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DAB2IP Loss in Luminal A Breast Cancer Leads to NF-kB Associated Aggressive Oncogenic Phenotypes. A 型乳腺癌中 DAB2IP 的缺失会导致与 NF-kB 相关的侵袭性致癌表型。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-17 DOI: 10.1172/jci.insight.171705
Angana Mukherjee, Rasha T Kakati, Sarah C Van Alsten, Tyler Laws, Aaron L Ebbs, Daniel P Hollern, Philip M Spanheimer, Katherine A Hoadley, Melissa A Troester, Jeremy M Simon, Albert S Baldwin

Despite proven therapy options for estrogen receptor (ER)-positive breast tumors, a substantial number of ER+ cancer patients exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the TCGA breast cancer RNA-sequencing dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in Luminal A breast cancer patients. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-kB. Integrating cell-based ChIP-sequencing with motif analysis and TCGA RNA-seq data, we identified a set of candidate NF-kB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.

尽管雌激素受体(ER)阳性乳腺肿瘤的治疗方案已得到证实,但仍有大量ER+癌症患者出现复发和相关转移。RasGAPs 的表达缺失会导致包括乳腺癌在内的多种癌症的不良预后。对 TCGA 乳腺癌 RNA 序列数据集的研究发现,RasGAP DAB2IP 的低表达与 Luminal A 型乳腺癌患者无复发生存率的显著下降有关。免疫染色表明,DAB2IP的缺失发生在2级及以上肿瘤中。与此相一致的是,DAB2IP低表达的Luminal A型肿瘤中上调的基因与侵袭性更强的肿瘤亚型相同,并且与增殖、转移和ER信号改变有关。ER+乳腺癌细胞中DAB2IP的低表达与增殖增加、干性表型增强以及转录因子NF-kB的上游调节因子IKK的激活有关。通过整合基于细胞的 ChIP 测序、主题分析和 TCGA RNA-seq 数据,我们确定了一组候选 NF-kB 靶基因,这些基因在 DAB2IP 缺失时会上调,并与多种致癌表型(包括 RNA 处理改变)相关。这项研究让我们深入了解了典型的侵袭性较低的 Luminal A 乳腺癌固有亚型的一个子集中与侵袭性和复发相关的机制。
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引用次数: 0
Inhibiting Triggering Receptor Expressed on Myeloid Cells-1 signaling to ameliorate skin fibrosis. 抑制髓系细胞上表达的触发受体-1 信号,改善皮肤纤维化。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-17 DOI: 10.1172/jci.insight.176319
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed Am Hasan, Jenna N Silverman, Katherine Broderick, Kris A Shah, Timothy Hamill, Dinesh Khanna, Alexander B Sigalov, Swati Bhattacharyya, John Varga

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. Transforming growth factor-beta (TGF-β) is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used novel ligand-independent TREM-1 inhibitors in order to investigate the pathogenic role of TREM-1 in SSc, using preclinical models of fibrosis, and explanted SSc skin fibroblasts. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.

系统性硬化症(SSc)以免疫系统衰竭、血管损伤、自身免疫和组织纤维化为特征。转化生长因子-β(TGF-β)是系统性硬化症肌成纤维细胞持续活化和细胞外基质异常生成的关键介质。造成这种情况的因素尚不清楚。通过放大模式识别受体信号,髓系细胞上表达的触发受体 1(TREM-1)被认为与多种炎症有关。在这项研究中,我们使用了新型配体依赖性 TREM-1 抑制剂,利用临床前纤维化模型和 SSc 皮肤成纤维细胞,研究了 TREM-1 在 SSc 中的致病作用。选择性药理TREM-1阻断剂可预防和逆转博莱霉素诱导的小鼠皮肤纤维化,并减轻体外SSc成纤维细胞的构成性胶原合成和肌成纤维细胞特征。我们的研究结果表明,异常激活的TREM-1信号与SSc的发病机制有关,确定了一种独特的TREM-1阻断方法,并提出了抑制TREM-1的潜在治疗效果。
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引用次数: 0
Granzyme B cleaves Tenascin-C to release its C-terminal domain in rheumatoid arthritis. 在类风湿性关节炎中,颗粒酶 B 可裂解 Tenascin-C 以释放其 C 端结构域。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-17 DOI: 10.1172/jci.insight.181935
Alexandre Aubert, Amy Liu, Martin Kao, Jenna Goeres, Katlyn C Richardson, Lorenz Nierves, Karen Jung, Layla Nabai, Hongyan Zhao, Gertraud Orend, Roman Krawetz, Philipp F Lange, Alastair Younger, Jonathan Chan, David J Granville

Rheumatoid arthritis (RA) is one of the most common autoimmune disorders and is characterized by exacerbated joint inflammation that can lead to tissue remodeling and autoantigen generation. Despite the well-documented accumulation of the serine protease Granzyme B (GzmB) in the biospecimens of patients with RA, little is understood pertaining to its role in pathobiology. In the present study Tenascin-C (TN-C), a large extracellular matrix glycoprotein and an endogenous trigger of inflammation, was identified as a substrate for GzmB in RA. GzmB cleaves TN-C in vitro to generate three fragments: a 130 kDa fragment that remains anchored to the matrix, and two 70 and 30 kDa fragments that are released and solubilized. Mass spectrometry results seem to indicate that the 30 kDa fragment generated by GzmB most likely contains TN-C pro-inflammatory C-terminal fibrinogen-like domain. Soluble levels of GzmB and TN-C are also significantly elevated in the synovial fluids of RA patients compared to healthy controls, with two 70 kDa and 30 kDa soluble TN-C fragments detectable in the synovial fluids of RA patients. The molecular weights of these fragments coincide with those generated by GzmB in vitro, suggesting that GzmB also cleaves TN-C in RA patients. Granzyme K (GzmK), another member of the granzyme family, also cleaves TN-C in vitro. However, unlike GzmB, the molecular weights of TN-C fragments generated by GzmK in vitro do not correspond to fragments identified in patients. Altogether, our data supports the contribution of Granzyme B, but not Granzyme K, to RA through the cleavage of Tenascin-C.

类风湿性关节炎(RA)是最常见的自身免疫性疾病之一,其特点是关节炎症加剧,可导致组织重塑和自身抗原生成。尽管有充分证据表明丝氨酸蛋白酶颗粒酶 B(GzmB)在 RA 患者的生物样本中积累,但人们对其在病理生物学中的作用却知之甚少。本研究发现,Tenascin-C(TN-C)是一种大型细胞外基质糖蛋白,也是炎症的内源性触发因子,它是 GzmB 在 RA 中的底物。GzmB 在体外裂解 TN-C,生成三个片段:一个 130 kDa 的片段固定在基质上,两个 70 kDa 和 30 kDa 的片段被释放和溶解。质谱分析结果似乎表明,GzmB 产生的 30 kDa 片段最有可能含有 TN-C 促炎 C 端纤维蛋白原样结构域。与健康对照组相比,RA 患者滑液中 GzmB 和 TN-C 的可溶性水平也明显升高,在 RA 患者的滑液中可检测到两个 70 kDa 和 30 kDa 的可溶性 TN-C 片段。这些片段的分子量与GzmB在体外产生的分子量相吻合,表明GzmB也能裂解RA患者体内的TN-C。颗粒酶家族的另一个成员颗粒酶 K(GzmK)也能在体外裂解 TN-C。然而,与 GzmB 不同的是,GzmK 在体外产生的 TN-C 片段的分子量与在患者体内发现的片段不一致。总之,我们的数据支持 Granzyme B(而非 Granzyme K)通过裂解 Tenascin-C 对 RA 起作用。
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引用次数: 0
Type 2 innate immunity promotes the development of pulmonary fibrosis in Hermansky-Pudlak syndrome. 2型先天性免疫促进了赫尔曼斯基-普德拉克综合征肺纤维化的发展。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.178381
Parand Sorkhdini, Kiran Klubock-Shukla, Selena Sheth, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Wendy J Introne, Bernadette R Gochuico, Yang Zhou

Hermansky-Pudlak syndrome (HPS), particularly in types 1 and 4, is characterized by progressive pulmonary fibrosis, a major cause of morbidity and mortality. However, the precise mechanisms driving pulmonary fibrosis in HPS are not fully elucidated. Our previous studies suggested that CHI3L1-driven fibroproliferation may be a notable factor in HPS-associated fibrosis. This study aimed to explore the role of CHI3L1-CRTH2 interaction on ILC2s and explored the potential contribution of ILC2-fibroblast crosstalk in the development of pulmonary fibrosis in HPS. We identified ILC2s in lung tissues from idiopathic pulmonary fibrosis (IPF) and HPS patients. Using bleomycin-challenged wild type (WT) and Hps1-/- mice we observed that ILC2s were recruited and appeared to contribute to fibrosis development in the Hps1-/- mice, with CRTH2 playing a notable role in ILC2 accumulation. We sorted ILC2s, profiled fibrosis-related genes and mediators, and conducted co-culture experiments with primary lung ILC2s and fibroblasts. Our findings suggest that ILC2s may directly stimulate the proliferation and differentiation of primary lung fibroblasts partially through Amphiregulin-EGFR-dependent mechanisms. Additionally, specific overexpression of CHI3L1 in the ILC2 population using the IL-7Rcre driver, which was associated with increased fibroproliferation, indicates that ILC2-mediated, CRTH2-dependent mechanisms might contribute to optimal CHI3L1-induced fibroproliferative repair in HPS-associated pulmonary fibrosis.

赫尔曼斯基-普德拉克综合征(HPS),尤其是 1 型和 4 型,以进行性肺纤维化为特征,是发病和死亡的主要原因。然而,驱动 HPS 肺纤维化的确切机制尚未完全阐明。我们之前的研究表明,CHI3L1 驱动的纤维增殖可能是 HPS 相关纤维化的一个显著因素。本研究旨在探索CHI3L1-CRTH2相互作用对ILC2的作用,并探讨ILC2-成纤维细胞串联在HPS肺纤维化发展中的潜在贡献。我们在特发性肺纤维化(IPF)和HPS患者的肺组织中发现了ILC2。通过使用博莱霉素诱导的野生型(WT)小鼠和 Hps1-/- 小鼠,我们观察到 ILC2 被招募并似乎促进了 Hps1-/- 小鼠肺纤维化的发展,其中 CRTH2 在 ILC2 的积累中发挥了显著作用。我们对 ILC2 进行了分类,分析了纤维化相关基因和介质,并与原代肺 ILC2 和成纤维细胞进行了共培养实验。我们的研究结果表明,ILC2可通过安非他酮-表皮生长因子受体依赖机制直接刺激原发性肺成纤维细胞的增殖和分化。此外,使用IL-7Rcre驱动程序在ILC2群体中特异性过表达CHI3L1与纤维增殖增加有关,这表明ILC2介导的CRTH2依赖性机制可能有助于HPS相关肺纤维化中CHI3L1诱导的最佳纤维增殖修复。
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引用次数: 0
Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians. 美国印第安人左心室质量和肥厚的纵向脂质体特征。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.181172
Mingjing Chen, Zhijie Huang, Guanhong Miao, Jin Ren, Jinling Liu, Mary J Roman, Richard B Devereux, Richard R Fabsitz, Ying Zhang, Jason G Umans, Shelley A Cole, Tanika N Kelly, Oliver Fiehn, Jinying Zhao

Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

左心室肥厚(LVH)和血脂异常是心血管疾病强有力的独立预测因素,但对它们之间的关系研究较少。目前还缺乏对左心室质量(LVM)和左心室肥厚的纵向脂质体分析。利用 LC-MS,我们对参加两次体检(平均相隔约 5 年)的 1,755 名独特的美国印第安人的 1,542 种脂质进行了反复测量。通过广义估计方程(GEE)检验了单个血脂种类与 LVM 指数(LVMI)的横断面关联,随后在一个独立的双种族队列(65% 白人,35% 黑人)中进行了复制。在美国印第安人中,通过 Cox 脆弱性模型确定了与 LVH 风险相关的基线血浆脂质,而非传统的风险因素。通过 GEE 检验了血脂变化与 LVMI 变化之间的纵向联系,并对基线血脂、基线 LVMI 和协变量进行了调整。多种脂质(如甘油磷脂、鞘磷脂、酰基肉碱)与美国印第安人的 LVMI 或 LVH 风险显著相关。一些血脂在黑人和白人中得到证实。此外,一些与左心室肥厚相关的脂质与冠心病(CHD)风险成反比。几种脂质(如甘油磷脂、鞘磷脂、胆固醇酯)的纵向变化与 LVMI 的变化显著相关。这些发现为脂质代谢在左心室重塑和左心室肥厚或冠心病风险中的作用提供了见解。
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引用次数: 0
Tissue resident memory T cells contribute to protectionagainst heterologousSARS-CoV-2 challenge. 组织驻留记忆 T 细胞有助于抵御异源 SARS-CoV-2 挑战。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.184074
Abby Odle, Meenakshi Kar, Abhishek K Verma, Alan Sariol, David K Meyerholz, Mehul S Suthar, Lok-Yin Roy Wong, Stanley Perlman

Widespread vaccination and natural infection have resulted in greatly decreased rates of severe disease, hospitalization and death after subsequent infection or reinfection with SARS-CoV-2. New vaccine formulations are based on circulating strains of virus, which have tended to evolve to more readily transmit human to human and to evade the neutralizing antibody response. An assumption of this approach is that ancestral strains of virus will not recur. Recurrence of these strains could be a problem for individuals not previously exposed to ancestral spike protein by vaccination or infection. Here, we addressed this question by infecting mice with recent SARS-CoV-2 variants and then challenging them with a highly pathogenic mouse-adapted virus closely related to the ancestral Wuhan-1 strain (SARS2-N501YMA30). We found that challenged mice were protected from death and substantial weight loss, even though they generally had low or no neutralizing antibody response to SARS2-N501YMA30 at the time of reinfection. T cell depletion from the previously infected mice did not diminish infection against clinical disease, although it did result in delayed kinetics of virus clearance in the nasal turbinate and in some cases, in the lungs. Levels of tissue resident memory T cells were significantly elevated in the nasal turbinate of previously infected mice compared to mice that had no previous exposure to SARS-CoV-2. However, this phenotype was not seen in lung tissues. Together, these results indicate that the immune response to newly circulating variants afforded protection against re-infection with the ancestral virus that was at least in part T cell based.

广泛的疫苗接种和自然感染已使随后感染或再次感染 SARS-CoV-2 后的严重疾病、住院和死亡率大大降低。新的疫苗配方是以流行的病毒株为基础的,这些病毒株在进化过程中更容易在人与人之间传播,也更容易逃避中和抗体反应。这种方法的一个假设是病毒的祖先毒株不会再次出现。对于以前没有通过接种疫苗或感染接触过祖先尖峰蛋白的人来说,这些毒株的复发可能是一个问题。为了解决这个问题,我们用最近的 SARS-CoV-2 变异株感染小鼠,然后用与祖先武汉-1 株(SARS2-N501YMA30)密切相关的高致病性小鼠适配病毒对小鼠进行挑战。我们发现,受挑战的小鼠虽然在再次感染时对 SARS2-N501YMA30 的中和抗体反应普遍较低或没有反应,但仍能免于死亡和体重大幅下降。先前感染过的小鼠的 T 细胞耗竭并没有减轻感染和临床疾病,但确实导致了鼻甲和某些肺部病毒清除动力学的延迟。与以前未接触过 SARS-CoV-2 的小鼠相比,以前感染过 SARS-CoV-2 的小鼠鼻甲中的组织常驻记忆 T 细胞水平明显升高。然而,在肺组织中却看不到这种表型。总之,这些结果表明,对新的循环变异体的免疫反应至少在一定程度上保护了小鼠免受祖先病毒的再次感染。
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引用次数: 0
Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages. 通过抑制 NLRP3+ 巨噬细胞,缺失 PADI2 和 PADI4 可改善败血症诱发的急性肺损伤。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.181686
Xin Yu, Yujing Song, Tao Dong, Wenlu Ouyang, Liujiazi Shao, Chao Quan, Kyung Eun Lee, Tao Tan, Allan Tsung, Katsuo Kurabayashi, Hasan B Alam, Mao Zhang, Jianjie Ma, Yongqing Li

Sepsis-induced acute lung injury (ALI) is prevalent in septic patients and has a high mortality rate. Peptidyl arginine deiminase (PADI) 2 and PADI4 play crucial roles in mediating the host's immune response in sepsis, but their specific functions remain unclear. Our study shows that Padi2-/-Padi4-/- double knockout (DKO) improved survival, reduced lung injury, decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia-induced sepsis mice. Using single-cell RNA sequencing (scRNA-seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3+ pro-inflammatory macrophages and fostered Chil3+ myeloid cell differentiation into anti-inflammatory macrophages. Additionally, we observed the regulatory role of NLRP3-Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3 KO experiments. Thus, eliminating Padi2 and Padi4 enhances the polarization of Ym1+ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. study unveils the PADI2/PADI4-NLRP3-Ym1 pathway as a potential target in treatment of sepsis-induced ALI.

脓毒症引起的急性肺损伤(ALI)在脓毒症患者中很常见,而且死亡率很高。肽基精氨酸脱氨酶(PADI)2和PADI4在脓毒症中介导宿主免疫反应方面起着至关重要的作用,但它们的具体功能仍不清楚。我们的研究表明,Padi2-/-Padi4-/-双基因敲除(DKO)提高了铜绿假单胞菌(PA)肺炎诱导的脓毒症小鼠的存活率,减少了肺损伤,降低了细菌负荷。通过单细胞 RNA 测序(scRNA-seq),我们发现 Padi2 和 Padi4 的缺失会减少 Nlrp3+ 促炎巨噬细胞,并促进 Chil3+ 髓系细胞分化为抗炎巨噬细胞。此外,我们通过 Chil3 敲除和 Nlrp3 KO 实验证实了 DKO 对 NLRP3-Ym1 轴的调控作用。因此,消除 Padi2 和 Padi4 可通过抑制 NLRP3 增强 Ym1+ M2 巨噬细胞的极化,从而帮助炎症消退和肺组织修复。
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引用次数: 0
Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis. 耐达托霉素粪肠球菌细胞膜适应性的分子基础。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.173836
April H Nguyen, Truc T Tran, Diana Panesso, Kara S Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A Arias

Daptomycin is a last resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis. Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by re-distributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a three-component regulatory system, designated LiaFSR, with a possible contribution of cardiolipin synthase (Cls). However, the mechanism by which LiaFSR controls the CM response and the role of Cls are unknown. Here, we show that cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance since deletion of the two genes (cls1 and cls2) encoding Cls abolished CM remodeling. We identified LiaY, a transmembrane protein regulated by LiaFSR, and Cls1 as important mediators of CM remodeling required for re-distribution of anionic phospholipid microdomains. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically.

达托霉素是一种最后的脂肽抗生素,会破坏细胞膜(CM)和肽聚糖的平衡。粪肠球菌已经开发出一种复杂的机制,通过重新分配细胞膜阴离子磷脂,使其远离隔膜,从而避免被达托霉素杀死。CM 的变化由一个名为 LiaFSR 的三组份调控系统协调,心磷脂合成酶(Cls)也可能参与其中。然而,LiaFSR 控制 CM 响应的机制以及 Cls 的作用尚不清楚。在这里,我们发现心磷脂合成酶的活性对阴离子磷脂的重新分布和达托霉素的抗性至关重要,因为缺失编码 Cls 的两个基因(cls1 和 cls2)会导致 CM 重塑。我们发现受 LiaFSR 调节的跨膜蛋白 LiaY 和 Cls1 是阴离子磷脂微域重新分布所需的 CM 重塑的重要介质。总之,我们的见解为肠球菌对细胞包膜抗生素的反应提供了一个可用于治疗的机理框架。
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引用次数: 0
Identification of LRP1+CD13+ human periosteal stem cells that require LRP1 for bone repair. 鉴定需要 LRP1 进行骨修复的 LRP1+CD13+ 人骨膜干细胞。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.173831
Youngjae Jeong, Lorenzo R Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, PDPN and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs (BM-SSCs), selectively expressed newly identified markers, LRP1 and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential expression of LRP1 and CD13 in Prx1+ P-SSCs. When Lrp1 was conditionally deleted in Prx1-lineage cells, it led to severe bone deformity, short statue, and periosteal defects. By contrast, local treatment with a LRP1 agonist at the injury sites induced early P-SSC proliferation and bone healing. Thus, human and mouse periosteum contains unique osteochondrogenic stem cell subsets, and these P-SSCs express specific markers, LRP1 and CD13, with regulatory mechanism through LRP1 that enhances P-SSC function and bone repair.

人类骨膜骨骼干细胞(P-SSCs)对皮质骨的维护和修复至关重要。然而,它们在体内的身份、分子特征和特异性标记仍然未知。在这里,单细胞测序发现人类骨膜含有表达已知SSC标记物PDPN和PDGFRA的SSC集群。值得注意的是,人类P-SSCs(而非骨髓SSCs(BM-SSCs))选择性地表达了新发现的标记物LRP1和CD13。这些 LRP1+CD13+ 人 P-SSCs 是血管周围细胞,具有很高的骨软骨生成潜能,但脂肪生成潜能极低。移植到小鼠骨损伤处后,它们在体内保持了自我更新能力。对小鼠骨膜的单细胞分析进一步证实了 LRP1 和 CD13 在 Prx1+ P-SSCs 中的优先表达。当Lrp1在Prx1系细胞中被有条件地删除时,会导致严重的骨畸形、短雕像和骨膜缺损。相比之下,在损伤部位使用 LRP1 激动剂进行局部治疗可诱导 P-SSC 早期增殖和骨愈合。因此,人类和小鼠的骨膜含有独特的骨软骨干细胞亚群,这些P-SSCs表达特异性标志物LRP1和CD13,通过LRP1的调节机制增强P-SSC的功能和骨修复。
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引用次数: 0
ClC-Kb pore mutation disrupts glycosylation and triggers distal tubular remodeling. ClC-Kb 孔突变会破坏糖基化并引发远端肾小管重塑。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/jci.insight.175998
Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Mutations in the CLCNKB gene (1p36), encoding a basolateral chloride channel, ClC-Kb, cause type 3 Bartter's syndrome. We identified a family with a mixed Bartter's / Gitelman's phenotype and early-onset kidney failure and employing a candidate gene approach, discovered a homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole exome sequencing. Compared to wild-type ClC-Kb, the Gly167Cys mutant conducted less current and impaired, complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, impairs complex glycosylation but that surface expression remains intact. Moreover, Asn364 was necessary for channel function and complex glycosylation. Morphologic evaluation of human kidney biopsies revealed typical basolateral localization of mutant Gly167Cys ClC-Kb in cortical distal tubular epithelia. However, we detected attenuated expression of distal sodium transport proteins, changes in abundance of distal tubule segments, and hypokalemia-associated intracellular condensates from the index patient compared to control nephrectomy specimens. The present data establish what we believe, are novel regulatory mechanisms of ClC-Kb activity and demonstrate nephron remodeling in man, caused by mutant ClC-Kb, with implications for renal electrolyte handling, blood pressure control, and kidney disease.

编码基底侧氯离子通道 ClC-Kb 的 CLCNKB 基因(1p36)突变会导致 3 型巴特氏综合征。我们发现了一个具有巴特综合征/吉特曼综合征混合表型和早发性肾衰竭的家族,并采用候选基因方法,在该患者的 CLCNKB 第 6 外显子中发现了一个同基因突变(CLCNKB c.499G>T [p.Gly167Cys])。随后,我们通过桑格测序和全外显子测序验证了这些结果。与野生型 ClC-Kb 相比,Gly167Cys 突变体在体外进行复杂的 N-连接糖基化的电流较小,且功能受损。我们证明,Gly-167 的缺失,而不是突变 Cys 的获得,会损害复合糖基化,但表面表达仍然完整。此外,Asn364 是通道功能和复合物糖基化所必需的。人体肾脏活检组织的形态学评估显示,突变型 Gly167Cys ClC-Kb 在皮质远端肾小管上皮中呈典型的基底侧定位。然而,与对照组肾切除标本相比,我们在该患者体内检测到远端钠转运蛋白的表达减弱、远端肾小管节段的丰度发生变化以及与低钾血症相关的细胞内凝集物。目前的数据建立了我们认为是新的 ClC-Kb 活性调控机制,并证明了突变体 ClC-Kb 对肾电解质处理、血压控制和肾脏疾病的影响。
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