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Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome. 内皮 YAP/TAZ 激活促进 Hutchinson-Gilford progeria 综合征小鼠模型的动脉粥样硬化。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI173448
Ana Barettino, Cristina González-Gómez, Pilar Gonzalo, María J Andrés-Manzano, Carlos R Guerrero, Francisco M Espinosa, Rosa M Carmona, Yaazan Blanco, Beatriz Dorado, Carlos Torroja, Fátima Sánchez-Cabo, Ana Quintas, Alberto Benguría, Ana Dopazo, Ricardo García, Ignacio Benedicto, Vicente Andrés

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortas, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ targeting drugs to ameliorate progerin-induced atherosclerosis.

哈钦森-吉尔福德早衰综合征(HGPS)是一种极其罕见的疾病,由早衰素表达引起,早衰素是一种由 LMNA 基因点突变产生的异常蛋白质。HGPS 患者衰老加速,主要死于动脉粥样硬化并发症,如心肌梗塞、心力衰竭或中风。然而,HGPS血管病理学的基本机制仍不明确。我们使用单细胞 RNA 测序技术分析了表达 LmnaG609G/G609G 的小鼠和野生型对照组的主动脉特征,重点研究了内皮细胞(ECs)。HGPS ECs的基因表达变化与细胞外基质改变、白细胞外渗增加以及具有PDZ结合域的YAP/TAZ转录激活因子机械传感途径的激活有关,所有这些变化都通过不同的技术进行了验证。原子力显微镜实验表明,原发性主动脉内皮下细胞外基质较硬,对活体HGPS小鼠的超声波评估显示主动脉血流紊乱,这两种情况都是诱导EC中YAP/TAZ通路的关键因素。用verteporfin抑制YAP/TAZ可减少主动脉内膜层的白细胞积聚,减轻类早衰小鼠的动脉粥样硬化负担。我们的研究结果表明,内皮YAP/TAZ信号传导是HGPS血管疾病的一个关键机制,并为开发YAP/TAZ靶向药物以改善早老素诱导的动脉粥样硬化开辟了一条新途径。
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引用次数: 0
Ciliary localization of GPR75 promotes fat accumulation in mice. GPR75 的纤毛定位促进了小鼠的脂肪积累。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI185059
Marcelo Chávez, Anushweta Asthana, Peter K Jackson

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.

肥胖症是一个日益严重的公共健康问题,它影响着包括儿童和老年人在内的所有人群的寿命和生活方式。导致肥胖的因素多种多样,因此了解和治疗肥胖具有挑战性。虽然最近的研究强调了 GPCR 信号传导对新陈代谢和脂肪积累的重要性,但我们缺乏对致肥信号如何在细胞、组织和器官中积累和传播的分子描述。在本期 JCI 杂志上,Jiang 等人利用种系突变产生了由 Thinner 等位基因编码的 GRP75 的错义变体,从而使小鼠具有瘦弱表型。GPR75 积聚在下丘脑神经元的纤毛中。然而,具有 Thinner 等位基因的小鼠显示出纤毛定位缺陷,对脂肪积累有抵抗力。此外,GPR75对脂肪积累的调控似乎独立于瘦素和ADCY3信号传导。这些发现揭示了GPR75在脂肪积累中的作用,并强调了确定相关配体的必要性。
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引用次数: 0
Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3-deficient autism model. 不眠之夜与社交困境:神经胶质蛋白 3 缺陷自闭症模型的内侧隔 GABA 能亢进。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI184795
Claire E Cho, Dahee Jung, Reesha R Patel

Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.

社交障碍是自闭症谱系障碍(ASD)的一个核心症状领域,通常与睡眠障碍并发。在本期 JCI 杂志上,Sun 等人在神经胶质蛋白 3 条件性基因敲除的自闭症模型中探索了连接这些行为的内隔膜(MS)回路。他们在 MS 中发现了神经胶质蛋白 3 缺失后的 GABA 能神经元亢进。这种亢进导致下游视前区(POA)和海马 CA2 区受到抑制,分别造成睡眠丧失和社会记忆缺陷。使过度活跃的MS GABA神经元失活,或激活POA或CA2,都能挽救行为缺陷。这些发现加深了我们对 ASD 社交和睡眠障碍神经回路的理解。
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引用次数: 0
The first century of JCI and beyond. 青年商会的第一个世纪及其后。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI186113
Elizabeth M McNally
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引用次数: 0
2024 Lasker Award Recipient Zhijian Chen elucidates how DNA stimulates immunity. 2024 年拉斯克奖获得者陈志坚阐明了 DNA 如何刺激免疫力。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-19 DOI: 10.1172/JCI186104
Amy B Heimberger
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引用次数: 0
Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen awarded Lasker prize for pioneering work on GLP-1. Joel Habener、Svetlana Mojsov 和 Lotte Bjerre Knudsen 因在 GLP-1 方面的开创性工作而荣获拉斯克奖。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-19 DOI: 10.1172/JCI186225
Hossein Ardehali
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引用次数: 0
Connecting the dots: sex, depression, and musculoskeletal health. 连接点:性别、抑郁和肌肉骨骼健康。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/JCI180072
Mackenzie Newman, Henry J Donahue, Gretchen N Neigh

Depression and multiple musculoskeletal disorders are overrepresented in women compared with men. Given that depression is a modifiable risk factor and improvement of depressive symptoms increases positive outcomes following orthopedic intervention, efforts to improve clinical recognition of depressive symptoms and increased action toward ameliorating depressive symptoms among orthopedic patients are positioned to reduce complications and positively affect patient-reported outcomes. Although psychosocial factors play a role in the manifestation and remittance of depression, it is also well appreciated that primary biochemical changes are capable of causing and perpetuating depression. Unique insight for novel treatments of depression may be facilitated by query of the bidirectional relationship between musculoskeletal health and depression. This Review aims to synthesize the diverse literature on sex, depression, and orthopedics and emphasize the potential for common underlying biological substrates. Given the overrepresentation of depression and musculoskeletal disorders among women, increased emphasis on the biological drivers of the co-occurrence of these disorders is positioned to improve women's health.

与男性相比,女性患抑郁症和多种肌肉骨骼疾病的比例更高。鉴于抑郁症是一种可改变的风险因素,而抑郁症状的改善会增加骨科干预后的积极疗效,因此,努力提高临床对抑郁症状的认识并加强行动以改善骨科患者的抑郁症状,将有助于减少并发症并对患者报告的疗效产生积极影响。虽然社会心理因素在抑郁症的表现和缓解中起着一定的作用,但人们也清楚地认识到,原发性生化变化能够引起抑郁症并使其长期存在。对肌肉骨骼健康与抑郁症之间的双向关系进行研究,有助于深入了解抑郁症的新型治疗方法。本综述旨在综合有关性、抑郁和骨科的各种文献,并强调潜在的共同生物学基础。鉴于抑郁症和肌肉骨骼疾病在女性中的比例过高,加强对这些疾病共同发生的生物学驱动因素的重视将有助于改善女性的健康状况。
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引用次数: 0
Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models. 在临床前模型中,周细胞表型转换可减轻免疫抑制,并使血管化肿瘤对免疫疗法敏感。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/JCI179860
Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss

T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.

以 T 细胞为基础的免疫疗法是治疗多种恶性肿瘤的一种很有前景的方法,但其疗效因血管功能失调导致的肿瘤缺氧而受到限制。在这里,我们报告了单个血管成分(即包膜细胞)的细胞内在特性有助于控制肿瘤氧合、巨噬细胞极化、血管炎症和 T 细胞浸润。将包膜表型从合成状态转换为分化状态可逆转免疫抑制,并使肿瘤对采纳性 T 细胞疗法敏感,从而导致小鼠黑色素瘤消退。在黑色素瘤患者中,生存率的提高与周细胞成熟度的提高相关。重要的是,周细胞的可塑性受汇聚于Rho激酶活性的信号通路调控,抑制周细胞MEK、AKT或notch信号传导的选择性低剂量疗法可诱导周细胞成熟。我们还表明,低剂量靶向抗癌疗法可以持久改变肿瘤微环境,而不会诱发适应性抗药性,这为结合免疫疗法重新使用抗癌靶向疗法以改善疗效创造了一个高度可转化的途径。
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引用次数: 0
Mechanisms underlying sex differences in autoimmunity. 自身免疫性别差异的内在机制
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/JCI180076
DeLisa Fairweather, Danielle J Beetler, Elizabeth J McCabe, Scott M Lieberman

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.

自身免疫性疾病是导致全球残疾的一个主要原因。大多数自身免疫性疾病在女性中的发病率高于男性,其中风湿性自身免疫性疾病在女性中的发病率最高。主要在动物模型和细胞培养实验中发现的几个关键因素对增加女性自身免疫性疾病非常重要。这些因素包括性激素、免疫基因(包括在 X 染色体上发现的基因)、雌激素和环境对基因的性别特异性表观遗传效应,以及细胞外囊泡中的微核糖核酸对基因和信使核糖核酸的调控。还有证据表明,病毒以及损害线粒体的药物或毒素可能导致针对核抗原和线粒体抗原的自身抗体水平升高,这在许多自身免疫性疾病中很常见。本综述旨在总结我们目前对可能决定自身免疫疾病性别差异的机制的认识。
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引用次数: 0
SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease. SARS-CoV-2 Delta 和 Omicron 变体可抵抗人类气道胰蛋白酶样蛋白酶的尖峰切割。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/JCI174304
Wenyan Ren, Weiqi Hong, Jingyun Yang, Jun Zou, Li Chen, Yanan Zhou, Hong Lei, Aqu Alu, Haiying Que, Yanqiu Gong, Zhenfei Bi, Cai He, Minyang Fu, Dandan Peng, Yun Yang, Wenhai Yu, Cong Tang, Qing Huang, Mengli Yang, Bai Li, Jingmei Li, Junbin Wang, Xuelei Ma, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Zhenling Wang, Guowen Jia, Zhaoming Su, Bin Shao, Hanpei Miao, Johnson Yiu-Nam Lau, Yuquan Wei, Kang Zhang, Lunzhi Dai, Shuaiyao Lu, Xiawei Wei

Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin-like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.

上呼吸道中的可溶性宿主因子可作为抵御 SARS-CoV-2 感染的第一道防线。在这项研究中,我们描述了一种人类气道胰蛋白酶样蛋白酶(HAT)的鉴定和功能,它能够降低祖先 SARS-CoV-2 的感染性。此外,在小鼠模型中,SARS-CoV-2 感染会上调 HAT 类似物的表达。HAT 的抗病毒活性通过裂解 SARS-CoV-2 穗状糖蛋白的 R682 起作用。这种裂解抑制了祖先尖峰蛋白附着到宿主细胞上,从而抑制了细胞-细胞膜融合过程。重要的是,外源添加 HAT 显著降低了祖先 SARS-CoV-2 在体内的感染性。然而,HAT 对 Delta 变体和大多数循环中的 Omicron 变体(包括 BQ.1.1 和 XBB.1.5 亚变体)无效。我们证明,Delta 突变体中的 P681R 突变和 Omicron 突变体中的 P681H 突变(邻近 R682 裂解位点)导致了 HAT 抗性。我们的研究报告了一种我们认为是抗 SARS-CoV-2 的新型可溶性防御因子及其在 Delta 和 Omicron 变体中的抗性作用。
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引用次数: 0
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Journal of Clinical Investigation
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