TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways

Zhao Zhenzhen,Zhang Yumeng,Zhang Chaoyang,Zhang Jingting,Luo Xueting,Qiu Qinghua,Luo Dawei,Zhang Jingfa 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Subretinal fibrosis remains a major obstacle to the management of neovascular age-related macular degeneration. Choroidal pericytes were found to be a significant source of subretinal fibrosis, but the underlying mechanisms of pericyte-myofibroblast transition (PMT) remain largely unknown. The goal of this study was to explore the role and potential mechanisms by which PMT contributes to subretinal fibrosis. Choroidal neovascularization (CNV) was induced by laser photocoagulation in transgenic mice with the collagen1α1-green fluorescent protein (Col1α1-GFP) reporter, and recombinant adeno-associated virus 2 (rAAV2)-mediated TGF-β2 (rAAV2-TGF-β2) was administered intravitreally to further induce PMT. Primary mouse choroidal GFP-positive pericytes were treated with TGF-β2 in combination with siRNAs targeting Smad2/3, the Akt inhibitor MK2206 or the mTOR inhibitor rapamycin to examine cell proliferation, migration, and differentiation into myofibroblasts. The involvement of the Akt/mTOR pathway in PMT in subretinal fibrosis was further investigated in vivo. Intraocular TGF-β2 overexpression induced GFP-positive pericyte infiltration and PMT in subretinal fibrosis, which was mimicked in vitro. Knockdown of Smad2/3 or inhibition of Akt/mTOR decreased cell proliferation, PMT and migration in primary mouse pericytes. Combined inhibition of Smad2/3 and mTOR showed synergistic effects on attenuating α-smooth muscle actin (α-SMA) expression and cell proliferation. In mice with laser-induced CNV, the administration of the Akt/mTOR inhibitors suppressed pericyte proliferation and alleviated the severity of subretinal fibrosis. Our results showed that PMT plays a pivotal role in subretinal fibrosis, which was induced by TGF-β2 through the Smad2/3 and Akt/mTOR pathways. Thus, inhibiting PMT may be a novel strategy for the treatment of subretinal fibrosis.

BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Sun, Chaoyang,Yin, Jun,Fang, Yong,Chen, Jian,Jeong, Kang Jin,Chen, Xiaohua,Vellano, Christopher P.,Ju, Zhenlin,Zhao, Wei,Zhang, Dong,Lu, Yiling,Meric-Bernstam, Funda,Yap, Timothy A.,Hattersley, Mauree Cell Press 2018 CANCER CELL Vol. No.

<P><B>Summary</B></P> <P>Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in <I>BRCA1</I>, <I>BRCA2</I>, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of <I>BRCA1/2</I>, <I>TP53</I>, <I>RAS</I>, or <I>BRAF</I> mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple <I>in vivo</I> models.</P> <P><B>Highlights</B></P> <P> <UL> <LI> BRD4 inhibition decreases homologous recombination competency by decreasing CtIP </LI> <LI> PARP and BRD4 inhibitors demonstrate synergy in multiple cancer lineages </LI> <LI> CtIP rescues DNA end resection and HR defect caused by BRD4 inhibition </LI> <LI> BRD4 inhibition resensitizes cells with acquired PARPi resistance to PARPi </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Low Chattering Trajectory Tracking Control of Non-singular Fast Terminal Sliding Mode Based on Disturbance Observer

Jiqing Chen,Chaoyang Zhao,Qingsong Tang,Xu Liu,Zhikui Wang,Chengzhi Tan,Jiahua Wu,Teng Long 제어·로봇·시스템학회 2023 International Journal of Control, Automation, and Vol.21 No.2

The improvement of the performance of the multi-joint manipulator control system is of great significance to improve the level of industrial automation. The existing sliding mode control methods are difficult to ensure the high-precision and fast-tracking of joints of a manipulator to the desired trajectory under low chattering control input. Therefore, a non-singular fast terminal sliding mode control method based on a nonlinear disturbance observer is proposed. In addition, a new non-singular fast terminal sliding mode surface is designed. The performance comparison method of the sliding mode surface proves its better control quality. Aiming at the problem of serious chattering, the nonlinear disturbance observer technology, and saturation function method are introduced to effectively weaken the chattering. Finally, taking the 3-DOF manipulator as the research object, a comparative simulation experiment is carried out in the MATLAB / Simulink environment. The results show that under the uncertainty of modeling error, external disturbance, and joint friction, the designed control method not only solves the problems of singular control input and serious chattering but also realizes the high-precision and fast-tracking of each joint to the desired trajectory. Thus, the effectiveness and feasibility of the design method are verified. The improvement of the performance of the multi-joint manipulator control system is of great significance to improve the level of industrial automation. The existing sliding mode control methods are difficult to ensure the high-precision and fast-tracking of joints of a manipulator to the desired trajectory under low chattering control input. Therefore, a non-singular fast terminal sliding mode control method based on a nonlinear disturbance observer is proposed. In addition, a new non-singular fast terminal sliding mode surface is designed. The performance comparison method of the sliding mode surface proves its better control quality. Aiming at the problem of serious chattering, the nonlinear disturbance observer technology, and saturation function method are introduced to effectively weaken the chattering. Finally, taking the 3-DOF manipulator as the research object, a comparative simulation experiment is carried out in the MATLAB / Simulink environment. The results show that under the uncertainty of modeling error, external disturbance, and joint friction, the designed control method not only solves the problems of singular control input and serious chattering but also realizes the high-precision and fast-tracking of each joint to the desired trajectory. Thus, the effectiveness and feasibility of the design method are verified.

Adaptive Extraction Method for Phase Foreground Region in Laser Interferometry of Gear

Xian Wang,Yichao Zhao,Chaoyang Ju,Chaoyong Zhang 한국광학회 2023 Current Optics and Photonics Vol.7 No.4

Tooth surface shape error is an important parameter in gear accuracy evaluation. When tooth surface shape error is measured by laser interferometry, the gear interferogram is highly distorted and the gray level distribution is not uniform. Therefore, it is important for gear interferometry to extract the foreground region from the gear interference fringe image directly and accurately. This paper presents an approach for foreground extraction in gear interference images by leveraging the sinusoidal variation characteristics shown by the interference fringes. A gray level mask with an adaptive threshold is established to capture the relevant features, while a local variance evaluation function is employed to analyze the fluctuation state of the interference image and derive a repair mask. By combining these masks, the foreground region is directly extracted. Comparative evaluations using qualitative and quantitative assessment methods are performed to compare the proposed algorithm with both reference results and traditional approaches. The experimental findings reveal a remarkable degree of matching between the algorithm and the reference results. As a result, this method shows great potential for widespread application in the foreground extraction of gear interference images.

Mapping QTLs for Tissue Culture Response in Soybean (Glycine max (L.) Merr.)

Chao Yang,Tuanjie Zhao,Deyue Yu,Junyi Gai 한국분자세포생물학회 2011 Molecules and cells Vol.32 No.4

Quantitative trait loci (QTLs) that control the tissue cul-ture response in soybean were detected by using 184 recombinant inbred lines (RILs) derived from two varieties: Kefeng No.1 and Nannong 1138-2. The molecular map consisting of 834 molecular markers using this population covered space 2307.83 cM of the genome throughout 24 linkage groups. The performance of tissue culture in soybean was evaluated by two indices: callus induction frequency (CIF) and somatic embryos initiation frequency (SEIF). They were expressed as the number of explants producing callus/ the number of total explants and the number of explants producing somatic embryos/ the number of total explants, respectively. The RIL lines showed continuous segregation for both indices. With the composite interval mapping (CIM) described in Windows QTL Cartographer Version 2.5, three quantitative trait loci (QTLs) were identified for the frequency of callus induction, on chromosomes B2 and D2, accounting for phenotypic variation from 5.84% to 16.60%; four QTLs on chromo-some G were detected for the frequency of somatic em-bryos initiation and explained the phenotypic variation from 7.79% to 14.16%. The information of new QTLs identified in the present study will contribute to genetic improvement of regeneration traits with marker-assisted selection (MAS) in soybean.