Mechanobiology in Medicine最新文献

{"title":"Matrix stiffness and viscoelasticity influence human mesenchymal stem cell immunomodulation","authors":"Sara J. Olsen ,&nbsp;Rose E. Leader ,&nbsp;Abigail L. Mortimer ,&nbsp;Bethany Almeida","doi":"10.1016/j.mbm.2024.100111","DOIUrl":"10.1016/j.mbm.2024.100111","url":null,"abstract":"<div><div>Human mesenchymal stem cells (hMSCs) have immense wound healing potential due to their immunomodulatory behavior. To control this behavior and reduce heterogeneity, researchers look to biomaterials, as matrix stiffness and viscoelasticity have been shown to control hMSC immunomodulation. However, the understanding of the effects of these biophysical cues on hMSC immunomodulation remains limited; a broad study investigating the potentially synergistic effects of matrix stiffness and viscoelasticity on hMSC immunomodulation is needed in order to support future work developing biomaterials for hMSC wound healing applications. We developed polyacrylamide (PAAm) gels with varying matrix stiffnesses with or without a viscoelastic element and explored the effects of these on hMSC-matrix interactions and immunomodulatory cytokine expression in both a normal growth media and an immunomodulatory growth media mimetic of a chronic, non-healing wound. Expression of IL-10, VEGF, and PGE₂ were upregulated in immunomodulatory growth media over normal growth media, demonstrating the synergistic effects of biochemical signaling on hMSC immunomodulatory behavior. In addition, the addition of a viscoelastic element had both inhibitory and accentuating effects based on the cytokine and biochemical signaling in the cell culture media. Overall, this study provides a broad perspective on the immunomodulatory behavior of hMSCs due to stiffness and viscoelasticity.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100111"},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143165418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The first embryo, the origin of cancer and animal phylogeny. V. Cancer stem cells as the unifying biomechanical principle between embryology and oncology","authors":"Jaime Cofre","doi":"10.1016/j.mbm.2024.100110","DOIUrl":"10.1016/j.mbm.2024.100110","url":null,"abstract":"<div><div>The role of embryology in metazoan evolution is rooted deeply in the history of science. Viewing Neoplasia as an evolutionary engine provides a scientific basis for reexamining the disease cancer. Once the embryo is understood as a benign tumor with a pivotal role in the evolution of all animal forms, there will be an immediate paradigm shift in the search for cancer cure, potentially revealing insights that may be buried within the great developmental transitions of metazoans. This article discusses one of the unifying principles between embryology and oncology, namely cancer stem cells. Some considerations are also provided on the central role of physics and biomechanics in the assembly of the first embryo, which can be regarded as a differentiated benign tumor. Mechanical impregnation of the nucleus of a stem cell, culminating in a totipotent/multipotent cell, was a major event safeguarding the success of embryogenesis throughout evolution. Germ cells in the earliest ctenophore embryos underwent delayed differentiation, subsequent to the mechanical assembly of the embryo. Finally, a discussion is presented on the concept that cancer and embryogenesis (cancer and healthy stem cells) are two sides of the same coin, that is, of the same process. The only difference is that cancer stem cells reveal themselves in inappropriate contexts. Neoplasia is a free force, whereas cancer is a force contained by animal organization.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100110"},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143165420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing mechanobiology to enhance cell therapy","authors":"Peixiang Ma ,&nbsp;An Qin ,&nbsp;Tobias Winkler ,&nbsp;Jie Zhao","doi":"10.1016/j.mbm.2024.100102","DOIUrl":"10.1016/j.mbm.2024.100102","url":null,"abstract":"<div><div>Recent developments in cell therapy have revolutionized medical treatment. While various methods of stimulation have been explored, the role of mechanical force has often been overlooked. Although mechanical loading is not easily visible, it can actively reshape organisms, and abnormal mechanical loading can lead to injury and disease. By leveraging the mechanobiology of cells, we can equip them with synthetic mechanosensors that can redirect genetic circuits to express protective factors, such as antibodies and cytokines, according to the mechanical force signal. The advancement of artificial intelligence (AI) presents a fascinating opportunity to redesign more complex mechanoreceptors, allowing cells to respond to intricate stimuli. Additionally, genetic engineering tools like CRISPR-Cas9, base editing, and prime editing enable the creation of multiple gene circuits for cells to react to complex mechanical environments. Advanced mechanical loading techniques, such as focused ultrasound, deliver signals in a confined spatial and temporal manner. Therefore, harnessing mechanobiology in cells can develop more flexible, personalized, and precise cell therapies.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"2 4","pages":"Article 100102"},"PeriodicalIF":0.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142723640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miRNA in mechanobiology: The exploration needs to continue","authors":"Kai Huang,&nbsp;Yingxin Qi","doi":"10.1016/j.mbm.2024.100101","DOIUrl":"10.1016/j.mbm.2024.100101","url":null,"abstract":"<div><div>The 2024 Nobel Prize in Physiology or Medicine has once again sparked considerable interest in microRNA (miRNA). Recent advances have unveiled that miRNAs play critical roles in mediating the effects of mechanical stimuli on gene expression, cellular functions, tissue development, and disease progression. This perspective summarized the history of miRNA research and highlighted the promising research directions of miRNAs in the field of mechanobiology.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"2 4","pages":"Article 100101"},"PeriodicalIF":0.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanobiological cues to bone cells during early metastasis drive later osteolysis: A computational mechanoregulation framework prediction","authors":"Anneke S.K. Verbruggen ,&nbsp;Elan C. McCarthy ,&nbsp;Roisin M. Dwyer ,&nbsp;Laoise M. McNamara","doi":"10.1016/j.mbm.2024.100100","DOIUrl":"10.1016/j.mbm.2024.100100","url":null,"abstract":"<div><div>Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100100"},"PeriodicalIF":0.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143165419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotransductive N-cadherin binding induces differentiation in human neural stem cells","authors":"McKay Cavanaugh ,&nbsp;Rebecca Kuntz Willits","doi":"10.1016/j.mbm.2024.100099","DOIUrl":"10.1016/j.mbm.2024.100099","url":null,"abstract":"<div><div>The neural stem cell niche is a complex microenvironment that includes cellular factors, secreted factors, and physical factors that impact stem cell behavior and development. Cellular interactions through cadherins, cell–cell binding proteins, have implications in embryonic development and mesenchymal stem cell differentiation. However, little is known about the influence of cadherins within the neural stem cell microenvironment and their effect on human stem cell maintenance and differentiation. Therefore, the purpose of this study was to develop synthetic substrates to examine the effect of cadherin mechanotransduction on human neural stem cells. Glass substrates were fabricated using silane, protein A, and recombinant N-cadherin; we used these substrates to examine the effect of N-cadherin binding on neural stem cell proliferation, cytoskeletal structure and morphology, Yes-associated protein-1 (YAP) translocation, and differentiation. Bound exogenous N-cadherin induced concentration-dependent increases in adherens junction formation, YAP translocation, and early expression of neurogenic differentiation markers. Strong F-actin ring structures were initiated by homophilic N-cadherin binding, eliciting neuronal differentiation of cells within 96 ​h without added soluble differentiation factors. Our findings show that active N-cadherin binding plays an important role for differentiation of human iPS-derived neural stem cells towards neurons, providing a new tool to differentiate cells <em>in vitro</em>.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100099"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142534812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between bilateral symmetry of foot posture and lower limb musculoskeletal injuries among workers engaged in physically demanding occupations: A cross-sectional investigation","authors":"Chunhua Liao ,&nbsp;Jing Liu ,&nbsp;Shuanglong Hou ,&nbsp;Wendong Zhang ,&nbsp;Xin Zhao ,&nbsp;Zhipan Hou ,&nbsp;Honglei Quan ,&nbsp;Zhaohui Tian ,&nbsp;Rui Liu ,&nbsp;Yuting Zhao","doi":"10.1016/j.mbm.2024.100098","DOIUrl":"10.1016/j.mbm.2024.100098","url":null,"abstract":"<div><div>Even though the link between foot posture and lower-extremity injuries remains controversial, there has been little research focus on bilateral foot symmetry. This study evaluated the correlation between bilateral symmetry in foot posture and lower extremity musculoskeletal injuries among workers in physically intensive occupations. A total of 248 participants with physically demanding roles were enrolled. Historical data on lower-limb musculoskeletal injuries were obtained through a review of medical records, supplemented by results from on-site consultations. The foot arch index (AI) was quantitatively measured using a 3D laser foot scanner, and foot posture was evaluated using the foot posture index-6 (FPI-6). The participants were categorized into subgroups based on bilateral symmetry assessments of their feet. Logistic regression analyses were performed for statistical comparisons after adjusting for potential confounding factors. The results indicate that abnormalities in foot posture and arch, assessed using the FPI-6 and AI, were identified in 42.3 ​% and 47.2 ​% of participants, respectively, with 20.9 ​% and 16.5 ​% demonstrating bilateral asymmetry in these parameters. When comparing bilateral and unilateral foot protonation with bilaterally normal feet, the risk adjustments revealed differences of 2.274 (95 ​% CI: 1.094–4.729, <em>P</em> ​= ​0.028) and 2.751 (95 ​% CI: 1.222–6.191, <em>P</em> ​= ​0.015), respectively. Furthermore, the risk adjustment for age, BMI, smoking status, physical training years, training time, training frequency, warm-up before training, relaxation after training, MIS prevention, and treatment learning for unilateral flatfoot relative to bilateral normal feet was 3.197 (95 ​% CI:1.235–8.279, <em>P</em> ​= ​0.017). This study demonstrates that workers in physically demanding occupations who exhibit unilateral foot protonation or unilateral flatfoot are at an increased risk of lower-extremity musculoskeletal injuries.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100098"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142534805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased deformations are dispensable for encapsulated cell mechanoresponse in engineered bone analogs mimicking aging bone marrow","authors":"Alexander M. Regner ,&nbsp;Maximilien DeLeon ,&nbsp;Kalin D. Gibbons ,&nbsp;Sean Howard ,&nbsp;Derek Q. Nesbitt ,&nbsp;Seyedeh F. Darghiasi ,&nbsp;Anamaria G. Zavala ,&nbsp;Trevor J. Lujan ,&nbsp;Clare K. Fitzpatrick ,&nbsp;Mary C. Farach-Carson ,&nbsp;Danielle Wu ,&nbsp;Gunes Uzer","doi":"10.1016/j.mbm.2024.100097","DOIUrl":"10.1016/j.mbm.2024.100097","url":null,"abstract":"<div><div>Aged individuals and astronauts experience bone loss despite rigorous physical activity. Bone mechanoresponse is in-part regulated by mesenchymal stem cells (MSCs) that respond to mechanical stimuli. Direct delivery of low intensity vibration (LIV) recovers MSC proliferation in senescence and simulated microgravity models, indicating that age-related reductions in mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse. To answer this question, we developed a 3D bone marrow analog that controls trabecular geometry, marrow mechanics and external stimuli. Validated finite element (FE) models were developed to quantify strain environment within hydrogels during LIV. Bone marrow analogs with gyroid-based trabeculae of scaffold volume fractions (SV/TV) corresponding to adult (25 ​%) and aged (13 ​%) mice were printed using polylactic acid (PLA). MSCs encapsulated in migration-permissive hydrogels within printed trabeculae showed robust cell populations on both PLA surface and hydrogel within a week. Following 14 days of LIV treatment (1 ​g, 100 ​Hz, 1 ​h/day), cell proliferation, type-I collagen (Collagen-I) and filamentous actin (F-actin) were quantified for the cells in the hydrogel fraction. While LIV increased all measured outcomes, FE models predicted higher von Mises strains for the 13 ​% SV/TV groups (0.2 ​%) when compared to the 25 ​% SV/TV group (0.1 ​%). While LIV increased collagen-I volume 34 ​% more in 13 ​% SV/TV groups when compared to 25 ​% SV/TV groups, collagen-I and F-actin measures remained lower in the 13 ​% SV/TV groups when compared to 25 ​% SV/TV counterparts, indicating that both LIV-induced strains and scaffold volume fraction (i.e. available scaffold surface) affect cell behavior in the hydrogel phase. Overall, bone marrow analogs offer a robust and repeatable platform to study bone mechanobiology.</div></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"3 1","pages":"Article 100097"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142534799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strain and hyaluronic acid interact to regulate ovarian cancer cell proliferation, migration, and drug resistance","authors":"Maranda Kramer ,&nbsp;Allyson Criswell ,&nbsp;Kamari Marzette ,&nbsp;Emerson Cutcliffe ,&nbsp;Mary Kathryn Sewell-Loftin","doi":"10.1016/j.mbm.2024.100094","DOIUrl":"10.1016/j.mbm.2024.100094","url":null,"abstract":"<div><p>The ovarian tumor microenvironment plays a critical yet is poorly understood role in the regulation of cancer cell behaviors including proliferation, migration, and response to chemotherapy treatments. Ovarian cancer is the deadliest gynecological cancer, due to diagnosis at late stages of the disease and increased resistance to chemotherapies for recurrent disease. Understanding how the tumor microenvironment (TME) interacts with biomechanical forces to drive changes to ovarian cancer cell behaviors could elucidate novel treatment strategies for this patient population. Additionally, limitations in current preclinical models of the ovarian TME do not permit investigation of crosstalk between signaling pathways and mechanical forces. Our study focused on uncovering how strains and hyaluronic acid (HA) interact to signal through the CD44 receptor to alter ovarian cancer cell growth, migration, and response to a commonly used chemotherapy, paclitaxel. Using an advanced 3D <em>in vitro</em> model, we were able to identify how interactions of strain and HA as in the TME synergistically drive enhanced proliferation and migration in an ovarian tumor model line, while decreasing response to paclitaxel treatment. This study demonstrates the importance of elucidating how the mechanical forces present in the ovarian TME drive disease progression and response to treatment.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"2 4","pages":"Article 100094"},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000573/pdfft?md5=bf83a1132a805e7989290d565149d346&pid=1-s2.0-S2949907024000573-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair","authors":"David Gothard ,&nbsp;Michael Rotherham ,&nbsp;Emma L. Smith ,&nbsp;Janos M. Kanczler ,&nbsp;James Henstock ,&nbsp;Julia A. Wells ,&nbsp;Carol A. Roberts ,&nbsp;Omar Qutachi ,&nbsp;Heather Peto ,&nbsp;Hassan Rashidi ,&nbsp;Luis Rojo ,&nbsp;Lisa J. White ,&nbsp;Molly M. Stevens ,&nbsp;Alicia J. El Haj ,&nbsp;Felicity R.A.J. Rose ,&nbsp;Richard O.C. Oreffo","doi":"10.1016/j.mbm.2024.100096","DOIUrl":"10.1016/j.mbm.2024.100096","url":null,"abstract":"<div><p>Bone tissue engineering requires a combination of materials, cells, growth factors and mechanical cues to recapitulate bone formation. In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction. Hybrid hydrogels consisting of alginate and decellularized, demineralised bone extracellular matrix (ALG/ECM) were seeded with Stro-1+ human bone marrow stromal cells (HBMSCs). Dual combinations of growth factors within staged-release polylactic-co-glycolic acid (PLGA) microparticles were added to hydrogels to mimic, in part, the signalling events in bone regeneration: VEGF, TGF-β_3, PTHrP (fast release), or BMP-2, vitamin D₃ (slow release). Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles (MNP) targeted to TREK1 ion channels. Hybrid hydrogels were implanted subcutaneously within mice for 28 days, and evaluated for bone formation using micro-CT and histology. Control hydrogels lacking HBMSCs, growth factors, or MNP became mineralised, and neither growth factors, HBMSCs, nor mechanotransduction increased bone formation. However, structural differences in the newly-formed bone were influenced by growth factors. Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD₃ increased bone formation. However, fast-release of TGF-β₃ and VEGF resulted in thin trabeculae. Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD₃. Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure. This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":"2 4","pages":"Article 100096"},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000597/pdfft?md5=c4df681df7c8d540057e5c6a0cc4449b&pid=1-s2.0-S2949907024000597-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142150304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}