scholarly journals Mechanical Pressure Driving Proteoglycan Expression in Mammographic Density: a Self-perpetuating Cycle?

2021 ◽  
Author(s):  
Gina Reye ◽  
Xuan Huang ◽  
Larisa M. Haupt ◽  
Ryan J. Murphy ◽  
Jason J. Northey ◽  
...  
Keyword(s):  
Mammographic Density ◽  
Positive Feedback ◽  
Weight Bearing ◽  
Fibrous Tissue ◽  
Feedback Mechanism ◽  
Mechanical Force ◽  
Mechanical Stiffness ◽  
Mechanical Pressure ◽  
Fibrous Stroma ◽  
High Mammographic Density

AbstractRegions of high mammographic density (MD) in the breast are characterised by a proteoglycan (PG)-rich fibrous stroma, where PGs mediate aligned collagen fibrils to control tissue stiffness and hence the response to mechanical forces. Literature is accumulating to support the notion that mechanical stiffness may drive PG synthesis in the breast contributing to MD. We review emerging patterns in MD and other biological settings, of a positive feedback cycle of force promoting PG synthesis, such as in articular cartilage, due to increased pressure on weight bearing joints. Furthermore, we present evidence to suggest a pro-tumorigenic effect of increased mechanical force on epithelial cells in contexts where PG-mediated, aligned collagen fibrous tissue abounds, with implications for breast cancer development attributable to high MD. Finally, we summarise means through which this positive feedback mechanism of PG synthesis may be intercepted to reduce mechanical force within tissues and thus reduce disease burden.

scholarly journals A positive feedback mechanism ensures proper assembly of the functional inner centromere during mitosis in human cells

2018 ◽  
Vol 294 (5) ◽  
pp. 1437-1450 ◽  
Author(s):  
Cai Liang ◽  
Zhenlei Zhang ◽  
Qinfu Chen ◽  
Haiyan Yan ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Histone H3 ◽  
Causal Link ◽  
Feedback Mechanism ◽  
Histone H2a ◽  
Defective Mutant ◽  
Chromosomal Passenger ◽  
Phosphatase 2A ◽  
Elevated Rate ◽  
Positive Feedback Mechanism

The inner centromere region of a mitotic chromosome critically regulates sister chromatid cohesion and kinetochore–microtubule attachments. However, the molecular mechanism underlying inner centromere assembly remains elusive. Here, using CRISPR/Cas9-based gene editing in HeLa cells, we disrupted the interaction of Shugoshin 1 (Sgo1) with histone H2A phosphorylated on Thr-120 (H2ApT120) to selectively release Sgo1 from mitotic centromeres. Interestingly, cells expressing the H2ApT120-binding defective mutant of Sgo1 have an elevated rate of chromosome missegregation accompanied by weakened centromeric cohesion and decreased centromere accumulation of the chromosomal passenger complex (CPC), an integral part of the inner centromere and a key player in the correction of erroneous kinetochore–microtubule attachments. When artificially tethered to centromeres, a Sgo1 mutant defective in binding protein phosphatase 2A (PP2A) is not able to support proper centromeric cohesion and CPC accumulation, indicating that the Sgo1–PP2A interaction is essential for the integrity of mitotic centromeres. We further provide evidence indicating that Sgo1 protects centromeric cohesin to create a binding site for the histone H3–associated protein kinase Haspin, which not only inhibits the cohesin release factor Wapl and thereby strengthens centromeric cohesion but also phosphorylates histone H3 at Thr-3 to position CPC at inner centromeres. Taken together, our findings reveal a positive feedback–based mechanism that ensures proper assembly of the functional inner centromere during mitosis. They further suggest a causal link between centromeric cohesion defects and chromosomal instability in cancer cells.

scholarly journals Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

2015 ◽  
Vol 112 (15) ◽  
pp. 4678-4683 ◽  
Author(s):  
Yu Shi ◽  
Jianquan Chen ◽  
Courtney M. Karner ◽  
Fanxin Long
Keyword(s):  
Transcriptional Activation ◽  
Positive Feedback ◽  
Hedgehog Signaling ◽  
Osteoblast Differentiation ◽  
Akt Signaling ◽  
Feedback Mechanism ◽  
Genetic Deletion ◽  
Positive Feedback Mechanism ◽  
Igf Signaling

Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

scholarly journals Survival and Proliferation of Neural Progenitor–Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism

2016 ◽  
Vol 23 (5) ◽  
pp. 1250-1262 ◽  
Author(s):  
Anda-Alexandra Calinescu ◽  
Viveka Nand Yadav ◽  
Erica Carballo ◽  
Padma Kadiyala ◽  
Dustin Tran ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Neural Progenitor ◽  
Feedback Mechanism ◽  
Hypoxic Stress ◽  
Positive Feedback Mechanism

Inverter design with positive feedback field-effect transistors

2021 ◽  
Author(s):  
Changhoon Lee ◽  
Changwoo Han ◽  
Changhwan Shin
Keyword(s):  
Positive Feedback ◽  
Computer Aided Design ◽  
Field Effect ◽  
Field Effect Transistors ◽  
Feedback Mechanism ◽  
Silicon On Insulator ◽  
Logic Device ◽  
Device Applications ◽  
Positive Feedback Mechanism ◽  
Switching Devices

Abstract As the physical size of semiconductor devices continues to be aggressively scaled down, feedback field-effect transistors (FBFET) with a positive feedback mechanism among a few promising steep switching devices have received attention as next-generation switching devices. Conventional FBFETs have been studied to explore their device performance. However, this has been restricted to the case of single FBFET; basic circuit designs with FBFETs have not been investigated extensively. In this work, we propose an inverter circuit design with silicon-on-insulator (SOI) FBFETs; we verified this inverter design with mixed-mode technology computer-aided design simulation. The basic principles and mechanisms for designing FBFET inverter circuits are explained because their configuration is different from conventional inverters. In addition, the device parameters necessary to optimize circuit construction are introduced for logic device applications.

scholarly journals YY1 is a cis-regulator in the organoid models of high mammographic density

2019 ◽  
Vol 36 (6) ◽  
pp. 1663-1667 ◽  
Author(s):  
Qingsu Cheng ◽  
Mina Khoshdeli ◽  
Bradley S Ferguson ◽  
Kosar Jabbari ◽  
Chongzhi Zang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Mammographic Density ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Human Mammary Epithelial Cell ◽  
Mammary Epithelial ◽  
Supplementary Information ◽  
Mrna Levels ◽  
High Mammographic Density

Abstract Motivation Our previous study has shown that ERBB2 is overexpressed in the organoid model of MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density (MD). We now aim to identify key transcription factors (TFs) and functional enhancers that regulate processes associated with increased stiffness of the microenvironment in the organoid models of premalignant human mammary cell lines. Results 3D colony organizations and the cis-regulatory networks of two human mammary epithelial cell lines (184A1 and MCF10A) are investigated as a function of the increased stiffness of the microenvironment within the range of MD. The 3D colonies are imaged using confocal microscopy, and the morphometries of colony organizations and heterogeneity are quantified as a function of the stiffness of the microenvironment using BioSig3D. In a surrogate assay, colony organizations are profiled by transcriptomics. Transcriptome data are enriched by correlative analysis with the computed morphometric indices. Next, a subset of enriched data are processed against publicly available ChIP-Seq data using Model-based Analysis of Regulation of Gene Expression to predict regulatory transcription factors. This integrative analysis of morphometric and transcriptomic data predicted YY1 as one of the cis-regulators in both cell lines as a result of the increased stiffness of the microenvironment. Subsequent experiments validated that YY1 is expressed at protein and mRNA levels for MCF10A and 184A1, respectively. Also, there is a causal relationship between activation of YY1 and ERBB2 when YY1 is overexpressed at the protein level in MCF10A. Supplementary information Supplementary data are available at Bioinformatics online.

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