Integrative Biology最新文献

{"title":"Tumor-on-a-chip platform to interrogate the role of macrophages in tumor progression.","authors":"Ye Bi,&nbsp;Venktesh S Shirure,&nbsp;Ruiyang Liu,&nbsp;Cassandra Cunningham,&nbsp;Li Ding,&nbsp;J Mark Meacham,&nbsp;S Peter Goedegebuure,&nbsp;Steven C George,&nbsp;Ryan C Fields","doi":"10.1093/intbio/zyaa017","DOIUrl":"https://doi.org/10.1093/intbio/zyaa017","url":null,"abstract":"<p><p>Tumor-infiltrating leukocytes, in particular macrophages, play an important role in tumor behavior and clinical outcome. The spectrum of macrophage subtypes ranges from antitumor 'M1'-type to protumor 'M2'-type macrophages. Tumor-associated macrophages (TAMs) typically display phenotypic features of both M1 and M2, and the population distribution is thought to be dynamic and evolves as the tumor progresses. However, our understanding of how TAMs impact the tumor microenvironment remains limited by the lack of appropriate 3D in vitro models that can capture cell-cell dynamics at high spatial and temporal resolution. Using our recently developed microphysiological 'tumor-on-a-chip' (TOC) device, we present here our findings on the impact of defined macrophage subsets on tumor behavior. The TOC device design contains three adjacent and connected chambers in which both the upper and lower chambers are loaded with tumor cells, whereas the central chamber contains a dynamic, perfused, living microvascular network. Introduction of human pancreatic or colorectal cancer cells together with M1-polarized macrophages significantly inhibited tumor growth and tumor-induced angiogenesis. Protein analysis and antibody-based neutralization studies confirmed that these effects were mediated through production of C-X-C motif chemokines (CXCL9), CXCL10 and CXCL11. By contrast, M2-macrophages mediated increased tumor cell migration into the vascularized chamber and did not inhibit tumor growth or angiogenesis. In fact, single-cell RNA sequencing showed that M2 macrophages further segregated endothelial cells into two distinct subsets, corresponding to static cells in vessels versus active cells involved in angiogenesis. The impact of M2 macrophages was mediated mostly by production of matrix metalloproteinase 7 and angiopoietin 2. In summary, our data demonstrate the utility of the TOC device to mechanistically probe biological questions in a 3D in vitro microenvironment.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 9","pages":"221-232"},"PeriodicalIF":2.5,"publicationDate":"2020-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38380702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of BRCA1 RING domain variants: computationally derived structural data can improve upon experimental features for training predictive models.","authors":"Majid Masso","doi":"10.1093/intbio/zyaa019","DOIUrl":"https://doi.org/10.1093/intbio/zyaa019","url":null,"abstract":"<p><p>Advancements in the interpretation of variants of unknown significance are critical for improving clinical outcomes. In a recent study, massive parallel assays were used to experimentally quantify the effects of missense substitutions in the RING domain of BRCA1 on E3 ubiquitin ligase activity as well as BARD1 RING domain binding. These attributes were subsequently used for training a predictive model of homology-directed DNA repair levels for these BRCA1 variants relative to wild type, which is critical for tumor suppression. Here, relative structural changes characterizing BRCA1 variants were quantified by using an efficient and cost-free computational mutagenesis technique, and we show that these features lead to improvements in model performance. This work underscores the potential for bench researchers to gain valuable insights from computational tools, prior to implementing costly and time-consuming experiments.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 9","pages":"233-239"},"PeriodicalIF":2.5,"publicationDate":"2020-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38426639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical stretch sustains myofibroblast phenotype and function in microtissues through latent TGF-β1 activation.","authors":"Matthew Walker,&nbsp;Michel Godin,&nbsp;Andrew E Pelling","doi":"10.1093/intbio/zyaa015","DOIUrl":"https://doi.org/10.1093/intbio/zyaa015","url":null,"abstract":"<p><p>Developing methods to study tissue mechanics and myofibroblast activation may lead to new targets for therapeutic treatments that are urgently needed for fibrotic disease. Microtissue arrays are a promising approach to conduct relatively high-throughput research into fibrosis as they recapitulate key biomechanical aspects of the disease through a relevant 3D extracellular environment. In early work, our group developed a device called the MVAS-force to stretch microtissues while enabling simultaneous assessment of their dynamic mechanical behavior. Here, we investigated TGF-β1-induced fibroblast to myofibroblast differentiation in microtissue cultures using our MVAS-force device through assessing α-SMA expression, contractility and stiffness. In doing so, we linked cell-level phenotypic changes to functional changes that characterize the clinical manifestation of fibrotic disease. As expected, TGF-β1 treatment promoted a myofibroblastic phenotype and microtissues became stiffer and possessed increased contractility. These changes were partially reversible upon TGF-β1 withdrawal under a static condition, while, in contrast, long-term cyclic stretching maintained myofibroblast activation. This pro-fibrotic effect of mechanical stretching was absent when TGF-β1 receptors were inhibited. Furthermore, stretching promoted myofibroblast differentiation when microtissues were given latent TGF-β1. Altogether, these results suggest that external mechanical stretch may activate latent TGF-β1 and, accordingly, might be a powerful stimulus for continued myofibroblast activation to progress fibrosis. Further exploration of this pathway with our approach may yield new insights into myofibroblast activation and more effective therapeutic treatments for fibrosis.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 8","pages":"199-210"},"PeriodicalIF":2.5,"publicationDate":"2020-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38338866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-phenotypic and bi-directional behavioral screening of zebrafish larvae.","authors":"Arezoo Khalili,&nbsp;Ellen van Wijngaarden,&nbsp;Georg R Zoidl,&nbsp;Pouya Rezai","doi":"10.1093/intbio/zyaa016","DOIUrl":"https://doi.org/10.1093/intbio/zyaa016","url":null,"abstract":"<p><p>Multi-phenotypic screening of zebrafish larvae, such as monitoring the heart and tail activities, is important in biological assays. Microfluidic devices have been developed for zebrafish phenotypic assays, but simultaneous lateral-dorsal screening of the same larva in a single chip is yet to be achieved. We present a multi-phenotypic microfluidic device for monitoring of tail movement and heart rate (HR) of 5-7-day postfertilization zebrafish larvae. Tail movements were stimulated using electric current and quantified in terms of response duration (RD) and tail beat frequency (TBF). The positioning of a right-angle prism provided a lateral view of the larvae and enabled HR monitoring. Investigations were performed on zebrafish larvae exposed to 3% ethanol, 250 μM 6-hydroxydopamine (6-OHDA) or 1 mM levodopa. Larvae exposed to ethanol showed a significant drop in HR, whereas electric stimulation increased the HR temporarily. Larvae experienced a significant drop in RD, TBF and HR when exposed to 6-OHDA. HR was not affected by levodopa post-treatment, whereas RD and TBF were restored to normal levels. The results showed potential for applications that involve monitoring of cardiac and behavioral parameters in zebrafish larvae. Tests can be done using the same chip, without changing the larvae's orientation. This eliminates undue stress caused by reorientation, which may affect their behavior, and the use of separate devices to obtain dorsal and lateral views. The device can be implemented to improve multi-phenotypic and quantitative screening of zebrafish larvae in response to chemical and physical stimuli in different zebrafish disease models.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 8","pages":"211-220"},"PeriodicalIF":2.5,"publicationDate":"2020-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38338864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pirfenidone reduces immune-suppressive capacity of cancer-associated fibroblasts through targeting CCL17 and TNF-beta.","authors":"Hamidreza Aboulkheyr Es,&nbsp;Sareh Zhand,&nbsp;Jean Paul Thiery,&nbsp;Majid Ebrahimi Warkiani","doi":"10.1093/intbio/zyaa014","DOIUrl":"https://doi.org/10.1093/intbio/zyaa014","url":null,"abstract":"<p><p>Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in carcinoma cells. The cancer-associated fibroblasts (CAFs) play a crucial role in regulating and rewiring TME to enhance their immune suppressive function and to favor the invasion of the malignant cells. Tumor progression may be retarded by targeting CAFs in the TME. Various studies highlighted the ability of targeting CAF with pirfenidone (PFD), leading to increased efficacy of chemotherapy. However, its potential for the reduction of immune-suppression capacity of CAFs remains to be elusive. Here, we assessed the effect of PFD on the expression of PD-L1 on CAF cells. Besides migration inhibitory effects of PFD on CAFs, the expression level of PD-L1 reduced in CAFs after treatment with PFD. The downstream analysis of released cytokines from CAFs showed that PFD significantly dropped the secretion of CCL17 and TNF-β, where a positive association between PFD-targeted proteins and PD-L1 was observed. These data suggest that the treatment of CAF within TME through the PFD may reduce the acquisition of CAF-mediated invasive and immune-suppressive capacity of breast carcinoma cells.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 7","pages":"188-197"},"PeriodicalIF":2.5,"publicationDate":"2020-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38129796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connecting secretome to hematopoietic stem cell phenotype shifts in an engineered bone marrow niche.","authors":"Aidan E Gilchrist, Brendan A C Harley","doi":"10.1093/intbio/zyaa013","DOIUrl":"10.1093/intbio/zyaa013","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) primarily reside in the bone marrow, where they receive external cues from their local microenvironment. The complex milieu of biophysical cues, cellular components and cell-secreted factors regulates the process by which HSC produce the blood and immune system. We previously showed direct coculture of primary murine hematopoietic stem and progenitor cells with a population of marrow-derived mesenchymal stromal and progenitor cells (MSPCs) in a methacrylamide-functionalized gelatin (GelMA) hydrogel improves hematopoietic progenitor maintenance. However, the mechanism by which MSPCs influenced HSC fate decisions remained unknown. Herein, we report the use of proteomic analysis to correlate HSC phenotype to a broad candidate pool of 200 soluble factors produced by combined mesenchymal and hematopoietic progeny. Partial least squares regression (PLSR), along with an iterative filter method, identified TGFβ-1, MMP-3, c-RP and TROY as positively correlated with HSC maintenance. Experimentally, we then observe exogenous stimulation of HSC monocultures in GelMA hydrogels with these combined cytokines increases the ratio of hematopoietic progenitors to committed progeny after a 7-day culture 7.52 ± 3.65-fold compared to non-stimulated monocultures. Findings suggest a cocktail of the downselected cytokines amplifies hematopoietic maintenance potential of HSCs beyond that of MSPC-secreted factors alone. This work integrates empirical and computation methods to identify cytokine combinations to improve HSC maintenance within an engineered HSC niche, suggesting a route toward identifying feeder-free culture platforms for HSC expansion. Insight Hematopoietic stem cells within an artificial niche receive maintenance cues in the form of soluble factors from hematopoietic and mesenchymal progeny. Applying a proteomic regression analysis, we identify a reduced set of soluble factors correlated to maintenance of a hematopoietic phenotype during culture in a biomaterial model of the bone marrow niche. We identify a minimum factor cocktail that promotes hematopoietic maintenance potential in a gelatin-based culture, regardless of the presence of mesenchymal feeder cells. By combining empirical and computational methods, we report an experimentally feasible number of factors from a large dataset, enabling exogenous integration of soluble factors into an engineered hematopoietic stem cell for enhanced maintenance potential of a quiescent stem cell population.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 7","pages":"175-187"},"PeriodicalIF":2.5,"publicationDate":"2020-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384206/pdf/nihms-1611031.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38059890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance.","authors":"Mai T Ngo,&nbsp;Elijah Karvelis,&nbsp;Brendan A C Harley","doi":"10.1093/intbio/zyaa010","DOIUrl":"https://doi.org/10.1093/intbio/zyaa010","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche is largely unknown. Soluble angiocrine factors secreted by tumor-associated vasculature have been shown to support such behaviors in other cancer types. Here, we exploit macroscopic and microfluidic gelatin hydrogel platforms to profile angiocrine factors secreted by self-assembled endothelial networks and evaluate their relevance to glioblastoma biology. Aggregate angiocrine factors support increases in U87-MG cell number, migration, and therapeutic resistance to temozolomide. We also identify a novel role for TIMP1 in facilitating glioblastoma tumor cell migration. Overall, this work highlights the use of multidimensional hydrogel models to evaluate the role of angiocrine signals in glioblastoma progression.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 6","pages":"139-149"},"PeriodicalIF":2.5,"publicationDate":"2020-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38017862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic extracellular matrix stiffening induces a phenotypic transformation and a migratory shift in epithelial cells.","authors":"Shane C Allen,&nbsp;Jessica A Widman,&nbsp;Anisha Datta,&nbsp;Laura J Suggs","doi":"10.1093/intbio/zyaa012","DOIUrl":"https://doi.org/10.1093/intbio/zyaa012","url":null,"abstract":"<p><p>Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate-matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 6","pages":"161-174"},"PeriodicalIF":2.5,"publicationDate":"2020-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37988043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative fluorescence imaging of mitochondria in body wall muscles of Caenorhabditis elegans under hyperglycemic conditions using a microfluidic chip.","authors":"Samuel Sofela,&nbsp;Sarah Sahloul,&nbsp;Sukanta Bhattacharjee,&nbsp;Ambar Bose,&nbsp;Ushna Usman,&nbsp;Yong-Ak Song","doi":"10.1093/intbio/zyaa011","DOIUrl":"https://doi.org/10.1093/intbio/zyaa011","url":null,"abstract":"<p><p>Type 2 diabetes is the most common metabolic disease, and insulin resistance plays a role in the pathogenesis of the disease. Because completely functional mitochondria are necessary to obtain glucose-stimulated insulin from pancreatic beta cells, dysfunction of mitochondrial oxidative pathway could be involved in the development of diabetes. As a simple animal model, Caenorhabditis elegans renders itself to investigate such metabolic mechanisms because it possesses insulin/insulin-like growth factor-1 signaling pathway similar to that in humans. Currently, the widely spread agarose pad-based immobilization technique for fluorescence imaging of the mitochondria in C. elegans is laborious, batchwise, and does not allow for facile handling of the worm. To overcome these technical challenges, we have developed a single-channel microfluidic device that can trap a C. elegans and allow to image the mitochondria in body wall muscles accurately and in higher throughput than the traditional approach. In specific, our microfluidic device took advantage of the proprioception of the worm to rotate its body in a microfluidic channel with an aspect ratio above one to gain more space for its undulation motion that was favorable for quantitative fluorescence imaging of mitochondria in the body wall muscles. Exploiting this unique feature of the microfluidic chip-based immobilization and fluorescence imaging, we observed a significant decrease in the mitochondrial fluorescence intensity under hyperglycemic conditions, whereas the agarose pad-based approach did not show any significant change under the same conditions. A machine learning model trained with these fluorescence images from the microfluidic device could classify healthy and hyperglycemic worms at high accuracy. Given this significant technological advantage, its easiness of use and low cost, our microfluidic imaging chip could become a useful immobilization tool for quantitative fluorescence imaging of the body wall muscles in C. elegans.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 6","pages":"150-160"},"PeriodicalIF":2.5,"publicationDate":"2020-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38020447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling and measurement of signaling outcomes affecting decision making in noisy intracellular networks using machine learning methods.","authors":"Mustafa Ozen,&nbsp;Tomasz Lipniacki,&nbsp;Andre Levchenko,&nbsp;Effat S Emamian,&nbsp;Ali Abdi","doi":"10.1093/intbio/zyaa009","DOIUrl":"https://doi.org/10.1093/intbio/zyaa009","url":null,"abstract":"<p><p>Characterization of decision-making in cells in response to received signals is of importance for understanding how cell fate is determined. The problem becomes multi-faceted and complex when we consider cellular heterogeneity and dynamics of biochemical processes. In this paper, we present a unified set of decision-theoretic, machine learning and statistical signal processing methods and metrics to model the precision of signaling decisions, in the presence of uncertainty, using single cell data. First, we introduce erroneous decisions that may result from signaling processes and identify false alarms and miss events associated with such decisions. Then, we present an optimal decision strategy which minimizes the total decision error probability. Additionally, we demonstrate how graphing receiver operating characteristic curves conveniently reveals the trade-off between false alarm and miss probabilities associated with different cell responses. Furthermore, we extend the introduced framework to incorporate the dynamics of biochemical processes and reactions in a cell, using multi-time point measurements and multi-dimensional outcome analysis and decision-making algorithms. The introduced multivariate signaling outcome modeling framework can be used to analyze several molecular species measured at the same or different time instants. We also show how the developed binary outcome analysis and decision-making approach can be extended to more than two possible outcomes. As an example and to show how the introduced methods can be used in practice, we apply them to single cell data of PTEN, an important intracellular regulatory molecule in a p53 system, in wild-type and abnormal cells. The unified signaling outcome modeling framework presented here can be applied to various organisms ranging from viruses, bacteria, yeast and lower metazoans to more complex organisms such as mammalian cells. Ultimately, this signaling outcome modeling approach can be utilized to better understand the transition from physiological to pathological conditions such as inflammation, various cancers and autoimmune diseases.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":"12 5","pages":"122-138"},"PeriodicalIF":2.5,"publicationDate":"2020-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37950785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}