exome sequencing (WES) and Sanger validation identified a novel PURA variant, which had not been previously reported. To explore the potential involvement of nonsense-mediated mRNA decay (NMD) in PURA syndrome, wild-type (WT) and variant (Var) PURA expression vectors were constructed and transiently transfected into 293 T cells via liposomal transfection. Real-time quantitative polymerase chain reaction (PCR) and Western blotting were performed to analyze the PURA expression. The levels of PURA mRNA and protein were assessed following treatment with the NMD inhibitor cycloheximide (CHX) and the small interfering RNA targeting Up-frameshift protein 1 (siRNA-UPF1), a key NMD factor.

Results

The WES identified a novel heterozygous frameshift variant in exon 1 of PURA (NM_005859.5): c.632_651dup; p.(Leu218Trpfs*14), which introduces a premature termination codon (PTC). However, no such variant was detected in his parents. Functional validation assays revealed that the variant construct expressed significantly lower levels of PURA mRNA and protein compared to the WT. CHX treatment and siRNA-UPF1 transfection significantly increased the mRNA and protein expression levels of PURA in the variant construct.

Conclusion

The novel PURA variant, c.632_651dup; p.(Leu218Trpfs*14), is a pathogenic heterozygous frameshift. The NMD pathway is involved in the degradation of its aberrant transcript. Our research expands the genotypic spectrum of pathogenic PURA variants, and offers a new perspective for potential therapeutic intervention.

背景：PURA综合征是由染色体5q31.2-q31.3上富嘌呤元素结合蛋白a （PURA）变异引起的一种罕见的常染色体显性遗传，以明显的神经松弛、进食困难、呼吸暂停、嗜睡为特征的遗传性疾病。这种情况对早期诊断和有效治疗提出了挑战。本研究旨在探讨其致病机制和潜在的治疗策略。方法：对1例重度张力低下新生儿及其父母进行外周血采集。全外显子组测序（WES）和Sanger验证鉴定了一种新的PURA变体，这在以前没有报道过。为了探讨无义介导的mRNA衰变（NMD）在PURA综合征中的潜在作用，构建了野生型（WT）和变异型（Var） PURA表达载体，并通过脂质体转染293 T细胞。采用实时定量聚合酶链反应（PCR）和Western blotting检测PURA的表达。在使用NMD抑制剂环己亚胺（CHX）和靶向上移码蛋白1 （siRNA-UPF1）的小干扰RNA （NMD关键因子）治疗后，评估PURA mRNA和蛋白水平。结果：WES在PURA的外显子1 （NM_005859.5）上鉴定出一个新的杂合移码变异：c.632_651dup；p.(Leu218Trpfs*14)，其中引入了一个过早终止密码子（PTC）。然而，在他的父母身上没有发现这种变异。功能验证分析显示，与WT相比，变异构建体的PURA mRNA和蛋白表达水平显著降低。CHX处理和siRNA-UPF1转染显著提高了变异构建体中PURA mRNA和蛋白表达水平。结论：新的PURA变异c.632_651dup；p.(Leu218Trpfs*14)，是一种致病性杂合移码。NMD通路参与其异常转录物的降解。我们的研究扩大了致病性PURA变异的基因型谱，并为潜在的治疗干预提供了新的视角。

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引用次数: 0

GGH intronic variant rs3780130 is associated with methotrexate levels in children with brain tumors GGH内含子变异rs3780130与脑肿瘤患儿甲氨蝶呤水平相关

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-29 DOI: 10.1016/j.gene.2025.149929

Si-han Liu , Xiao-yan Kong , Miao Li , Shu-mei Wang

Background

Pediatric brain tumors (PBTs) are the leading type of solid tumors in children, profoundly affecting both survival rates and quality of life. Methotrexate (MTX) is an essential chemotherapy drug for treating these tumors; however, its efficacy and toxicity vary among patients due to genetic factors.

Objective

This study examined the impact of the intronic rs3780130 polymorphism in the gamma-glutamyl hydrolase (GGH) gene on MTX concentrations and related toxicities in patients with PBTs.

Methods

The GGH rs3780130 T > A polymorphism was genotyped using the Sequenom MassARRAY iPLEX platform in a cohort of 73 PBT patients.

Results

We found that children with the AA genotype had significantly higher MTX concentrations compared to those with TT and TA genotypes (P < 0.05). Additionally, the AA genotype was significantly associated with a higher incidence of hepatotoxicity relative to the TT genotype (P < 0.05). It showed a significantly lower occurrence of gastrointestinal toxicities when compared to the TA genotype (P < 0.05). Bioinformatics analysis revealed that the rs3780130 polymorphism had a significant effect on GGH expression across various tissues, suggesting a potential mechanism by which this variant modulated MTX metabolism.

Conclusion

Our findings highlight the importance of GGH polymorphisms in personalizing MTX therapy for PBT patients and emphasize the necessity for further research to explore the clinical implications of GGH genotypes in larger cohorts, ultimately aiming for more precise therapeutic strategies.

背景：儿童脑肿瘤（PBTs）是儿童实体肿瘤的主要类型，深刻影响着儿童的生存率和生活质量。甲氨蝶呤（MTX）是治疗这些肿瘤的重要化疗药物；然而，由于遗传因素，其疗效和毒性因患者而异。目的：研究γ -谷氨酰水解酶（GGH）基因rs3780130内含子多态性对pbt患者MTX浓度及相关毒性的影响。方法：使用Sequenom MassARRAY iPLEX平台对73例PBT患者的GGH rs3780130 T > A多态性进行基因分型。结果：我们发现AA基因型儿童的MTX浓度明显高于TT和TA基因型儿童（P ）。结论：我们的研究结果强调了GGH多态性对PBT患者个性化MTX治疗的重要性，并强调了进一步研究的必要性，以在更大的队列中探索GGH基因型的临床意义，最终旨在制定更精确的治疗策略。

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引用次数: 0

Reassessing the tmRNA-SmpB complex as a virulence determinant 重新评估tmRNA-SmpB复合体作为毒力决定因素的作用。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-28 DOI: 10.1016/j.gene.2025.149928

T. Nagarajan , N. Arulmuthu Kumaran

Rescuing stalled ribosomes from the truncated mRNA is identified as a crucial process for the survival of a bacterial cell. A small RNA named tmRNA (transfer messenger RNA), and protein SmpB (Small protein B), together constitute a ribosome rescue apparatus which is ubiquitous among most of the eubacteria. tmRNA mediated ribosome rescue process (also called trans-translation) has been found to be the major pathway of clearance of stalled ribosome complexes. In the process, tmRNA-SmpB complex recycles stalled ribosomes by making them undergo normal translation and termination. Apart from rescuing stalled ribosomes, trans-translation modulates other cellular pathways (such as cell cycle, oxidative stress, nutritional stress, DNA damage response and so on) by regulating the intracellular level of various proteins. It becomes more and more obvious that the function of trans-translation apparatus is diverse and plays a role in bacterial pathogenesis also. This review will focus on the key findings on the involvement of tmRNA and its partner SmpB in regulation of pathogenesis and virulence in different pathogenic bacteria.

从截断的mRNA中挽救停滞的核糖体被认为是细菌细胞存活的关键过程。一种名为tmRNA （transfer messenger RNA）的小RNA和蛋白质SmpB （small protein B）共同构成了一种核糖体拯救装置，在大多数真细菌和古细菌中普遍存在。tmRNA介导的核糖体拯救过程（也称为反翻译）被发现是清除停滞核糖体复合物的主要途径。在这个过程中，tmRNA-SmpB复合体循环通过使核糖体进行正常的翻译和终止而使核糖体停滞。除了挽救停滞的核糖体外，反翻译还通过调节细胞内各种蛋白质的水平来调节其他细胞通路（如细胞周期、氧化应激、营养应激、DNA损伤反应等）。反翻译体的功能多样性越来越明显，在细菌的发病机制中也发挥着重要作用。本文将重点介绍tmRNA及其伴合体SmpB在不同致病菌的发病机制和毒力调控中的重要发现。

引用次数: 0

Identification of ascorbate peroxidase family genes reveals expression of TkAPX250a confers heat stress tolerance in Taraxacum kok-saghyz 抗坏血酸过氧化物酶家族基因的鉴定表明，TkAPX250a基因的表达使紫杉树具有耐热性。

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene

Pub Date : 2025-11-25 DOI: 10.1016/j.gene.2025.149918

Shiqi Long, Boxuan Yuan, Minmin He, Guoen Ao, Baoqiang Wang, Xuchu Wang

Ascorbate peroxidase (APX) enzymes are pivotal in scavenging reactive oxygen species (ROS) and maintaining redox homeostasis in plants, a function critical for survival under abiotic stress conditions. To investigate this key enzyme system in the rubber-producing dandelion Taraxacum kok-saghyz (Tk)—an emerging model for sustainable rubber production—we conducted a genome-wide analysis of its APX genes. We identified seven TkAPX genes, whose predicted subcellular localizations include the cytoplasm, plasma membrane, and chloroplasts. Promoter analysis revealed an abundance of stress-responsive motifs, supporting their potential role in stress adaptation. By integrating time-course qPCR of the TkAPX family under heat stress with transcriptome-wide expression profiling across tissues, we identified TkAPX250a as a pivotal candidate. This gene showed a remarkable ∼ 20-fold increase in transcript levels in subsequent transgenic lines compared to wild-type controls, confirming highly efficient transgene expression without silencing. Under thermal stress, these transgenic lines exhibited reduced ROS accumulation and membrane lipid peroxidation while maintaining higher chlorophyll content and biomass, demonstrating that TkAPX250a coordinately enhances thermotolerance and photosynthetic stability. Mechanistically, TkAPX250a overexpression not only enhanced APX activity and lowered H₂O₂ accumulation but also synergistically upregulated the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). Time-resolved assays under heat stress further delineated a stratified antioxidant hierarchy within this coordinated response, with SOD and CAT acting as core responders. These findings establish TkAPX250a as a central genetic regulator in abiotic stress adaptation and provide a molecular basis for breeding stressresilient rubber crops, addressing a critical need in agriculture under changing climate conditions.

抗坏血酸过氧化物酶（APX）在清除活性氧（ROS）和维持植物氧化还原稳态中起着关键作用，是在非生物胁迫条件下生存的关键功能。为了研究生产橡胶的蒲公英Taraxacum kok-saghyz (Tk)（一种新兴的可持续橡胶生产模式）的关键酶系统，我们对其APX基因进行了全基因组分析。我们鉴定了7个TkAPX基因，其预测的亚细胞定位包括细胞质、质膜和叶绿体。启动子分析揭示了大量的应激反应基序，支持它们在应激适应中的潜在作用。通过整合热应激下TkAPX家族的时间过程qPCR和组织间转录组全表达谱，我们确定了TkAPX250a是一个关键的候选者。与野生型对照相比，该基因在随后的转基因系中转录水平显著增加 ~ 20倍，证实了高效的转基因表达而不沉默。在热胁迫下，这些转基因品系表现出ROS积累和膜脂过氧化的减少，同时保持较高的叶绿素含量和生物量，表明TkAPX250a协同增强了耐热性和光合稳定性。机制上，TkAPX250a过表达不仅能增强APX活性，降低H2O2积累，还能协同上调超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和过氧化物酶（POD）的活性。热应激下的时间分辨实验进一步描绘了这种协调反应中的分层抗氧化层次，SOD和CAT作为核心应答者。这些发现确立了TkAPX250a作为非生物胁迫适应的核心遗传调控因子，并为培育抗逆性橡胶作物提供了分子基础，解决了气候条件变化下农业的关键需求。

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