Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Her...Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.展开更多
二穗短柄草是一年生温带早熟禾亚科植物,具有遗传资源丰富、与禾谷类作物亲缘关系密切等特点,是一种重要的禾谷类模式植物。TEOSINTE BRANCHED1/CINCINNATA/PROLIFERATING CEL FACTOR(TCP)家族是植物特异转录因子,广泛调控植物生长发育...二穗短柄草是一年生温带早熟禾亚科植物,具有遗传资源丰富、与禾谷类作物亲缘关系密切等特点,是一种重要的禾谷类模式植物。TEOSINTE BRANCHED1/CINCINNATA/PROLIFERATING CEL FACTOR(TCP)家族是植物特异转录因子,广泛调控植物生长发育。然而,有关二穗短柄草TCP转录因子的信息仍不清楚。本文对二穗短柄草的TCP基因进行了全基因组鉴定,共鉴定出了21个TCP基因(BdTCPs)。分类结果显示,21个BdTCPs主要分为以下两个亚组:11个PROLIFERATING CEL FACTOR(PCF)基因(Ⅰ类)、7个CINCINNATA(CIN)基因和3个CYCLOIDEA(CYC)基因(Ⅱ类)。序列分析表明,二穗短柄草TCP蛋白均包含TCP/TCP superfamily结构域,且外显子-内含子结构各不相同。Motif分析表明,二穗短柄草TCP家族成员均含有Motif 1和Motif 2,暗示这两个基序是其发挥功能所必需的保守区域。顺式作用元件分析表明,所有BdTCPs的启动子区域都含有植物激素和环境响应元件,暗示BdTCPs基因可能参与非生物胁迫响应。荧光定量PCR结果显示,21个BdTCPs均对盐胁迫不敏感,但其中2个基因(BdTCP10、BdTCP15)参与了干旱胁迫的瞬时响应,且表达量均发生了极显著上调,表明Bd TCP10和BdTCP15基因在二穗短柄草应对干旱胁迫中起正调控作用。上述结果为进一步研究TCP在调控二穗短柄草的生长发育及其在非生物胁迫响应中的作用提供了重要线索。展开更多
分布式电源(distributed resources,DR)中智能边缘设备数据传输的安全问题为电力系统带来了安全隐患。Modbus TCP(transmission control protocol)协议作为边缘设备采用的通信手段之一,其协议安全性的不足使得系统易遭到网络空间的攻击...分布式电源(distributed resources,DR)中智能边缘设备数据传输的安全问题为电力系统带来了安全隐患。Modbus TCP(transmission control protocol)协议作为边缘设备采用的通信手段之一,其协议安全性的不足使得系统易遭到网络空间的攻击。为保障电力设备数据传输安全,对现有安全手段进行整理,分析现有安全手段在DR应用场景下的不足,提出一种非侵入式Modbus TCP协议安全增强方法。该方法采用云边协同的架构,利用电力控制中心云平台管理访问控制原则,将实际访问控制决策模块部署在边缘设备,并通过细粒度的访问控制组合限制恶意行为。依据Modbus协议参考指南,搭建DR应用场景进行渗透测试,验证该方法能有效防御重放攻击和中间人攻击,可将安全开销控制在百微秒以内,显著优于其他安全手段,满足DR对实时性的需求。展开更多
基金supported by the National Key Research and Development Program of China,No.2022YFC2402701(to WC)Key International(Regional)Joint Research Program of the National Natural Science Foundation of China,No.81820108009(to SY)+5 种基金the National Natural Science Foundation of China,Nos.81970890(to WC)and 82371148(to WG)Fujian Provincial Healthcare Young and Middle-aged Backbone Talent Training Project,No.2023GGA035(to XC)Spring City Planthe High-level Talent Promotion and Training Project of Kunming,No.2022SCP001(to SY)the Natural Science Foundation of Hainan Province of China,No.824MS052(to XS)the Sixth Medical Center of Chinese PLA General Hospital Innovation Cultivation,No.CXPY202116(to LX)。
文摘Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.
文摘二穗短柄草是一年生温带早熟禾亚科植物,具有遗传资源丰富、与禾谷类作物亲缘关系密切等特点,是一种重要的禾谷类模式植物。TEOSINTE BRANCHED1/CINCINNATA/PROLIFERATING CEL FACTOR(TCP)家族是植物特异转录因子,广泛调控植物生长发育。然而,有关二穗短柄草TCP转录因子的信息仍不清楚。本文对二穗短柄草的TCP基因进行了全基因组鉴定,共鉴定出了21个TCP基因(BdTCPs)。分类结果显示,21个BdTCPs主要分为以下两个亚组:11个PROLIFERATING CEL FACTOR(PCF)基因(Ⅰ类)、7个CINCINNATA(CIN)基因和3个CYCLOIDEA(CYC)基因(Ⅱ类)。序列分析表明,二穗短柄草TCP蛋白均包含TCP/TCP superfamily结构域,且外显子-内含子结构各不相同。Motif分析表明,二穗短柄草TCP家族成员均含有Motif 1和Motif 2,暗示这两个基序是其发挥功能所必需的保守区域。顺式作用元件分析表明,所有BdTCPs的启动子区域都含有植物激素和环境响应元件,暗示BdTCPs基因可能参与非生物胁迫响应。荧光定量PCR结果显示,21个BdTCPs均对盐胁迫不敏感,但其中2个基因(BdTCP10、BdTCP15)参与了干旱胁迫的瞬时响应,且表达量均发生了极显著上调,表明Bd TCP10和BdTCP15基因在二穗短柄草应对干旱胁迫中起正调控作用。上述结果为进一步研究TCP在调控二穗短柄草的生长发育及其在非生物胁迫响应中的作用提供了重要线索。
