TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2

Pulmonary fibrosis(PF)is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration(LAR).Here,we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells(AEC2s).The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells(AEC1s).We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s,which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK,two critical kinases supporting LAR,leading to LAR failure.TRIB3,a stress sensor,interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination.Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF.Our study reveals a mechanism of the TRIB3—MDM2—SLUG—SLC34A2 axis causing the LAR failure in PF,which confers a potential strategy for treating patients with fibroproliferative lung diseases.

骨质疏松性椎体压缩骨折椎体强化术后骨水泥血管渗漏的危险因素分析

目的探讨骨质疏松性椎体压缩骨折(OVCF)椎体强化术后骨水泥血管渗漏的危险因素。方法采用病例对照研究分析2019年10月至2020年10月昆明医科大学第一及第二附属医院收治的217例OVCF行椎体强化术[经皮椎体成形术(PVP)或经皮椎体后凸成形术(PKP)]患者的临床资料, 其中男79例, 女138例;年龄58~88岁[(73.1±6.9)岁]。根据是否出现骨水泥血管渗漏分为血管渗漏组(39例)和无血管渗漏组(178例)。记录两组患者性别、年龄、骨密度、受伤至手术时间、伤椎解剖位置、压缩程度、后壁完整性、椎内裂隙征、椎基静脉孔、手术入路、手术方式, 以及骨水泥注入时期、注入速度、注射量、注射区域。采用单因素分析上述指标与椎体强化术后骨水泥血管渗漏的相关性, 再通过多因素Logistic回归分析明确椎体强化术后骨水泥血管渗漏的独立危险因素。结果单因素分析结果显示, 受伤至手术时间、压缩程度、后壁完整性、椎内裂隙征、椎基静脉孔、手术方式, 以及骨水泥注入时期、注入速度、注射量、注射区域与椎体强化术后骨水泥血管渗漏相关(P<0.05);性别、年龄、骨密度、伤椎解剖位置、手术入路与椎体强化术后骨水泥血管渗漏不相关(P>0.05)。多因素Logistic 回归分析结果显示, 椎内裂隙征(OR=7.00, 95%CI 1.57~31.30, P<0.05)、椎基静脉孔(OR=7.52, 95%CI 1.94~29.16, P<0.01)、PVP(OR=10.98, 95%CI 2.51~47.94, P<0.01)、骨水泥稀薄期注入(OR=5.91, 95%CI 1.45~24.15, P<0.05)、骨水泥注射量大(OR=3.60, 95%CI 1.70~7.65, P<0.01)、骨水泥边缘区注射(OR=24.80, 95%CI 5.28~116.37, P<0.01)与OVCF椎体强化术后骨水泥血管渗漏显著相关。结论椎内裂隙征、椎基静脉孔、PVP, 以及骨水泥稀薄期注入、注射量大、边缘区注射是OVCF椎体强化术后骨水泥血管渗漏的独立危险因素。

The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury.Pulmonary fibrosis(PF)is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells.In this study,we report that P21 expression was increased in alveolar epithelial type 2 cells(AEC2 s)in a time-dependent manner following multiple bleomycin-induced PF.Repeated injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell senescence.AEC2 s with elevated expression of P21 lost their self-renewal and differentiation abilities.In particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction.Meanwhile,senescent AEC2 s triggered myofibroblast activation by releasing profibrotic cytokines.Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF.The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development,which suggests a potential strategy for the treatment of fibrotic lung diseases.

The CST bounce universe model——A parametric study

A bounce universe model with a scale-invariant and stable spectrum of primordial density perturbations was constructed using a consistent truncation of the D-brane dynamics from Type IIB string theory. A coupling was introduced between the tachyon field and the adjoint Higgs field on the D3-branes to lock the tachyon at the top of its potential hill and to model the bounce process,which is known as the Coupled Scalar and Tachyon Bounce(CSTB) Universe. The CSTB model has been shown to be ghost free,and it fulfils the null energy condition; in addition, it can also solve the Big Bang cosmic singularity problem. In this paper we conduct an extensive follow-up study of the parameter space of the CSTB model. In particular we are interested in the parameter values that can produce a single bounce to arrive at a radiation-dominated universe. We further establish that the CSTB universe is a viable alternative to inflation, as it can naturally produce a sufficient number of e-foldings in the locked inflation epoch and in the post-bounce expansion to overcome the four fundamental limitations of the Big Bang cosmology, which are flatness, horizon,homogeneity and singularity, resulting in a universe of the current size.