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Reprogramming of ovarian granulosa cells by YAP1 leads to development of high-grade cancer with mesenchymal lineage and serous features

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Science Bulletin 2020年第15期65卷 1281-1296,M0004页

作者： Xiangmin lv Chunbo He Cong Huang Guohua Hua Xingcheng Chen Barbara K.Timm Victoria M.Maclin Abigail A.Haggerty Shelly K.Aust Denae M.Golden Bhavana J.Dave Yun-An Tseng li Chen Hongbo Wang Peichao Chen david l.klinkebiel Adam R.Karpf Jixin Dong Ronny I.Drapkin Bo R.Rueda John S.Davis Cheng Wang Vincent Center for Reproductive Biology Department of Obstetrics and GynecologyMassachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Olson Center for Women's Health Department of Obstetrics and GynecologyUniversity of Nebraska Medical CenterOmahaNE 68198USA College of Animal Sciences and Veterinary Medicine Huazhong Agricultural UniversityWuhan 470000China Fred&Pamela Buffett Cancer Center University of Nebraska Medical CenterOmahaNE 68198USA Department of Pathology and Microbiology.University of Nebraska Medical Center OmahaNE 68198USA Heartland Center for Reproductive Medicine OmahaNE 68198USA Munroe-Meyer Institute University of Nebraska Medical CenterOmahaNE 68198USA Key laboratory of Animal Ecology and Conservation Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China College of life and Environmental Science Wenzhou UniversityWenzhou 325035China Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNE 68198USA Department of Obstetrics and Gynecology University of PennsylvaniaPhiladelphiaPA 19104USA

Understanding the cell-of-origin of ovarian high grade serous cancer(HGSC)is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological ***,a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS *** cell-of-origin of this subtype of ovarian cancer is *** pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology,we unexpectedly found that the Yes-associated protein 1(YAP1),the major effector of the Hippo signaling pathway,induced dedifferentiation and reprogramming of the ovarian granulosa cells,a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity,leading to the development of high grade ovarian cancer with serous *** research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

关键词： Ovarian granulosa cells Cell reprogramming Cell dedifferentiation The Hippo pathway YAP1 oncogene Mesenchymal type of high grade serous cancer

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Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick Heimel Markus Kerbl lászlóGál Sylvia Nürnberger Barbara Schaedl James Ferguson Nicole Swiadek Xavier Monforte Johannes C.Heinzel Antal Nógrádi Andreas H.Teuschl-Woller david Hercher Department life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk-based nerve guidance conduit vascularization

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph david Gimbel Jonathan Grossberg Daniel l.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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TOPOlOGY AND CASCADING lINE OUTAGES IN POWER GRIDS

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Journal of Systems Science and Systems Engineering 2007年第2期16卷 202-221页

作者： david l. PEPYNE University of Massachusetts Amherst MA USA

Motivated by the small world network research of Watts ＆ Strogatz, this paper studies relationships between topology and cascading line outages in electric power grids. Cascading line outages are a type of cascading collapse that can occur in power grids when the transmission network is congested. It is characterized by a self-sustaining sequence of line outages followed by grid breakup, which generally leads to widespread blackout. The main findings of this work are twofold： On one hand, the work suggests that topologies with more disorder in their interconnection topology tend to be robust with respect to cascading line outages in the sense of being able to support greater generation and demand levels than more regularly interconnected topologies. On the other hand, the work suggests that topologies with more disorder tend to be more fragile in that should a cascade get started, they tend to break apart after fewer outages than more regularly interconnected topologies. Thus, as has been observed in other complex networks, there appears to be a tradeoff between robustness and fragility. These results were established using synthetically generated power grid topologies and verified using the IEEE 57 bus and 188 bus power grid test cases.

关键词： Power grid blackout cascading line failure complex networks robust yet fragile

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乳腺癌发生模型MCF10各细胞系中WT1基因启动子区甲基化及mRNA表达研究

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中华病理学杂志 2007年第4期36卷 253-258页

作者：杨举伦 david klinkebiel Michael J Boland lin Tang Judith K Christman 成都军区昆明总医院病理科 650032 Department of Biochemistry and Molecular Biology University of Nebraska Medical Center NE U S A

目的通过观察乳腺癌发生模型 MCF10中 WT1基因启动子区甲基化状态和 mRNA 表达水平,探讨该基因在乳腺癌发生中的作用。方法应用甲基化特异性 PCR 及双亚硫酸钠基因测序技术检测 MCF10模型的乳腺增生细胞系 MCF10A、癌前细胞系 MCF10AT... 详细信息

目的通过观察乳腺癌发生模型 MCF10中 WT1基因启动子区甲基化状态和 mRNA 表达水平,探讨该基因在乳腺癌发生中的作用。方法应用甲基化特异性 PCR 及双亚硫酸钠基因测序技术检测 MCF10模型的乳腺增生细胞系 MCF10A、癌前细胞系 MCF10AT、导管内癌细胞系***、浸润癌细胞系(MCF10CAla、MCF10CAld、MCF10CAlh)、经典乳腺癌细胞系 MCF7及正常乳腺组织中 WT1基因启动子区甲基化状态,然后用逆转录-聚合酶链反应(RT-PCR)和即时定量 PCR 技术检测上述样品的 mRNA 表达水平。结果在 MCF10模型的增生细胞系 MCF10A、癌前细胞系 MCF10AT、导管内癌细胞系 ***、浸润癌细胞系(MCF10CAla、MCF10CAld、MCF10CAlh)、经典乳腺癌细胞系 MCF7中,WT1基因启动子均处于高度甲基化状态。与正常乳腺组织相比,WT1基因 mRNA 在 MCF10模型的增生细胞系、癌前细胞系、导管内癌细胞系、浸润癌细胞系和经典乳腺癌细胞系 MCF7中的表达均有不同程度的增加(MCF10A、MCF10AT、MCF10CAla、MCF10CAld、MCF10CAlh、MCF10DCIS、MCF7的 WT1基因 mRNA 表达量分别是正常乳腺组织3.23、1.94、4.20、1.53、4.20、4.35、28.69倍)。结论乳腺癌发生过程中 WT1 mRNA 的表达不被启动子甲基化所抑制;WT1mRNA 过表达出现于乳腺癌发牛的早期阶段,提示该基因在乳腺癌发生中起作用。

关键词：乳腺肿瘤甲基化基因表达谱启动区(遗传学) 细胞系

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乳腺癌发生模型MCF10抑癌基因NOEY2启动子区甲基化及mRNA表达

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中华病理学杂志 2005年第3期34卷 177-178页

作者：杨举伦 david klinkebiel Michael J Boland lin Tang Judith K Christman 成都军区昆明总医院病理科 650032 美国内布拉斯加大学医学院生化与分子生物学系

DNA甲基化是常见的表观遗传学变化[1].越来越多的证据表明,抑癌基因启动子区CpG岛甲基化可使其转录沉默,从而解除其抑癌作用,导致肿瘤的发生和发展.NOEY2是近年来发现的抑癌基因,表达于正常乳腺导管上皮细胞和卵巢生发上皮细胞,但在乳... 详细信息

DNA甲基化是常见的表观遗传学变化[1].越来越多的证据表明,抑癌基因启动子区CpG岛甲基化可使其转录沉默,从而解除其抑癌作用,导致肿瘤的发生和发展.NOEY2是近年来发现的抑癌基因,表达于正常乳腺导管上皮细胞和卵巢生发上皮细胞,但在乳腺癌和卵巢癌细胞中表达显著减少或不表达[2, 3].在本实验中检测乳腺癌发生模型MCF10[4]中不同阶段的细胞系NOEY2基因启动子区CpG岛Ⅰ甲基化状态,并与mRNA表达水平进行比较,以研究乳腺癌的发生机制和早期诊断。

关键词：乳腺癌启动子区癌发生 mRNA表达抑癌基因肿瘤甲基化表观遗传学转录 CpG岛

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OPTIMAl INVERSE lQG CONTROl FOR CERTAIN ODE AND PDE STATIONARY PROCESSES

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Journal of Systems Science & Complexity 2010年第3期23卷 584-599页

作者： david l.RUSSEll Department of Mathematics Virginia Tech

Following work carried out earlier on linear-quadratic optimal control for linear finitedimensional stationary systems we report,in this article,on extension of some of those results to certaininfinite dimensional systems;in particular a class of PDE systems of elliptic *** systems arestudied in the now familiar framework developed by *** and ***,specialized to asubclass of such systems important in a variety of *** an extended example this paperstudies an optimal redistribution problem in a groundwater flow system governed by Darcy's equation,presenting both analytic and computational work related to such problems.

关键词： Elliptic PDE linear feedback control stationary system.

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Dislocation Creep Accommodated by Grain Boundary Sliding in Dunite

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Journal of Earth Science 2010年第5期21卷 541-554页

作者： Yonghong Zhao david l Kohlstedt School of Earth and Space Sciences Peking University Department of Geology and Geophysics University of Minnesota

To investigate the role of grain boundary sliding during dislocation creep of dunite, a series of deformation experiments were carried out under anhydrous conditions on fine-grained （-15 μm） samples synthesized from powdered San Carlos olivine and powdered San Carlos olivine＋1.5 vol.% MORB. Triaxial compressive creep tests were conducted at a temperature of 1 473 K and confining pressures of 200 and 400 MPa using a high-resolution, gas-medium deformation apparatus. Each sample was deformed at several levels of differential stress between 100 and 250 MPa to yield strain rates in the range of 10^-6 to 10^-4 s^-1. Under these conditions, the dominant creep mechanism involves the motion of dislocations, largely on the easy slip system （010）[100], accommodated by grain boundary sliding （gbs）. This grain size-sensitive creep regime is characterized by a stress exponent of n=3.4±0.2 and a grain size exponent of p=2.0±0.2. The activation volume for this gbs-accommodated dislocation creep regime is V＊=（26±3）×10^-6 m2·mol^-1. Comparison of our flow law for gbs-accommodated dislocation creep with those for diffusion creep and for dislocation creep reveals that the present flow law is important for the flow of mantle rocks with grain sizes of 〈100μm at differential stresses 〉20 MPa. Hence, gbs-accommodated dislocation creep is likely to be an important deformation mechanism in deep-rooted, highly localized shear zones in the lithospheric upper mantle.

关键词： grain boundary sliding creep olivine flow law.

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MEMS-in-the-lens architecture for a miniature high-NA laser scanning microscope

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light(Science & Applications) 2019年第1期8卷 665-675页

作者： Tianbo liu Milind Rajadhyaksha david l.Dickensheets Electrical and Computer Engineering Department Montana State UniversityBozemanMT 59715USA Dermatology Department Memorial Sloan Kettering Cancer CenterNew YorkNY 10022USA

laser scanning microscopes can be miniaturized for in vivo imaging by substituting optical microelectromechanical system(MEMS)devices in place of larger *** emergence of multifunctional active optical devices can support further miniaturization beyond direct component replacement because those active devices enable diffraction-limited performance using simpler optical system *** this paper,we propose a catadioptric microscope objective lens that features an integrated MEMS device for performing biaxial scanning,axial focus adjustment,and control of spherical *** MEMS-in-the-lens architecture incorporates a reflective MEMS scanner between a low-numerical-aperture back lens group and an aplanatic hyperhemisphere front refractive element to support high-numerical-aperture *** implemented this new optical system using a recently developed hybrid polymer/silicon MEMS three-dimensional scan mirror that features an annular aperture that allows it to be coaxially aligned within the objective lens without the need for a beam *** optical performance of the active catadioptric system is simulated and imaging of hard targets and human cheek cells is demonstrated with a confocal microscope that is based on the new objective lens design.

关键词： scanning scanner mirror

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Turning the corner from observation to intervention in human genetics

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Journal of Genetics and Genomics 2018年第2期45卷 57-59页

作者： david l.Nelson Department of Molecular and Human Genetics Baylor College of Medicine Jan and Dan Duncan Neurological Research Institute

In the early 1990s,shortly after we identified the genetic defect in FMR1 that results in fragile X syndrome（Verkerk et al.,1991）,I attended a conference sponsored by the US National Fragile X *** biannual meeting m... 详细信息

关键词： Turning the corner from observation to intervention in human genetics

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