Extracellular vesicle最新文献

{"title":"Extracellular vesicle-based drug delivery systems in cancer","authors":"Ruotong Huang ,&nbsp;Jiajun Zhu ,&nbsp;Ru Fan ,&nbsp;Yiting Tang ,&nbsp;Lianlong Hu ,&nbsp;HaeJu Lee ,&nbsp;Shuying Chen","doi":"10.1016/j.vesic.2024.100053","DOIUrl":"10.1016/j.vesic.2024.100053","url":null,"abstract":"<div><div>Extracellular vesicles are lipid bilayer-enclosed extracellular membrane vesicles secreted from cells that have gradually shown promise in cancer treatment. As an essential intercellular communication mediator, extracellular vesicles carry bioactive molecules including proteins, lipids, and nucleic acids, which aid in the control and reprogramming of cell signals and ultimately accelerate the spread of cancer. Simultaneously, extracellular vesicles have become a highly desirable option for drug delivery carriers because of the special capacity to cross boundaries and low immunogenicity. Bypassing the endosomal pathway and lysosomal degradation, they can provide medications directly, increasing their effectiveness and decreasing their negative effects. We review the extracellular vesicles’ development, drug loading techniques, and discuss their potential in clinical applications to provide new avenues for precise and targeted treatment strategies. Additionally, engineering modifications of extracellular vesicles can enhance their ability to target specific cells, improving the stability and effectiveness of cargoes, further driving the development of cancer therapy. In this review, we particularly highlight new therapeutic applications of extracellular vesicles, including the latest progress in extracellular vesicle vaccines in tumors. Nonetheless, there are still a lot of obstacles to be overcome before extracellular vesicles may be used to treat cancer. Future research needs to focus on the characteristics of extracellular vesicles from various sources and explore their specific roles in disease treatment to fully leverage the potential of extracellular vesicles in clinical applications such as drug delivery.</div></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100053"},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142424308","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":"Ultrasonication outperforms electroporation for extracellular vesicle cargo depletion","authors":"Yundi Chen ,&nbsp;Le Wang ,&nbsp;Xu Yu ,&nbsp;Wenjun Mao ,&nbsp;Yuan Wan","doi":"10.1016/j.vesic.2024.100052","DOIUrl":"10.1016/j.vesic.2024.100052","url":null,"abstract":"<div><div>Extracellular vesicles (EVs), submicron-sized membranous structures released by cells, serve as vehicles of tissue-specific proteins and nucleic acids, facilitating intercellular communication and playing roles in pathophysiological processes. Leveraging their unique characteristics, EVs have emerged as promising drug delivery nanocarriers. Electroporation (EP) and ultrasonication (US) are among the prevalent techniques used for loading exogenous drugs into EVs owing to their simplicity and efficiency. However, the effectiveness of the two methods in depleting initial EV cargo has been overlooked. But this information is indispensable, as the bioactive residuals of EVs, notably derived from tumor or stem donor cells, may impact downstream therapeutic effects. Bridging this knowledge gap, therefore, can guide the selection of optimal drugs and loading methods tailored to therapeutic objectives. Here, we used high-throughput sequencing to investigate the protein and small RNA cargo of EVs treated with EP and US, respectively. We found that US exhibits higher efficacy in depleting EV cargo compared to EP, while US may also deplete essential endogenous molecules for combination therapy. Neither method demonstrated significant selectivity in cargo depletion, but they might preferentially retain few specific molecules. Additionally, membrane proteins are more prone to loss during US and EP treatments than cytoplasmic proteins.</div></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100052"},"PeriodicalIF":0.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142424307","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":"A bibliometric analysis of extracellular vesicles as drug delivery vehicles in disease treatment (2010–2024)","authors":"Wuli Guo ,&nbsp;Qi Shu ,&nbsp;Lina Gao,&nbsp;Na Gao,&nbsp;Zhen Wang,&nbsp;Wenjing Wei,&nbsp;Yuhan Zhang,&nbsp;Ting Huyan,&nbsp;Qi Li","doi":"10.1016/j.vesic.2024.100051","DOIUrl":"10.1016/j.vesic.2024.100051","url":null,"abstract":"<div><div>To comprehensively summarize the progress of utilizing extracellular vesicles (EVs) as drug delivery vehicles in disease treatment, bibliometric and visualization tools were employed to analyze and exhibit the key information from 6515 literatures that collected by searching “drug delivery” and “extracellular vesicles”, as well as “drug delivery” and “exosomes” as the keywords in Web of Science Core Collection. The obtained articles are from 90 countries/regions, 3343 institutions, 17,989 authors, and 591 journals. Among them, the “nanoparticles”, “cancer” and “biomarkers” are the keywords with the highest frequency. According to experimental articles, EVs are mainly used in the treatment of cancer as drug vehicles.</div></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100051"},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318709","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":"Accelerating extracellular vesicle research and biotechnological applications using synthetic biology approaches","authors":"Richard J.R. Kelwick ,&nbsp;Alexander J. Webb ,&nbsp;Paul S. Freemont","doi":"10.1016/j.vesic.2024.100050","DOIUrl":"10.1016/j.vesic.2024.100050","url":null,"abstract":"<div><p>Can a combination of the extracellular vesicle (EV) research community’s latest consensus guidance (MISEV2023) along with synthetic biology’s engineering approaches and responsible innovation framework help to accelerate future EV-based industrial and medical applications?</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100050"},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000179/pdfft?md5=720e1cb2e048bcb19c26bb9c90ec5840&pid=1-s2.0-S2773041724000179-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142238163","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":"Role of Extracellular vesicle microRNAs and RNA binding proteins on glioblastoma dynamics and therapeutics development","authors":"Shilpi Singh ,&nbsp;Clark C. Chen ,&nbsp;Stefan Kim ,&nbsp;Amar Singh ,&nbsp;Gatikrushna Singh","doi":"10.1016/j.vesic.2024.100049","DOIUrl":"10.1016/j.vesic.2024.100049","url":null,"abstract":"<div><p>The intricate interplay between extracellular vesicles (EVs), microRNAs, and RNA binding proteins (RBPs) constitutes a crucial mechanism in glioblastoma pathogenesis. The regulated sorting of microRNAs into EVs, influenced by RBPs and specific RNA motifs, plays a pivotal role in intercellular communication and significantly impacts various biological processes associated with glioblastoma development. Glioblastoma cells exploit this mechanism to exchange genetic information, influencing tumor progression, heterogeneity, and treatment response. This review highlights the dysregulation of EV-encapsulated microRNAs as a modulator of key signaling the disease. The versatile role of EV-microRNAs extends to impacting glioma behavior, immune response, angiogenesis, and serving as valuable diagnostic, prognostic, and therapeutic targets. Furthermore, the involvement of RBPs in microRNA sorting into EVs presents therapeutic targets that bridge cellular signaling with EV cargo composition. This comprehensive understanding and the strategic approaches targeting the complex interactions within the EV-microRNA-RBP axis opens promising avenues for advancing diagnostics and developing targeted therapies against the heterogeneous nature of glioblastoma and enhance treatment efficacy. The personalized and effective treatment strategies that may emerge from this research have the potential to revolutionize the approach to combating this devastating brain cancer.</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100049"},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000167/pdfft?md5=65f1184d771358a37b490b40b3ddee79&pid=1-s2.0-S2773041724000167-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161956","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":"An extracellular vesicle based hypothesis for the genesis of the polycystic kidney diseases","authors":"Marie C. Hogan ,&nbsp;Christopher J. Ward","doi":"10.1016/j.vesic.2024.100048","DOIUrl":"10.1016/j.vesic.2024.100048","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Autosomal dominant polycystic kidney (ADPKD) disease is the commonest genetic cause of kidney failure (affecting 1:800 individuals) and is due to heterozygous germline mutations in either of two genes, &lt;em&gt;PKD1&lt;/em&gt; and &lt;em&gt;PKD2&lt;/em&gt;. Homozygous germline mutations in &lt;em&gt;PKHD1&lt;/em&gt; are responsible for autosomal recessive polycystic kidney (ARPKD) disease a rare (1:20,000) but severe neonatal disease. The products of these three genes, &lt;em&gt;PKD1&lt;/em&gt; (polycystin-1 (PC1 4302(3)aa)), &lt;em&gt;PKD2&lt;/em&gt; (polycystin-2 (PC2 968aa)) and &lt;em&gt;PKHD1&lt;/em&gt; (fibrocystin (4074aa)) are all present on extracellular vesicles (EVs) termed, PKD-exosome-like vesicles (PKD-ELVs). PKD-ELVs are defined as 100&lt;!--&gt; &lt;!--&gt;nm PC1/PC2/CD133 and fibrocystin positive EVs which are shed into the urine from the apical plasma membrane of proximal tubule (PT) cells. PKD-ELVs are therefore ectosomes and are distinct from classical exosomes from the multivesicular body. PC1, PC2, fibrocystin and exosomal polycystin-1 interacting protein (EPIC, CU062) form a higher order ion channel complex termed the polycystin complex (PCC) on the surface of the PKD-ELV. We hypothesize that the PCC is involved in the generation of the PKD-ELV and is a structural component thereof. The PCC has also been detected on the primary cilium, a hair like 9+0 microtubule based structure present on all cells except hepatocytes. In kidney epithelial cells, the primary cilium protrudes into the lumen of the tubule where it regulates planar cell polarity (PCP) and tubule lumen diameter. Here we present a theory that explains the presence of the PCC on PKD-ELVs and primary cilia as well as other cryptic aspects of ADPKD and ARPKD. We suggest that the fundamental role of the PCC is to assemble PKD-ELVs on the plasma membrane and then shed them into the extracellular space or the lumen of the tubule. The resultant PKD-ELVs can have multiple functions in different biological contexts. One of the roles of the resultant PKD-ELVs is to generate a planar cell polarity (PCP) signaling gradient along kidney tubules in developing or regenerating kidney. This is mediated via an adhesion event between the PKD-ELV and primary cilium. Defects in the primary cilium or PKD-ELV assembly lead to cystogenesis, the major feature of ADPKD. The other important role for the PCC dependent PKD-ELV is the detection, packaging and extrusion of defective mitochondria. The PKD-ELV is also critical in the transfer of mRNA and miRNAs between cells and as a vector for extracellular proteinases and hyaluronidases involved in tissue remodeling. A PKD-ELV centric view of polycystic disease (EV theory) can explain the requirement for primary cilium function in ADPKD (where the primary cilium is the PKD-ELV receptor), the observation of defective mitochondria in the disease, the abnormalities detected in the extracellular matrix (ECM) as well as the resistance to carcinoma noted in ADPKD patients and individuals carrying &lt;em&gt;PKHD1&lt;/em&gt; mutations,","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100048"},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000155/pdfft?md5=48b923544849d6c3c1821ca5848edc6c&pid=1-s2.0-S2773041724000155-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141954453","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":"Artificially engineered vesicular vehicles for targeted therapy","authors":"Zhigang Wang ,&nbsp;Yufei Yan ,&nbsp;Rui Li,&nbsp;Ying Zhu,&nbsp;Gen Yang","doi":"10.1016/j.vesic.2024.100047","DOIUrl":"10.1016/j.vesic.2024.100047","url":null,"abstract":"<div><p>Vesicular vehicles have been one of the most potential platforms for therapeutic delivery. Here, we commentate on recent advances in the development of therapeutic vesicular delivery platforms, emphasizing two intriguing works, namely, the chimeric nanobody-decorated immunoliposomes (Wan et al.) and the retrovirus-like capsids incorporated extracellular vesicles (Jiang et al.). In the work of Wan et al., the researchers proposed a novel strategy for antitumor immunoliposome construction by the one-step self-assembly of lipids with rationally designed chimeric nanobody that comprises a nanobody against human epidermal growth factor receptor 2, a flexible peptide linker, and a human single transmembrane domain. By leveraging the natural cell systems (e.g., <em>E coli.</em>) to synthesize the chimeric nanobody, this technique provides a facile and robust strategy for producing immunoliposome platforms, ensuring suitability for industrial manufacturing and distribution, regulatory compliance, and clinical use. In the work of Jiang et al., taking advantage of the natural extracellular vesicle biogenesis system, the researchers introduced the activity-regulated cytoskeleton-associated protein inside the vesicle lumen and thus constructed endogenous retrovirus-like vesicles for mRNA drug delivery to neurons. This technique offers a significative strategy for developing sophisticated delivery platforms, manifesting broad application potential for different disease therapeutics. Overall, these two works have represented two typical paradigms for the artificial construction of vesicular vesicles. Considering their complementary merits, in the future, the integration of artificial engineering technologies and natural biosynthesis systems is anticipated to be a promising strategy to expedite the development of potent delivery systems.</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100047"},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000143/pdfft?md5=892695f80d592b8b035d791f34e79689&pid=1-s2.0-S2773041724000143-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141960705","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":"Stem cell-derived exosomes prevent the development of thoracic aortic aneurysm/dissection by inhibiting AIM2 inflammasome and pyroptosis","authors":"Lin Lu ,&nbsp;Feng Liu ,&nbsp;Weiliang Wu ,&nbsp;Yu Zhang ,&nbsp;Bin Liu ,&nbsp;Qingfang Han ,&nbsp;Tonggan Lu ,&nbsp;Huiling Zhang ,&nbsp;Xi-yong Yu ,&nbsp;Yangxin Li","doi":"10.1016/j.vesic.2024.100046","DOIUrl":"https://doi.org/10.1016/j.vesic.2024.100046","url":null,"abstract":"<div><p>Thoracic aortic aneurysm/dissection (TAAD) is a severe vascular condition associated with life-threatening complications, and its underlying molecular mechanisms remain largely unexplored. Previous research indicates that the aberrant activation of cytosolic DNA and its receptors plays a crucial role in vascular inflammation and dysfunction. Specifically, Absent in Melanoma 2 (AIM2), an intracellular DNA receptor, can trigger the inflammasome pathway, leading to extracellular matrix destruction. In this investigation, we delved into the mechanism underlying AIM2 activation in TAAD development and explored the potential of exosomes to impede TAAD progression by suppressing AIM2 expression. Our findings revealed that heightened AIM2 expression and activation contribute to TAAD development by fostering vascular inflammation and disrupting vascular homeostasis. Activated AIM2 induces pyroptosis through the recruitment of the deubiquitination enzyme USP21, which stabilizes AIM2 by reducing its ubiquitination and degradation. Moreover, we demonstrated that exosome-derived miR-485-5p exerts an anti-inflammatory and protective effect on the thoracic aorta by inhibiting AIM2 activation. This study introduces novel perspectives for the treatment of TAAD.</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100046"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000131/pdfft?md5=8a900f4bbb54766ace6f15d1f225c232&pid=1-s2.0-S2773041724000131-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141484849","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":"Therapeutic potential of human stem cell-derived extracellular vesicles in idiopathic pulmonary fibrosis","authors":"Kyoung Soo Lee ,&nbsp;Seung Ho Yeom ,&nbsp;Min Kang Kim ,&nbsp;Chang Hee Woo ,&nbsp;Young Chan Choi ,&nbsp;Ji Suk Choi ,&nbsp;Yong Woo Cho","doi":"10.1016/j.vesic.2024.100045","DOIUrl":"https://doi.org/10.1016/j.vesic.2024.100045","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a lethal and chronic lung disease that occurs due to persistent epithelial cell injury and abnormal extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been proposed as a potential therapeutic option of IPF because of their functions, such as anti-inflammation, anti-fibrosis, microenvironment regulation, and tissue repair. In this study, we investigated the therapeutic potential of human adipose-derived mesenchymal stem cell (AD-MSC) EVs in IPF model. AD-MSC EVs were isolated by a multi-filtration system based on the tangential flow filtration (TFF) and characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), flow cytometry analysis, zeta potential, and small RNA sequencing. <em>In vitro</em> analysis reveals that AD-MSC EVs treatments inhibited migration of pulmonary fibroblasts and myofibroblast differentiation through down regulation of fibrosis-associated TGF-β and WNT signaling. In addition, inhalation treatment of AD-MSC EVs significantly alleviated bleomycin (BLM)-induced pulmonary fibrosis. These results reveal that AD-MSC EVs are highly promising as a treatment option for pulmonary fibrosis.</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"4 ","pages":"Article 100045"},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S277304172400012X/pdfft?md5=d3ec1dc4b1a879c67ab2d843a901c474&pid=1-s2.0-S277304172400012X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141484868","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":"Host innate immune systems gather intel on invading microbes via pathogen-derived extracellular vesicles","authors":"Geneva N. Kwaku ,&nbsp;Rebecca A. Ward ,&nbsp;Jatin M. Vyas ,&nbsp;Hannah Brown Harding","doi":"10.1016/j.vesic.2024.100043","DOIUrl":"https://doi.org/10.1016/j.vesic.2024.100043","url":null,"abstract":"<div><p>Extracellular vesicles (EVs) are membrane-bound vesicles released into the extracellular milieu from various cell types including host cells and pathogens that infect them. As carriers of nucleic acids, proteins, lipids, metabolites, and virulence factors, EVs act as delivery vehicles for intercellular communication and quorum sensing. Innate immune cells have the capacity to intercept, internalize, and interpret ‘messages’ contained within these EVs. This review categorizes the ability of EVs secreted by bacterial, parasitic, and fungal pathogens to trigger both pro- and anti-inflammatory innate immune responses in the host. Understanding molecular pathways and inflammatory responses activated in innate immune cells upon pathogen-derived EV stimulation is critical to gain insight into potential therapeutics and combat these infectious diseases.</p></div>","PeriodicalId":73007,"journal":{"name":"Extracellular vesicle","volume":"3 ","pages":"Article 100043"},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2773041724000106/pdfft?md5=78b753990842574e97fefc41590a2b3c&pid=1-s2.0-S2773041724000106-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141066937","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}