Age‐associated reduction of cellular spreading/mechanical force up‐regulates matrix metalloproteinase‐1 expression and collagen fibril fragmentation via c‐Jun/ AP ‐1 in human dermal fibroblasts

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109644/1/acel12265.pd

The gradient projection algorithm with adaptive mutation step length for non-probabilistic reliability index

Ciljajući na probleme odabira parametra korak-veličina i prerane konvergencije koja se dogodila kod pretraživanja na lokalnom optimalnom području u dizajnu adaptivnog gradijenta projekcijskog algoritma u ovom radu, uspostavljena je strategija mehanizma prilagodljive varijable korak-veličina i mehanizma prilagodljive promjenljive varijable korak-veličina. Uvedene su u algoritam gradijenta projekcije i upotrebljene za reguliranje duljine koraka iteracije. Kroz primjere indeksa nevjerojatnosne pouzdanosti može se pokazati da se tom metodom može brzo i točno izračunati indeks pouzdanosti kad model ima višestruke varijable i složenu funkciju graničnog stanja. Kod komparacije i kontrastiranja ovog algoritma s algoritmom gradijenta projekcije, taj algoritam nije osjetljiv na položaj polazne točke. Tako on ne samo da uzima u obzir i lokalnu performansu i globalnu sposobnost pretraživanja već posjeduje i veliku brzinu konvergencije i visoku preciznost. Stoga je to učinkovit i praktičan algoritam optimizacije.Aiming at the problems of selection parameter step-size and premature convergence that occurred when searching the local area in the optimal design of adaptive gradient projection algorithm in this paper, adaptive variable step-size mechanism strategy and adaptive variable step-size mechanism were established. They were introduced into the gradient projection algorithm, and were used to control iteration step length. Through the examples of non-probabilistic reliability index, it can be showed that the method could quickly and accurately calculate the reliability index when the model had multiple variables and complex limit state function. To compare and contrast this algorithm with the simple gradient projection algorithm, this algorithm is not sensitive to the initial point position. And it not only takes into account both local performance and global search ability, but also has fast convergence speed and high precision. So it is an efficient and practical optimization algorithm

Optimal decisions of sharing rate and ticket price of different transportation modes in inter-city transportation corridor

Purpose: The paper concerns competition of different transportation modes coexist in intercity transportation corridor. The purpose of this paper is to express the competitive relationship by building mathematical model and obtain the best sharing rate and the optimal ticket price of different transportation modes. Design/methodology/approach: Firstly, analyzing influencing factors of passenger choice about transportation modes, we designed a utility function of transportation modes. Secondly, referring to the game theory and logit modle, a non-cooperative game model between railway and highway was built. Finally, the model was applied to Nanchang-Jiujiang transportation corridor in China for an empirical analysis. Findings: The results indicate that the proposed non-cooperative game model is rational and reliable, and it supplies a scientific method to determine the optimal ticket price and passenger sharing rate of different transportation modes, and can be applied to the competition study on different transportation modes in inter-city transportation corridor. Originality/value: The main contribution of this paper is to built the non-cooperative game model, which can consider the needs of different travelers, and achieve reasonable passenger divergence of different transportation modes and coordinated development of whole transport market.Peer Reviewe

Physical properties of the photodamaged human skin dermis: Rougher collagen surface and stiffer/harder mechanical properties

Fragmentation of collagen fibrils and aberrant elastic material (solar elastosis) in the dermal extracellular matrix (ECM) is among the most prominent features of photodamaged human skin. These alterations impair the structural integrity and create a dermal microenvironment prone to skin disorders. The objective of this study was to determine the physical properties (surface roughness, stiffness and hardness) of the dermal ECM in photodamaged and subject‐matched sun‐protected human skin. Skin samples were sectioned and analysed by histology, atomic force microscopy and nanoindentation. Dermal ECM collagen fibrils were more disorganized (ie, rougher surface), and the dermal ECM was stiffer and harder, in photodamaged forearm, compared to sun‐protected underarm skin. Cleavage of collagen fibrils in sun‐protected underarm dermis by recombinant human matrix metalloproteinase‐1 resulted in rougher collagen fibril surface and reduced dermal stiffness and hardness. Degradation of elastotic material in photodamaged skin by treatment with purified neutrophil elastase reduced stiffness and hardness, without altering collagen fibril surface roughness. Additionally, expression of two members of the lysyl oxidase gene family, which insert cross‐links that stiffen and harden collagen fibrils, was elevated in photodamaged forearm dermis. These data elucidate the contributions of fragmented collagen fibrils, solar elastosis and elevated collagen cross‐linking to the physical properties of the dermal ECM in photodamaged human skin. This new knowledge extends current understanding of the impact of photodamage on the dermal ECM microenvironment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150500/1/exd13728_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150500/2/exd13728.pd

YAP/TAZ regulates TGF-β/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibroblasts

Abstract Background Transcription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-β/Smad signaling pathway in human skin dermal fibroblasts. Methods YAP and TAZ levels in dermal fibroblasts were reduced in dermal fibroblasts by siRNA-mediated knockdown. The effects of YAP and TAZ reduction on TGF-β/Smad signaling were examined by quantitative real-time PCR, Western analysis, and immunostaining. Luciferase reporter assays and electrophoretic mobility shift assays were conducted to investigate the transcription factor DNA-binding and transcriptional activities. Results Knockdown of both YAP and TAZ (YAP/TAZ), but not either separately, impaired TGF-β1-induced Smad3 phosphorylation and Smad3 transcriptional activity, thereby inhibiting the expression of TGF-β target genes. This reduction by reduced levels of YAP/TAZ results from induction of inhibitory Smad7, which inhibits Smad3 phosphorylation and activity by TGF-β1. Conversely, prevention of Smad7 induction restores Smad3 phosphorylation and Smad3 transcriptional activity in fibroblasts that have reduced YAP/TAZ. In agreement with these findings, inhibition of YAP/TAZ transcriptional activity, similar to the reduction of YAP/TAZ levels, also significantly induced Smad7 and impaired TGF-β/Smad signaling. Further investigations revealed that reduced levels of YAP/TAZ led to induction of activator protein-1 (AP-1) activity, Activated AP-1 bound to DNA sequences in the Smad7 gene promoter, and deletion of these AP-1 binding sequences substantially reduced Smad7 promoter reporter activity. Conclusion YAP/TAZ functions in concert with transcription factor AP-1 and Smad7 to regulate TGF-β signaling, in human dermal fibroblasts. Reduction of YAP/TAZ levels leads to activation of AP-1 activity, which induces Smad7. Smad7 suppresses the TGF-β pathway.https://deepblue.lib.umich.edu/bitstream/2027.42/143193/1/12964_2018_Article_232.pd

Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis

Summary To defend against pulmonary infections, lung epithelial cells are equipped with complex innate immunity closely linked to inflammation. Dysregulated innate immunity / inflammation leads to self-perpetuating lung injury. The CpG motif in bacterial DNA is one of the factors involved in bacterial infection-associated inflammation. Bacterial DNA and synthetic CpG oligonucleotide (ODN) induced CCN1 secretion from lung epithelial cells, functioning as a potential “braking” signal to prevent uncontrolled inflammatory responses. CpG ODN-induced ER stress resulted in Src-Y527 phosphorylation (pY527) and Src/CCN1 vWF domain dissociation. Src-Y527 activated caveolin-1 (cav-1) phosphorylation at Y14 and then modulated CCN1 secretion via pCav-1 interaction with CCN1 IGFbp domain. Functionally, secreted CCN1 promoted anti-inflammatory cytokine IL-10 release from epithelial cells via integrin αVβ6 PKC, and this subsequently suppressed TNF-α, MIP-2 secretion and neutrophil infiltration in the lungs. Collectively, bacterial DNA/CpG ODN-stimulated CCN1 secretion via BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway and CpG-induced CCN1 conferred anti-inflammatory roles. Our studies suggested a novel paradigm by which the lung epithelium maintains innate immune homeostasis after bacterial infection

Dermal Fibroblast CCN1 Expression in Mice Recapitulates Human Skin Dermal Aging

The aging process deleteriously alters the structure and function of dermal collagen. These alterations result in thinning, fragility, wrinkles, laxity, impaired wound healing, and a microenvironment conducive to cancer. However, the key factors responsible for these changes have not been fully elucidated and relevant models for the study of skin aging progression are lacking. CCN1, a secreted extracellular matrix (ECM) associated matricellular protein, is elevated in dermal fibroblasts in aged human skin. Towards constructing a mouse model to study key factors involved in skin aging progression, we demonstrate that transgenic mice, with selective expression of CCN1 in dermal fibroblasts (COL1A2-CCN1), display accelerated skin dermal aging. The aged phenotype in COL1A2-CCN1 mice resembles aged human dermis: the skin is wrinkled, and the dermis is thin and composed of loose, disorganized, and fragmented collagen fibrils. These dermal alterations reflect reduced production of collagen due to impaired TGF-β signaling and increased expression of matrix metalloproteinases, driven up induction of c-Jun/AP-1. Importantly, similar mechanisms drive human dermal aging. Taken together, the data demonstrate that elevated expression of CCN1 by dermal fibroblasts functions as a key mediator of dermal aging. The COL1A2-CCN1 mouse model provides a novel tool for understanding and studying mechanisms of skin aging and age-related skin disorders

Expression of CCN family of genes in human skin in vivo and alterations by solar-simulated ultraviolet irradiation

The CCN family of proteins is involved in diverse biological functions such as cell growth, adhesion, migration, angiogenesis, and regulation of extracellular matrix. We have investigated expression of CCN family genes and alternations induced by solar-simulated ultraviolet irradiation in human skin in vivo. Transcripts of all six CCN genes were expressed in human skin in vivo. CCN5 was most abundantly expressed followed by CCN2>CCN3>CCN1>CCN4>CCN6. Solar-simulated ultraviolet irradiation increased mRNA expression of CCN1 and CCN2. In contrast, mRNA levels of CCN3, CCN4, CCN5, and CCN6, were reduced. Knowledge gained from this study provides the foundation to explore the functional roles of CCN gene products in cutaneous biology and responses to solar ultraviolet irradiation

Ecological risk assessment of geohazards in Natural World Heritage Sites: an empirical analysis of Bogda, Tianshan

Ecological risk assessment plays an important role in avoiding disasters and reducing losses. Natural world heritage site is the most precious natural assets on earth, yet few studies have assessed ecological risks from the perspective of world heritage conservation and management. A methodology for considering ecological threats and vulnerabilities and focusing on heritage value was introduced and discussed for the Bogda component of the Xinjiang Tianshan Natural World Heritage Site. Three important results are presented. (1) Criteria layers and ecological risk showed obvious spatial heterogeneity. Extremely high-risk and high-risk areas, accounting for 13.60% and 32.56%, respectively, were mainly gathered at Tianchi Lake and Bogda Glacier, whereas the extremely low-risk and low-risk areas, covering 1.33% and 17.51% of the site,were mainly distributed to the north and scattered around in the southwest montane region. (2) The level of risk was positively correlated with the type of risk, and as the level of risk increases, the types of risk increase. Only two risk types were observed in the extremely low-risk areas, whereas six risk types were observed in the high-risk areas and eight risk types were observed in the extremely high-risk areas. (3) From the perspective of risk probability and ecological damage, four risk management categories were proposed, and correlative strategies were proposed to reduce the possibility of ecological risk and to sustain or enhance heritage value

Optimal decisions of sharing rate and ticket price of different transportation modes in inter-city transportation corridor

Purpose: The paper concerns competition of different transportation modes coexist in intercity transportation corridor. The purpose of this paper is to express the competitive relationship by building mathematical model and obtain the best sharing rate and the optimal ticket price of different transportation modes. Design/methodology/approach: Firstly, analyzing influencing factors of passenger choice about transportation modes, we designed a utility function of transportation modes. Secondly, referring to the game theory and logit modle, a non-cooperative game model between railway and highway was built. Finally, the model was applied to Nanchang-Jiujiang transportation corridor in China for an empirical analysis. Findings: The results indicate that the proposed non-cooperative game model is rational and reliable, and it supplies a scientific method to determine the optimal ticket price and passenger sharing rate of different transportation modes, and can be applied to the competition study on different transportation modes in inter-city transportation corridor. Originality/value: The main contribution of this paper is to built the non-cooperative game model, which can consider the needs of different travelers, and achieve reasonable passenger divergence of different transportation modes and coordinated development of whole transport market