Integrative Biology最新文献

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An integrative biology approach to understanding keratinocyte collective migration as stimulated by bioglass. 用综合生物学方法理解生物玻璃刺激的角质细胞集体迁移。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae008
Joseph Siegfreid, Ali Crampton, Saghi Saghazadeh, Randilynn Christensen, Jacob Notbohm, Jason Bjork, Bryan Baker
{"title":"An integrative biology approach to understanding keratinocyte collective migration as stimulated by bioglass.","authors":"Joseph Siegfreid, Ali Crampton, Saghi Saghazadeh, Randilynn Christensen, Jacob Notbohm, Jason Bjork, Bryan Baker","doi":"10.1093/intbio/zyae008","DOIUrl":"10.1093/intbio/zyae008","url":null,"abstract":"<p><p>A critical phase of wound healing is the coordinated movement of keratinocytes. To this end, bioglasses show promise in speeding healing in hard tissues and skin wounds. Studies suggest that bioglass materials may promote wound healing by inducing positive cell responses in proliferation, growth factor production, expression of angiogenic factors, and migration. Precise details of how bioglass may stimulate migration are unclear, however, because the common assays for studying migration in wound healing focus on simplified outputs like rate of migration or total change in wound area. These outputs are limited in that they represent the average behavior of the collective, with no connection between the motion of the individual cells and the collective wound healing response. There is a need to apply more refined tools that identify how the motion of the individual cells changes in response to perturbations, such as by bioglass, and in turn affects motion of the cell collective. Here, we apply an integrative biology strategy that combines an in vitro wound healing assay using primary neonatal human keratinocytes with time lapse microscopy and quantitative image analysis. The resulting data set provides the cell velocity field, from which we define key metrics that describe cooperative migration phenotypes. Treatment with growth factors led to faster single-cell speeds compared to control, but the migration was not cooperative, with cells breaking away from their neighbors and migrating as individuals. Treatment with calcium or bioglass led to migration phenotypes that were highly collective, with greater coordination in space compared to control. We discuss the link between bioglass treatment and observed increases in free calcium ions that are hypothesized to promote these distinct coordinated behaviors in primary keratinocytes. These findings have been enabled by the unique descriptors developed through applying image analysis to interpret biological response in migration models. Insight Box/Paragraph Statement: Bioglasses are important materials for tissue engineering and have more recently shown promise in skin and wound healing by mechanisms tied to their unique ionic properties. The precise details, however, of how cell migration may be affected by bioglass are left unclear by traditional cell assay methods. The following describes the integration of migration assays of keratinocytes, cells critical for skin and wound healing, with the tools of time lapse microscopy and image analysis to generate a quantitative description of coordinated, tissue-like migration behavior, stimulated by bioglass, that would not have been accessible without the combination of these analytical tools.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183220","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}
引用次数: 0
A multilayer microfluidic system for studies of the dynamic responses of cellular proteins to oxygen switches at the single-cell level. 用于在单细胞水平研究细胞蛋白质对氧气开关的动态响应的多层微流体系统。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae011
Wei Fu, Shujing Wang, Qi Ouyang, Chunxiong Luo
{"title":"A multilayer microfluidic system for studies of the dynamic responses of cellular proteins to oxygen switches at the single-cell level.","authors":"Wei Fu, Shujing Wang, Qi Ouyang, Chunxiong Luo","doi":"10.1093/intbio/zyae011","DOIUrl":"https://doi.org/10.1093/intbio/zyae011","url":null,"abstract":"<p><p>Oxygen levels vary in the environment. Oxygen availability has a major effect on almost all organisms, and oxygen is far more than a substrate for energy production. However, less is known about related biological processes under hypoxic conditions and about the adaptations to changing oxygen concentrations. The yeast Saccharomyces cerevisiae can adapt its metabolism for growth under different oxygen concentrations and can grow even under anaerobic conditions. Therefore, we developed a microfluidic device that can generate serial, accurately controlled oxygen concentrations for single-cell studies of multiple yeast strains. This device can construct a broad range of oxygen concentrations, [O2] through on-chip gas-mixing channels from two gases fed to the inlets. Gas diffusion through thin polydimethylsiloxane (PDMS) can lead to the equilibration of [O2] in the medium in the cell culture layer under gas cover regions within 2 min. Here, we established six different and stable [O2] varying between ~0.1 and 20.9% in the corresponding layers of the device designed for multiple parallel single-cell culture of four different yeast strains. Using this device, the dynamic responses of different yeast transcription factors and metabolism-related proteins were studied when the [O2] decreased from 20.9% to serial hypoxic concentrations. We showed that different hypoxic conditions induced varying degrees of transcription factor responses and changes in respiratory metabolism levels. This device can also be used in studies of the aging and physiology of yeast under different oxygen conditions and can provide new insights into the relationship between oxygen and organisms. Integration, innovation and insight: Most living cells are sensitive to the oxygen concentration because they depend on oxygen for survival and proper cellular functions. Here, a composite microfluidic device was designed for yeast single-cell studies at a series of accurately controlled oxygen concentrations. Using this device, we studied the dynamic responses of various transcription factors and proteins to changes in the oxygen concentration. This study is the first to examine protein dynamics and temporal behaviors under different hypoxic conditions at the single yeast cell level, which may provide insights into the processes involved in yeast and even mammalian cells. This device also provides a base model that can be extended to oxygen-related biology and can acquire more information about the complex networks of organisms.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425742","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}
引用次数: 0
A systems framework for investigating the roles of multiple transporters and their impact on drug resistance. 研究多种转运体的作用及其对耐药性影响的系统框架。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae007
Manfredi di San Germano, J Krishnan
{"title":"A systems framework for investigating the roles of multiple transporters and their impact on drug resistance.","authors":"Manfredi di San Germano, J Krishnan","doi":"10.1093/intbio/zyae007","DOIUrl":"10.1093/intbio/zyae007","url":null,"abstract":"<p><p>Efflux transporters are a fundamental component of both prokaryotic and eukaryotic cells, play a crucial role in maintaining cellular homeostasis, and represent a key bridge between single cell and population levels. From a biomedical perspective, they play a crucial role in drug resistance (and especially multi-drug resistance, MDR) in a range of systems spanning bacteria and human cancer cells. Typically, multiple efflux transporters are present in these cells, and the efflux transporters transport a range of substrates (with partially overlapping substrates between transporters). Furthermore, in the context of drug resistance, the levels of transporters may be elevated either due to extra or intracellular factors (feedforward regulation) or due to the drug itself (feedback regulation). As a consequence, there is a real need for a transparent systems-level understanding of the collective functioning of a set of transporters and their response to one or more drugs. We develop a systems framework for this purpose and examine the functioning of sets of transporters, their interplay with one or more drugs and their regulation (both feedforward and feedback). Using computational and analytical work, we obtain transparent insights into the systems level functioning of a set of transporters arising from the interplay between the multiplicity of drugs and transporters, different drug-transporter interaction parameters, sequestration and feedback and feedforward regulation. These insights transparently arising from the most basic consideration of a multiplicity of transporters have broad relevance in natural biology, biomedical engineering and synthetic biology. Insight, Innovation, Integration: Innovation: creating a structured systems framework for evaluating the impact of multiple transporters on drug efflux and drug resistance. Systematic analysis allows us to evaluate the effect of multiple transporters on one/more drugs, and dissect associated resistance mechanisms. Integration allows for elucidation of key cause-and-effect relationships and a transparent systems-level understanding of the collective functioning of transporters and their impact on resistance, revealing the interplay of key underlying factors. Systems-level insights include the essentially different behaviour of transporters as part of a group; unintuitive effects of influx; effects of elevated transporter-levels by feedforward and drug-induced mechanisms. Relevance: a systems understanding of efflux, their role in MDR, providing a framework/platform for use in designing treatment, and in synthetic biology design.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304061","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}
引用次数: 0
Hub genes, key miRNAs and interaction analyses in type 2 diabetes mellitus: an integrative in silico approach. 2 型糖尿病中的枢纽基因、关键 miRNA 和相互作用分析:一种综合的硅学方法。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae002
Zeinab Nematollahi, Shiva Karimian, Ali Taghavirashidizadeh, Mohammad Darvishi, SeyedAbbas Pakmehr, Amin Erfan, Mohammad Javad Teimoury, Neda Mansouri, Iraj Alipourfard
{"title":"Hub genes, key miRNAs and interaction analyses in type 2 diabetes mellitus: an integrative in silico approach.","authors":"Zeinab Nematollahi, Shiva Karimian, Ali Taghavirashidizadeh, Mohammad Darvishi, SeyedAbbas Pakmehr, Amin Erfan, Mohammad Javad Teimoury, Neda Mansouri, Iraj Alipourfard","doi":"10.1093/intbio/zyae002","DOIUrl":"10.1093/intbio/zyae002","url":null,"abstract":"<p><p>Diabetes is a rising global metabolic disorder and leads to long-term consequences. As a multifactorial disease, the gene-associated mechanisms are important to know. This study applied a bioinformatics approach to explore the molecular underpinning of type 2 diabetes mellitus through differential gene expression analysis. We used microarray datasets GSE16415 and GSE29226 to identify differentially expressed genes between type 2 diabetes and normal samples using R software. Following that, using the STRING database, the protein-protein interaction network was constructed and further analyzed by Cytoscape software. The EnrichR database was used for Gene Ontology and pathway enrichment analysis to explore key pathways and functional annotations of hub genes. We also used miRTarBase and TargetScan databases to predict miRNAs targeting hub genes. We identified 21 hub genes in type 2 diabetes, some showing more significant changes in the PPI network. Our results revealed that GLUL, SLC32A1, PC, MAPK10, MAPT, and POSTN genes are more important in the PPI network and can be experimentally investigated as therapeutic targets. Hsa-miR-492 and hsa-miR-16-5p are suggested for diagnosis and prognosis by targeting GLUL, SLC32A1, PC, MAPK10, and MAPT genes involved in the insulin signaling pathway. Insight: Type 2 diabetes, as a rising global and multifactorial disorder, is important to know the gene-associated mechanisms. In an integrative bioinformatics analysis, we integrated different finding datasets to put together and find valuable diagnostic and prognostic hub genes and miRNAs. In contrast, genes, RNAs, and enzymes interact systematically in pathways. Using multiple databases and software, we identified differential expression between hub genes of diabetes and normal samples. We explored different protein-protein interaction networks, gene ontology, key pathway analysis, and predicted miRNAs that target hub genes. This study reported 21 significant hub genes and some miRNAs in the insulin signaling pathway for innovative and potential diagnostic and therapeutic purposes.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139897790","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}
引用次数: 0
The cellular zeta potential: cell electrophysiology beyond the membrane. 细胞泽塔电位:超越膜的细胞电生理学。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae003
Michael Pycraft Hughes
{"title":"The cellular zeta potential: cell electrophysiology beyond the membrane.","authors":"Michael Pycraft Hughes","doi":"10.1093/intbio/zyae003","DOIUrl":"10.1093/intbio/zyae003","url":null,"abstract":"<p><p>The standard model of the cell membrane potential Vm describes it as arising from diffusion currents across a membrane with a constant electric field, with zero electric field outside the cell membrane. However, the influence of Vm has been shown to extend into the extracellular space where it alters the cell's ζ-potential, the electrical potential measured a few nm from the cell surface which defines how the cell interacts with charged entities in its environment, including ions, molecules, and other cells. The paradigm arising from surface science is that the ζ-potential arises only from fixed membrane surface charge, and has consequently received little interest. However, if the ζ-potential can mechanistically and dynamically change by alteration of Vm, it allows the cell to dynamically alter cell-cell and cell-molecule interactions and may explain previously unexplained electrophysiological behaviours. Whilst the two potentials Vm and ζ are rarely reported together, they are occasionally described in different studies for the same cell type. By considering published data on these parameters across multiple cell types, as well as incidences of unexplained but seemingly functional Vm changes correlating with changes in cell behaviour, evidence is presented that this may play a functional role in the physiology of red blood cells, macrophages, platelets, sperm, ova, bacteria and cancer. Understanding how these properties will improve understanding of the role of electrical potentials and charges in the regulation of cell function and in the way in which cells interact with their environment. Insight  The zeta (ζ) potential is the electrical potential a few nm beyond the surface of any suspensoid in water. Whilst typically assumed to arise only from fixed charges on the cell surface, recent and historical evidence shows a strong link to the cell's membrane potential Vm, which the cell can alter mechanistically through the use of ion channels. Whilst these two potentials have rarely been studied simultaneously, this review collates data across multiple studies reporting Vm, ζ-potential, electrical properties of changes in cell behaviour. Collectively, this points to Vm-mediated ζ-potential playing a significant role in the physiology and activity of blood cells, immune response, developmental biology and egg fertilization, and cancer among others.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139641216","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}
引用次数: 0
Asymmetric response emerges between creation and disintegration of force-bearing subcellular structures as revealed by percolation analysis. 渗流分析显示,受力亚细胞结构的形成和解体之间出现了不对称反应。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae012
Yuika Ueda, Daiki Matsunaga, Shinji Deguchi
{"title":"Asymmetric response emerges between creation and disintegration of force-bearing subcellular structures as revealed by percolation analysis.","authors":"Yuika Ueda, Daiki Matsunaga, Shinji Deguchi","doi":"10.1093/intbio/zyae012","DOIUrl":"https://doi.org/10.1093/intbio/zyae012","url":null,"abstract":"<p><p>Cells dynamically remodel their internal structures by modulating the arrangement of actin filaments (AFs). In this process, individual AFs exhibit stochastic behavior without knowing the macroscopic higher-order structures they are meant to create or disintegrate, but the mechanism allowing for such stochastic process-driven remodeling of subcellular structures remains incompletely understood. Here we employ percolation theory to explore how AFs interacting only with neighboring ones without recognizing the overall configuration can nonetheless create a substantial structure referred to as stress fibers (SFs) at particular locations. We determined the interaction probabilities of AFs undergoing cellular tensional homeostasis, a fundamental property maintaining intracellular tension. We showed that the duration required for the creation of SFs is shortened by the increased amount of preexisting actin meshwork, while the disintegration occurs independently of the presence of actin meshwork, suggesting that the coexistence of tension-bearing and non-bearing elements allows cells to promptly transition to new states in accordance with transient environmental changes. The origin of this asymmetry between creation and disintegration, consistently observed in actual cells, is elucidated through a minimal model analysis by examining the intrinsic nature of mechano-signal transmission. Specifically, unlike the symmetric case involving biochemical communication, physical communication to sense environmental changes is facilitated via AFs under tension, while other free AFs dissociated from tension-bearing structures exhibit stochastic behavior. Thus, both the numerical and minimal models demonstrate the essence of intracellular percolation, in which macroscopic asymmetry observed at the cellular level emerges not from microscopic asymmetry in the interaction probabilities of individual molecules, but rather only as a consequence of the manner of the mechano-signal transmission. These results provide novel insights into the role of the mutual interplay between distinct subcellular structures with and without tension-bearing capability. Insight: Cells continuously remodel their internal elements or structural proteins in response to environmental changes. Despite the stochastic behavior of individual structural proteins, which lack awareness of the larger subcellular structures they are meant to create or disintegrate, this self-assembly process somehow occurs to enable adaptation to the environment. Here we demonstrated through percolation simulations and minimal model analyses that there is an asymmetry in the response between the creation and disintegration of subcellular structures, which can aid environmental adaptation. This asymmetry inherently arises from the nature of mechano-signal transmission through structural proteins, namely tension-mediated information exchange within cells, despite the stochastic behavior of individual proteins lackin","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425743","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}
引用次数: 0
Correction to: The cellular zeta potential: cell electrophysiology beyond the membrane. Correction to:细胞泽塔电位:超越膜的细胞电生理学。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae006
{"title":"Correction to: The cellular zeta potential: cell electrophysiology beyond the membrane.","authors":"","doi":"10.1093/intbio/zyae006","DOIUrl":"https://doi.org/10.1093/intbio/zyae006","url":null,"abstract":"","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140011677","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}
引用次数: 0
Integrated analysis revealing novel associations between dietary patterns and the immune system in older adults. 综合分析揭示了老年人饮食模式与免疫系统之间的新关联。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae010
Jessica Conway, Animesh Acharjee, Niharika A Duggal
{"title":"Integrated analysis revealing novel associations between dietary patterns and the immune system in older adults.","authors":"Jessica Conway, Animesh Acharjee, Niharika A Duggal","doi":"10.1093/intbio/zyae010","DOIUrl":"https://doi.org/10.1093/intbio/zyae010","url":null,"abstract":"<p><p>With the expanding ageing population, there is a growing interest in the maintenance of immune health to support healthy ageing. Enthusiasm exists for unravelling the impact of diet on the immune system and its therapeutic potential. However, a key challenge is the lack of studies investigating the effect of dietary patterns and nutrients on immune responses. Thus, we have used an integrative analysis approach to improve our understanding of diet-immune system interactions in older adults. To do so, dietary data were collected in parallel with performing immunophenotyping and functional assays from healthy older (n = 40) participants. Food Frequency Questionnaire (FFQ) was utilised to derive food group intake and multi-colour flow cytometry was performed for immune phenotypic and functional analysis. Spearman correlation revealed the strength of association between all combinations of dietary components, micronutrients, and hallmarks of immunesenescence. In this study, we propose for the first time that higher adherence to the Mediterranean diet is associated with a positive immune-ageing trajectory (Lower IMM-AGE score) in older adults due to the immune protective effects of high dietary fibre and PUFA intake in combating accumulation or pro-inflammatory senescent T cells. Furthermore, a diet rich in Vit A, Vit B6 and Vit B12 is associated with fewer features of immunesenescence [such as accumulation of terminally differentiated memory CD8 T cells] in older adults. Based on our findings we propose a future nutrition-based intervention study evaluating the efficacy of adherence to the MED diet alongside a multi-nutrient supplementation on immune ageing in older adults to set reliable dietary recommendations with policymakers that can be given to geriatricians and older adults. Insight box: There is a growing interest in the maintenance of immune health to boost healthy ageing. However, a key challenge is the lack of studies investigating the effect of dietary patterns and nutrients on immune responses. Thus, to do so we collected dietary data in parallel with performing immunophenotyping and functional assays on healthy older (n = 40) participants, followed by an integrative analysis approach to improve our understanding of diet-immune system interactions in older adults. We strongly believe that these new findings are appropriate for IB and will be of considerable interest to its broad audience.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173749","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}
引用次数: 0
An integrative biology approach to understanding keratinocyte collective migration as stimulated by bioglass. 用综合生物学方法理解生物玻璃刺激的角质细胞集体迁移。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae009
{"title":"An integrative biology approach to understanding keratinocyte collective migration as stimulated by bioglass.","authors":"","doi":"10.1093/intbio/zyae009","DOIUrl":"https://doi.org/10.1093/intbio/zyae009","url":null,"abstract":"","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853559","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}
引用次数: 0
Modeling Shiga toxin-induced human renal-specific microvascular injury. 模拟志贺毒素诱导的人体肾脏特异性微血管损伤。
IF 2.5 4区 生物学
Integrative Biology Pub Date : 2024-01-23 DOI: 10.1093/intbio/zyae001
Russell Whelan, Daniel Lih, Jun Xue, Jonathan Himmelfarb, Ying Zheng
{"title":"Modeling Shiga toxin-induced human renal-specific microvascular injury.","authors":"Russell Whelan, Daniel Lih, Jun Xue, Jonathan Himmelfarb, Ying Zheng","doi":"10.1093/intbio/zyae001","DOIUrl":"10.1093/intbio/zyae001","url":null,"abstract":"<p><p>Shiga toxin (Stx) causes significant renal microvascular injury and kidney failure in the pediatric population, and an effective targeted therapy has yet to be demonstrated. Here we established a human kidney microvascular endothelial cell line for the study of Stx mediated injuries with respect to their morphologic, phenotypic, and transcriptional changes, and modeled Stx induced thrombotic microangiopathy (TMA) in flow-mediated 3D microvessels. Distinct from other endothelial cell lines, both isolated primary and immortalized human kidney microvascular endothelial cells demonstrate robust cell-surface expression of the Stx receptor Gb3, and concomitant dose-dependent toxicity to Stx, with significant contributions from caspase-dependent cell death. Use of a glucosylceramide synthase inhibitor (GCSi) to target disruption of the synthetic pathway of Gb3 resulted in remarkable protection of kidney microvascular cells from Stx injury, shown in both cellular morphologies, caspase activation and transcriptional analysis from RNA sequencing. Importantly, these findings are recapitulated in 3D engineered kidney microvessels under flow. Moreover, whole blood perfusion through Stx-treated microvessels led to marked platelet binding on the vessel wall, which was significantly reduced with the treatment of GCSi. These results validate the feasibility and utility of a bioengineered ex vivo human microvascular model under flow to recapitulate relevant blood-endothelial interactions in STEC-HUS. The profound protection afforded by GCSi demonstrates a preclinical opportunity for investigation in human tissue approximating physiologic conditions. Moreover, this work provides a broad foundation for novel investigation into TMA injury pathogenesis and treatment. Insight Box: Shiga toxin (Stx) causes endothelial injury that results in significant morbidity and mortality in the pediatric population, with no effective targeted therapy. This paper utilizes human kidney microvascular cells to examine Stx mediated cell death in both 2D culture and flow-mediated 3D microvessels, with injured microvessels also developing marked platelet binding and thrombi formation when perfused with blood, consistent with the clinical picture of HUS. This injury is abrogated with a small molecule inhibitor targeting the synthetic pathway of the Shiga toxin receptor. Our findings shed light onto Stx-induced vascular injuries and pave a way for broad investigation into thrombotic microangiopathies.</p>","PeriodicalId":80,"journal":{"name":"Integrative Biology","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139544881","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}
引用次数: 0
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