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Force-sensing protein expression in response to cardiovascular mechanotransduction. 力传感蛋白在心血管机械传导中的表达。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1016/j.ebiom.2024.105412
Yongtao Wang, Emeli Chatterjee, Guoping Li, Jiahong Xu, Junjie Xiao

Force-sensing biophysical cues in microenvironment, including extracellular matrix performances, stretch-mediated mechanics, shear stress and flow-induced hemodynamics, have a significant influence in regulating vascular morphogenesis and cardiac remodeling by mechanotransduction. Once cells perceive these extracellular mechanical stimuli, Piezo activation promotes calcium influx by forming integrin-adhesion-coupling receptors. This induces robust contractility of cytoskeleton structures to further transmit biomechanical alternations into nuclei by regulating Hippo-Yes associated protein (YAP) signaling pathway between cytoplasmic and nuclear translocation. Although biomechanical stimuli are widely studied in cardiovascular diseases, the expression of force-sensing proteins in response to cardiovascular mechanotransduction has not been systematically concluded. Therefore, this review will summarize the force-sensing Piezo, cytoskeleton and YAP proteins to mediate extracellular mechanics, and also give the prominent emphasis on intrinsic connection of these mechanical proteins and cardiovascular mechanotransduction. Extensive insights into cardiovascular mechanics may provide some new strategies for cardiovascular clinical therapy.

微环境中的力感应生物物理线索,包括细胞外基质的表现、拉伸介导的力学、剪切应力和流动诱导的血流动力学,在通过机械传导调节血管形态发生和心脏重塑方面具有重要影响。一旦细胞感知到这些细胞外机械刺激,Piezo 激活就会通过形成整合素-粘附偶联受体促进钙离子流入。这将诱导细胞骨架结构的强力收缩,通过调节希波-耶斯相关蛋白(YAP)在细胞质和细胞核之间的信号转导途径,进一步将生物力学交替传递到细胞核中。尽管生物力学刺激在心血管疾病中被广泛研究,但力传感蛋白在心血管机械传导中的表达尚未得到系统总结。因此,本综述将总结介导细胞外力学的力传感 Piezo 蛋白、细胞骨架蛋白和 YAP 蛋白,并突出强调这些力学蛋白与心血管机械传导的内在联系。对心血管力学的广泛了解可为心血管临床治疗提供一些新策略。
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引用次数: 0
Intrapartum antibiotic exposure and infectious diseases in childhood - a population-based cohort study. 产前接触抗生素与儿童传染病--一项基于人群的队列研究。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1016/j.ebiom.2024.105426
Mikael Hakkola, Sofia Ainonen, Eveliina Ronkainen, Minna Honkila, Marika Paalanne, Tytti Pokka, Eero Kajantie, Niko Paalanne, Terhi Ruuska-Loewald

Background: Intrapartum antibiotics are used to prevent group B streptococcus disease in newborn infants. We hypothesised that intrapartum antibiotic exposure is associated with the occurrence of childhood infectious diseases because it influences the development of the gut microbiome.

Methods: The cohort for this population-based study comprised vaginally delivered children born in Northern Finland in 2007-2018. We used structured electronic medical records linked to comprehensive national registers. Primary outcome was the number of infectious disease episodes leading to an emergency room visit, outpatient hospital visit, or hospitalisation from birth until five years of age.

Findings: Analyses were performed on 9733 children (48.8% girls) exposed to intrapartum antibiotics and on 35,842 unexposed children (49.9% girls). Exposure to intrapartum antibiotics was associated with increased risk of any infectious disease episode at the ages 7-28 days (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.10-1.54) and 1-2 years (aIRR 1.10, 95% CI 1.02-1.18). The occurrence of urinary tract infections was associated with the exposure to intrapartum antibiotics whereas the occurrence of severe infections caused by pathogens susceptible to penicillin was reversely associated with the exposure to intrapartum antibiotics.

Interpretation: Maternal intrapartum antibiotics were associated with the occurrence of infectious diseases in the offspring. The observed associations appeared to depend on bacterial pathogens and their antimicrobial susceptibility to penicillin.

Funding: Pediatric Research Foundation, Alma och K.A. Snellman Foundation, Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Medical Foundation, Academy of Finland, Finland.

背景:产前使用抗生素可预防新生儿B组链球菌疾病。我们假设,产前接触抗生素会影响肠道微生物组的发育,因此与儿童传染病的发生有关:这项人群研究的队列包括 2007-2018 年在芬兰北部阴道分娩的婴儿。我们使用了与国家综合登记册相链接的结构化电子病历。主要结果是儿童从出生到五岁期间因传染病导致急诊就诊、医院门诊就诊或住院的次数:对9733名产前接触过抗生素的儿童(48.8%为女童)和35842名未接触过抗生素的儿童(49.9%为女童)进行了分析。接触产前抗生素与 7-28 天(调整后发病率比 [aIRR] 1.30,95% CI 1.10-1.54)和 1-2 岁(调整后发病率比 1.10,95% CI 1.02-1.18)的感染性疾病发病风险增加有关。尿路感染的发生与产前抗生素的接触有关,而对青霉素敏感的病原体引起的严重感染的发生与产前抗生素的接触成反比:解释:母体产前使用抗生素与后代感染性疾病的发生有关。观察到的关联似乎取决于细菌病原体及其对青霉素的抗菌敏感性:芬兰儿科研究基金会、Alma och K.A. Snellman基金会、猎户座研究基金会、Päivikki和Sakari Sohlberg基金会、芬兰医学基金会、芬兰科学院。
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引用次数: 0
Protective effects of an mRNA vaccine candidate encoding H5HA clade 2.3.4.4b against the newly emerged dairy cattle H5N1 virus. 编码 H5HA 2.3.4.4b 支系的 mRNA 候选疫苗对新出现的奶牛 H5N1 病毒的保护作用。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1016/j.ebiom.2024.105408
Shiho Chiba, Maki Kiso, Shinya Yamada, Kazuhiko Someya, Yoshikuni Onodera, Aya Yamaguchi, Satoko Matsunaga, Nao Jounai, Seiya Yamayoshi, Fumihiko Takeshita, Yoshihiro Kawaoka
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引用次数: 0
Correlation between evoked neurotransmitter release and adaptive functions in SYT1-associated neurodevelopmental disorder. SYT1相关神经发育障碍中诱发神经递质释放与适应功能之间的相关性
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1016/j.ebiom.2024.105416
Paul Yangho Park, Lauren Elizabeth Bleakley, Nadia Saraya, Reem Al-Jawahiri, Josefine Eck, Marc Anthony Aloi, Holly Melland, Kate Baker, Sarah Louise Gordon

Background: Pathogenic missense variants in the essential synaptic vesicle protein synaptotagmin-1 (SYT1) cause a neurodevelopmental disorder characterised by motor delay and intellectual disability, hyperkinetic movement disorder, episodic agitation, and visual impairments. SYT1 is the presynaptic calcium sensor that triggers synchronous neurotransmitter release. We have previously shown that pathogenic variants around the calcium-sensing region of the critical C2B domain decrease synaptic vesicle exocytosis in neurons.

Methods: Here, we have used cultured hippocampal neurons transfected with SYT1-pHluorin to examine how variants within the C2A and C2B domain of SYT1 impact evoked exocytosis.

Findings: We show that recently identified variants within the facilitatory C2A domain of the protein (L159R, T196K, E209K, E219Q), as well as additional variants in the C2B domain (M303V, S309P, Y365C, G369D), share an underlying pathogenic mechanism, causing a graded and variant-dependent dominant-negative impairment in exocytosis. We establish that the extent of evoked exocytosis observed in vitro in the presence of SYT1 variants correlates with neurodevelopmental impacts of this disorder. Specifically, the severity of motor and communication impairments exhibited by individuals harbouring these variants correlates with multiple measures of exocytic efficiency.

Interpretation: Together, this suggests that there is a genotype-function-phenotype relationship in SYT1-associated neurodevelopmental disorder, centring impaired evoked neurotransmitter release as a common pathogenic driver. Moreover, this points toward a direct link between control of neurotransmitter release and development of adaptive functions, providing a tractable target for therapeutic amelioration.

Funding: Australian National Health and Medical Research Council, UK Medical Research Council, Great Ormond Street Hospital Children's Charity, University of Melbourne.

背景:突触囊泡必需蛋白突触标记蛋白-1(SYT1)中的致病性错义变体会导致一种神经发育障碍,其特征是运动迟缓和智力残疾、过度运动障碍、发作性激动和视力障碍。SYT1 是突触前钙离子传感器,可触发神经递质的同步释放。方法:在此,我们使用转染有 SYT1-pHluorin 的培养海马神经元,研究 SYT1 的 C2A 和 C2B 结构域内的变异如何影响诱发的外泌:我们的研究结果表明,最近在该蛋白的促进性 C2A 结构域中发现的变体(L159R、T196K、E209K、E219Q)以及在 C2B 结构域中发现的其他变体(M303V、S309P、Y365C、G369D)具有共同的潜在致病机制,它们会导致分级和变体依赖性显性阴性外渗功能障碍。我们发现,在体外观察到的 SYT1 变体诱发外泌的程度与这种疾病对神经发育的影响相关。具体来说,携带这些变异体的个体所表现出的运动和交流障碍的严重程度与外泌效率的多种测量结果相关:这表明,SYT1相关神经发育障碍存在基因型-功能型-表型的关系,而诱发神经递质释放受损是共同的致病驱动因素。此外,这表明神经递质释放的控制与适应功能的发展之间存在直接联系,为改善治疗提供了一个可行的目标:澳大利亚国家健康与医学研究委员会、英国医学研究委员会、大奥蒙德街医院儿童慈善机构、墨尔本大学。
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引用次数: 0
Single-cell RNA transcriptomics in mice reveals embryonic origin of fibrosis due to maternal obesity. 小鼠单细胞 RNA 转录组学揭示了母体肥胖导致纤维化的胚胎起源。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1016/j.ebiom.2024.105421
Md Nazmul Hossain, Yao Gao, Xinrui Li, Liang Zhao, Xiangdong Liu, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du

Background: Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear.

Methods: C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice.

Findings: Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis.

Interpretation: MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children.

Funding: This work was funded by National Institutes of Health Grant R01HD067449.

背景美国超过 40% 的孕妇肥胖,这对胎儿发育和后代健康产生了负面影响。母体肥胖(MO)会导致后代成年后多个组织和器官发生纤维化浸润,但其起源和机制尚不清楚:方法:用对照组和高脂饮食喂养 C57BL/6J 雌性小鼠,以模拟 MO 状态。从对照组(CON)和MO组小鼠的E9.5、E11.5和E13.5(相当于人类怀孕6周)获得胚胎体细胞组织,进行单细胞RNA测序(scRNA-seq)。为了探索AMP激活蛋白激酶(AMPK)的作用,AMPK被二甲双胍和A769662激活,并在胚胎间充质细胞(EMC)中被AMPKα1基因缺失小鼠敲除:通过无监督聚类,我们发现了三种具有纤维化能力的主要细胞群。与CON相比,MO导致的纤维化细胞数量急剧增加(增加了125%),支持了后代纤维化的胚胎起源。MO诱导了胚胎的炎症反应和转化生长因子β(TGFβ)信号及纤维化基因的表达。MO 可抑制 AMPK,二甲双胍和 A769662 可抑制 TGFβ 信号传导和纤维形成:MO能显著增强胚胎纤维化,解释了肥胖母亲后代纤维化的起源。我们的数据强调了在怀孕5-6周前进行早期干预对改善胚胎发育的重要性,AMPK是抑制MO胚胎过度纤维化的一个有利靶点,可帮助越来越多的肥胖母亲生育健康子女:本研究由美国国立卫生研究院 R01HD067449 号基金资助。
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引用次数: 0
Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progression. 凝胶栓塞剂可抑制临床 TACE 诱导的促转移微环境,防止肝细胞癌恶化。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1016/j.ebiom.2024.105436
Li Song, Chunyan Zhu, Qing Shi, Yuhan Xia, Xiayi Liang, Wen Qin, Tao Ye, Biwei Yang, Xin Cao, Jinglin Xia, Kun Zhang

Background: Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis.

Methods: Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO2 (HMnO2). The conditions and capacity of HMnO2 to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO2@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO2@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism.

Findings: The high adhesion and crosslinking of Zein with HMnO2@DOX impart Zein-HMnO2@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO2 decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O2 release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O2 release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression.

Interpretation: This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation.

Funding: Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.

背景:目前用于经导管动脉化疗栓塞术(TACE)治疗肝细胞癌(HCC)的栓塞剂存在不稳定性和易渗漏问题,导致残留HCC的TACE疗效打折扣。方法:在此,我们开发了基于Zein的栓塞剂,利用不溶于水但可溶于乙醇的Zein将多柔比星(Doxorubicin,DOX)载入介孔空心二氧化锰(Mesoporous hollow MnO2,HMnO2)。对 HMnO2 产生活性氧(ROS)的条件和能力进行了测定。对 Zein-HMnO2@DOX 进行了机械测试,以评估其作为栓塞剂的潜力。体外实验评估了 Zein-HMnO2@DOX 对 HCC 的影响。建立了皮下 HCC 小鼠模型和兔 VX2 HCC 模型,以研究其抗肿瘤和抗转移功效,并探索其潜在的抗肿瘤机制:研究结果:Zein与HMnO2@DOX的高粘附性和交联性使Zein-HMnO2@DOX具有很强的抗变形和抗冲刷的机械强度。Zein 的凝胶化和 HMnO2 在水和酸性肿瘤微环境中的分解,可使 DOX 持续释放,并通过 Fenton 类反应产生活性氧(ROS)和释放氧气,从而实施 ROS 增强型 TACE。因此,Zein 类栓塞剂在显著抑制原位 HCC 生长方面优于临床使用的脂碘。更重要的是,氧气释放能下调缺氧诱导因子(HIF-1α)、血管内皮生长因子(VEGF)和葡萄糖转运蛋白1(GLUT1),从而重新规划TACE加重的缺氧和促转移微环境,抑制HCC向肺部转移。机理探索发现,这种基于 Zein 的 TACE 药剂会破坏氧化应激、血管生成和糖代谢途径,从而抑制 HCC 的进展:这项创新性工作不仅为HCC提供了一种新的TACE制剂,而且针对临床上常见的TACE术后HCC转移,建立了一种改善TACE加重的缺氧和转移动力的新策略:国家自然科学基金优秀青年科学基金(82022033);国家自然科学基金(82373086、82102761);温州市科技局重大科技创新项目(ZY2021009);上海市青年拔尖人才。
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引用次数: 0
Association between prenatal maternal sleep quality, neonatal uncinate fasciculus white matter, and infant negative emotionality. 产前母体睡眠质量、新生儿钩状束白质与婴儿负面情绪之间的关系。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1016/j.ebiom.2024.105384
Melissa Nevarez-Brewster, Catherine H Demers, LillyBelle K Deer, Özlü Aran, Robert J Gallop, Mercedes Hoeflich Haase, Khalid Al-Ali, Maria M Bagonis, John H Gilmore, M Camille Hoffman, Martin A Styner, Benjamin L Hankin, Elysia Poggi Davis

Background: Poor prenatal maternal sleep is a pervasive, yet modifiable, health concern affecting maternal and foetal wellbeing. Experimental rodent studies demonstrate that prenatal maternal sleep deprivation affects offspring brain development and leads to adverse outcomes, including increased anxiety-like behaviour. We examined the relation between prenatal maternal sleep quality and neonatal white matter development and subsequent infant negative emotionality.

Methods: Participants included 116 mother-infant (53% female) dyads. Prenatal sleep quality was prospectively assessed three times during gestation (16, 29, and 35 gestational weeks) using the Pittsburgh Sleep Quality Index. Neonatal white matter, as indexed by fractional anisotropy (FA), was assessed via diffusion weighted magnetic resonance imaging. Negative emotionality was measured via behavioural observation and maternal report when the infant was 6-months of age.

Findings: More prenatal sleep problems across pregnancy were associated with higher neonatal FA in the uncinate fasciculus (left: b = 0.20, p = .004; right: b = 0.15, p = .027). Higher neonatal uncinate FA was linked to infant negative emotionality, and uncinate FA partially mediated the association between prenatal maternal sleep and behavioural observation of infant negative emotionality.

Interpretation: Findings highlight prenatal sleep as an environmental signal that affects the developing neonatal brain and later infant negative emotionality.

Funding: National Institutes of Health (R01MH109662, R01HL155744, P50HD103573, K12AR084226, F32 Training fellowships MH125572, HL165844, MH106440, and diversity supplement R01HL155744-01S1).

背景:产前母体睡眠不足是一个普遍存在但可改变的健康问题,会影响母体和胎儿的健康。啮齿动物实验研究表明,产前母亲睡眠不足会影响后代的大脑发育并导致不良后果,包括焦虑行为的增加。我们研究了产前母亲睡眠质量与新生儿白质发育及随后婴儿负面情绪之间的关系:研究对象包括116对母婴组合(53%为女性)。在妊娠期间(16、29 和 35 孕周),使用匹兹堡睡眠质量指数对产前睡眠质量进行了三次前瞻性评估。新生儿白质以分数各向异性(FA)为指标,通过扩散加权磁共振成像进行评估。在婴儿6个月大时,通过行为观察和母亲报告来测量负面情绪:结果:妊娠期产前睡眠问题较多与新生儿钩状束FA较高有关(左侧:b = 0.20,p = .004;右侧:b = 0.15,p = .027)。新生儿较高的钩状束FA与婴儿的消极情绪有关,钩状束FA部分介导了产前母亲睡眠与婴儿消极情绪行为观察之间的关联:研究结果表明,产前睡眠是影响新生儿大脑发育和日后婴儿负面情绪的环境信号:美国国立卫生研究院(R01MH109662、R01HL155744、P50HD103573、K12AR084226、F32培训奖学金MH125572、HL165844、MH106440和多样性补充R01HL155744-01S1)。
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引用次数: 0
The regulation of pyroptosis by post-translational modifications: molecular mechanisms and therapeutic targets. 翻译后修饰对热蛋白沉积的调控:分子机制和治疗靶点。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1016/j.ebiom.2024.105420
Yi-Rao Zhou, Jun-Jie Dang, Qi-Chao Yang, Zhi-Jun Sun

Pyroptosis, a type of programmed cell death mediated by gasdermin family proteins, releases a large amount of immune stimulatory substances, which further contribute to inflammation and elicit an adaptive immune response against tumours and pathogens. And it occurs through multiple pathways that involve the activation of specific caspases and the cleavage of gasdermins. Post-translational modifications (PTMs) could influence the chemical properties of the modified residues and neighbouring regions, ultimately affecting the activity, stability, and functions of proteins to regulate pyroptosis. Many studies have been conducted to explore the influence of PTMs on the regulation of pyroptosis. In this review, we provide a comprehensive summary of different types of PTMs that influence pyroptosis, along with their corresponding modifying enzymes. Moreover, it elaborates on the specific contributions of different PTMs to pyroptosis and delves into how the regulation of these modifications can be leveraged for therapeutic interventions in cancer and inflammatory diseases.

细胞凋亡是一种由气体蛋白家族蛋白介导的程序性细胞死亡,它释放出大量的免疫刺激物质,进一步促进炎症,并引发针对肿瘤和病原体的适应性免疫反应。它通过多种途径发生,包括激活特定的 Caspases 和裂解 gasdermins。翻译后修饰(PTM)可影响修饰残基和邻近区域的化学性质,最终影响蛋白质的活性、稳定性和功能,从而调控热蛋白沉积。许多研究都在探索 PTM 对热核糖变调控的影响。在这篇综述中,我们全面总结了影响化脓过程的不同类型的 PTMs 及其相应的修饰酶。此外,它还阐述了不同 PTM 对热蛋白沉积的具体贡献,并深入探讨了如何利用这些修饰的调控对癌症和炎症性疾病进行治疗干预。
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引用次数: 0
Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families. 调查 "单基因 "家族中多基因背景对癫痫表型的影响。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-29 DOI: 10.1016/j.ebiom.2024.105404
Karen L Oliver, Ingrid E Scheffer, Colin A Ellis, Bronwyn E Grinton, Samuel F Berkovic, Melanie Bahlo

Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.

Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.

Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.

Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.

Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

背景:即使亲属具有相同的单基因病因,癫痫家族内部也经常出现表型变异。我们的目的是研究癫痫的共同多基因风险能否解释家族性癫痫中罕见致病变异的渗透性和表型表达:我们研究了 58 个临床异质性遗传性癫痫伴发热性癫痫发作(GEFS+)家族。亲属被编码为未受影响或受癫痫影响,并根据表型严重程度进行分级:无癫痫发作、仅发热性癫痫发作(FS)、发热性癫痫发作加(FS+)、全身性/局灶性癫痫或发育性和癫痫性脑病(DEE)。对癫痫多基因风险评分(PRS)与癫痫表型的相关性进行了检测。在家族内部,比较了表型严重程度一致与不一致的两对之间的平均 PRS 差异。统计分析采用混合效应回归模型进行:研究了 304 个具有已知或推测的大效应罕见变异的个体。在家族中,较高的癫痫多基因风险与癫痫诊断有关(OR = 1.39,95% CI 1.08,1.80,padj = 0.040)。与表型较轻的亲属相比,表型较重的亲属的平均配对 PRS 差异为 +0.19(padj = 0.010)。亲属间的表型不一致程度越高,差异越大。由于队列中包括两个罕见变体,每个变体的亲属数均大于 30,因此还可以分析变体特异性基因型与表型之间的关联。虽然遗传 GABRG2 p.Arg82Gln 致病变异的亲属的癫痫 PRS 效应很强(padj = 0.0010),但 SCN1B p.Cys121Trp 的效应并不显著:我们为遗传背景改变与 "单基因 "癫痫相关的罕见变异的渗透性和表型表达提供了支持。在GEFS+家族中,癫痫PRS较高的亲属更有可能表现出渗透性(癫痫诊断)和更严重的表型。变体特异性分析表明,一些罕见变体可能更容易受到PRS改变的影响,这对患者的遗传咨询和疾病预后具有重要意义:澳大利亚国家健康与医学研究委员会、澳大利亚医学研究未来基金。
{"title":"Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families.","authors":"Karen L Oliver, Ingrid E Scheffer, Colin A Ellis, Bronwyn E Grinton, Samuel F Berkovic, Melanie Bahlo","doi":"10.1016/j.ebiom.2024.105404","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105404","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.</p><p><strong>Methods: </strong>We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.</p><p><strong>Findings: </strong>304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, p<sub>adj</sub> = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (p<sub>adj</sub> = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (p<sub>adj</sub> = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.</p><p><strong>Interpretation: </strong>We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.</p><p><strong>Funding: </strong>National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity. Charcot-Leyden 晶体蛋白对间皮瘤化疗的影响:针对嗜酸性粒细胞增强化疗敏感性。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-28 DOI: 10.1016/j.ebiom.2024.105418
Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems

Background: In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.

Methods: The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.

Findings: Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.

Interpretation: This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.

Funding: Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.

背景:临床证据表明,在间皮瘤(MPM)中,嗜酸性粒细胞绝对数与总生存率和对标准化疗的反应呈负相关。由于嗜酸性粒细胞很少浸润间皮瘤肿瘤,我们假设是内分泌途径而不是旁分泌途径介导了治疗反应。因此,我们研究了嗜酸性粒细胞相关因子对间皮瘤化疗反应的影响:方法:将原代人嗜酸性粒细胞条件培养上清液加入间皮瘤细胞,同时使用标准化疗方案。在移植了间皮瘤肿瘤细胞的 C57BL/6 小鼠临床前模型中评估了抗嗜酸性粒细胞治疗的有效性:从 EOL1 细胞分化出的嗜酸性粒细胞上清液或直接从外周血中分离出的嗜酸性粒细胞上清液抑制了顺铂和培美曲塞在二维培养物和球形培养物中诱导的细胞凋亡。转录组分析表明,嗜酸性粒细胞介导的抗凋亡效应涉及与夏科-莱登晶体蛋白或Galectin-10(CLC-P/Gal10)的分子相互作用。抗体介导的耗竭证明了 CLC-P/Gal10 的功能相关性。重组人 CLC-P/Gal10 模拟了嗜酸性粒细胞上清液的抗凋亡活性。在小鼠模型中,嗜酸性粒细胞增多并不会明显影响肿瘤的生长,但会改变对化疗的反应。最后,在化疗前用抗Siglec-F抗体对嗜酸性粒细胞进行预处理可恢复治疗效果:这项研究为间皮瘤患者的不良预后与嗜酸性粒细胞衍生的CLC-P/Gal10相关的临床证据提供了机理依据,为干预这种致命的实体瘤开辟了新的前景:比利时抗癌基金会、国家科学研究基金会(FNRS)、Télévie、Léon Fredericq 基金会、ULiège。
{"title":"The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity.","authors":"Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems","doi":"10.1016/j.ebiom.2024.105418","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105418","url":null,"abstract":"<p><strong>Background: </strong>In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.</p><p><strong>Methods: </strong>The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.</p><p><strong>Findings: </strong>Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.</p><p><strong>Interpretation: </strong>This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.</p><p><strong>Funding: </strong>Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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