Integrative biology : quantitative biosciences from nano to macro最新文献

{"title":"Immune cell mediated cabozantinib resistance for patients with renal cell carcinoma.","authors":"Keon Young Park, Hunter O Hefti, Peng Liu, Karina M Lugo-Cintrón, Sheena C Kerr, David J Beebe","doi":"10.1093/intbio/zyab018","DOIUrl":"10.1093/intbio/zyab018","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is the third most common genitourinary cancer in the USA. Despite recent advances in the treatment for advanced and metastatic clear cell RCC (ccRCC), the 5-year relative survival rate for the distant disease remains at 12%. Cabozantinib, a tyrosine kinase inhibitor (TKI), which is one of the first-line therapies approved to treat advanced ccRCC as a single agent, is now being investigated as a combination therapy with newer immunotherapeutic agents. However, not much is known about how cabozantinib modulates the immune system. Here, we present a high throughput tri-culture model that incorporates cancer cells, endothelial cells, and patient-derived immune cells to study the effect of immune cells from patients with ccRCC on angiogenesis and cabozantinib resistance. We show that circulating immune cells from patients with ccRCC induce cabozantinib resistance via increased secretion of a set of pro-angiogenic factors. Using multivariate partial least square regression modeling, we identified CD4+ T cell subsets that are correlated with cabozantinib resistance and report the changes in the frequency of these populations in ccRCC patients who are undergoing cabozantinib therapy. These findings provide a potential set of biomarkers that should be further investigated in the current TKI-immunotherapy combination clinical trials to improve personalized treatments for patients with ccRCC.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"259-268"},"PeriodicalIF":1.4,"publicationDate":"2021-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39743590","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":"Creation of a synthesis-friendly inflammation-inducible promoter suitable for cell therapy.","authors":"Anish Jadav,&nbsp;Kevin Truong","doi":"10.1093/intbio/zyab015","DOIUrl":"https://doi.org/10.1093/intbio/zyab015","url":null,"abstract":"<p><p>The development of 'smart' cell-based therapeutics requires cells that first recognize conditions consistent with disease (e.g. inflammation) and then subsequently release therapeutic proteins, thereby reducing potential toxicity from otherwise continuous expression. Promoters containing NF-κB response elements are often used as reporters of inflammation; however, endogenous promoters have crosstalk with other pathways, and current synthetic promoters have many exact sequence repeats of NF-κB response elements which make them both difficult to synthesize and inherently genetically unstable. Herein, a synthesis-friendly inflammation-inducible promoter (named SFNp) was created by the packing of 14 NF-κB response elements, which have no repeats >9 bp, followed by a minimal cytomegalovirus promoter. In stably expressing human embryonic kidney 293 cells, we assessed the ability of SFNp to inducibly transcribe genes for reporting expression, changing cell morphology, and performing cell fusion. These experiments represent simple milestones for potentially using SFNp in the development of cell-based therapeutics. As strongly repeated DNA can compromise the long-term stability of genetic circuits, new designs used in 'smart' cell therapy will become more reliant on synthesis-friendly components like SFNp.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"230-236"},"PeriodicalIF":2.5,"publicationDate":"2021-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521041/pdf/zyab015.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39505549","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 novel two-layer-integrated microfluidic device for high-throughput yeast proteomic dynamics analysis at the single-cell level.","authors":"Kaiyue Chen,&nbsp;Nan Rong,&nbsp;Shujing Wang,&nbsp;Chunxiong Luo","doi":"10.1093/intbio/zyaa018","DOIUrl":"https://doi.org/10.1093/intbio/zyaa018","url":null,"abstract":"<p><p>Current microfluidic methods for studying multicell strains (e.g., m-types) with multienvironments (e.g., n-types) require large numbers of inlets/outlets (m*n), a complicated procedure or expensive machinery. Here, we developed a novel two-layer-integrated method to combine different PDMS microchannel layers with different functions into one chip by a PDMS through-hole array, which improved the design of a PDMS-based microfluidic system. Using this method, we succeeded in converting 2 × m × n inlets/outlets into m + n inlets/outlets and reduced the time cost of loading processing (from m × n to m) of the device for studying multicell strains (e.g., m-types) in varied multitemporal environments (i.e., n-types). Using this device, the dynamic behavior of the cell-stress-response proteins was studied when the glucose concentration decreased from 2% to a series of lower concentrations. Our device could also be widely used in high-throughput studies of various stress responses, and the new concept of a multilayer-integrated fabrication method could greatly improve the design of PDMS-based microfluidic systems.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"241-249"},"PeriodicalIF":2.5,"publicationDate":"2020-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/intbio/zyaa018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38439189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fingerprinting microbiomes towards screening for microbial antibiotic resistance.","authors":"Naifu Jin,&nbsp;Dayi Zhang,&nbsp;Francis L Martin","doi":"10.1039/c7ib00009j","DOIUrl":"https://doi.org/10.1039/c7ib00009j","url":null,"abstract":"<p><p>There is an increasing need to investigate microbiomes in their entirety in a variety of contexts ranging from environmental to human health scenarios. This requirement is becoming increasingly important with the emergence of antibiotic resistance. In general, more conventional approaches are too expensive and/or time-consuming and often predicated on prior knowledge of the microorganisms one wishes to study. Herein, we propose the use of biospectroscopy tools as relatively high-throughput, non-destructive approaches to profile microbiomes under study. Fourier-transform infrared (FTIR) or Raman spectroscopy both generate fingerprint spectra of biological material and such spectra can readily be subsequently classed according to biochemical changes in the microbiota, such as emergence of antibiotic resistance. FTIR spectroscopy techniques generally can only be applied to desiccated material whereas Raman approaches can be applied to more hydrated samples. The ability to readily fingerprint microbiomes could lend itself to new approaches in determining microbial behaviours and emergence of antibiotic resistance.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"406-417"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00009j","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34976390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk of two-component signal transduction systems in regulating central carbohydrate and energy metabolism during autotrophic and photomixotrophic growth of Synechocystis sp. PCC 6803.","authors":"Guangsheng Pei,&nbsp;Xiangfeng Niu,&nbsp;Yuqing Zhou,&nbsp;Lei Chen,&nbsp;Weiwen Zhang","doi":"10.1039/c7ib00049a","DOIUrl":"https://doi.org/10.1039/c7ib00049a","url":null,"abstract":"<p><p>Unicellular model cyanobacterium Synechocystis sp. PCC 6803 has received considerable attention as a sustainable energy resource because of its photosynthetic machinery. However, two-component signal transduction systems (TCSTSs) in regulating central carbohydrate and energy metabolism of cyanobacteria are still poorly understood due to their diversity and functional complication. In this study, by comparing the growth of knockout mutants of 44 response regulators (RRs) of TCSTSs in Synechocystis, several RR mutants demonstrating differential growth patterns were identified under auto- or photomixotrophic conditions. However, in spite of no growth difference observed for the remaining RR mutants, liquid chromatography-mass spectrometry based metabolomic profile analysis showed that a widespread crosstalk of TCSTSs in regulating central carbohydrate and energy metabolism of Synechocystis was identified, while most of them showed diverse patterns during different trophic types or growth stages. Furthermore, an integrative analysis between evolutionary relationships and metabolomic profiles revealed some pairs of paralogous RRs with highly functional convergence, suggesting the possible conserved functions of Synechocystis TCSTSs during evolution. This study laid an important basis for understanding the function of TCSTSs in photosynthetic cyanobacteria.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"485-496"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00049a","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34978372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing endogenous signals from hepatocytes using a low volume multi-well plate.","authors":"Pantea Gheibi,&nbsp;Kyung Jin Son,&nbsp;Gulnaz Stybayeva,&nbsp;Alexander Revzin","doi":"10.1039/c7ib00010c","DOIUrl":"https://doi.org/10.1039/c7ib00010c","url":null,"abstract":"<p><p>Hepatocytes are highly differentiated epithelial cells that lose their phenotype and function when removed from the in vivo environment. Given the importance of hepatic cultures for drug toxicity, bioartificial liver assist devices and basic biology studies, considerable efforts have been focused on the maintenance of hepatic function in vitro. The methods used to date include co-cultivation of hepatocytes with stromal cells, organizing these cells into spheroids and imbedding them into bioactive gels. Our team has recently demonstrated that primary rat hepatocytes confined to microfluidic channels in the absence of convection maintained the epithelial phenotype through upregulation of endogenous signals including hepatocyte growth factor (HGF). The objective of the present study was to transition from microfluidic devices, which are somewhat specialized and challenging to use, towards low volume multiwell plates ubiquitous in biology laboratories. Using a combination of 3D printing and micromolding we have constructed inserts that can be placed into standard 12-well plates and can be used to create low volume culture conditions under which primary hepatocytes maintained a differentiated phenotype. This phenotype enhancement was confirmed by hepatic function assays including albumin synthesis and expression. Importantly we confirmed upregulation of HGF inside the low volume culture plates and demonstrated that inhibition of HGF signaling degraded the hepatic phenotype in our cell culture platform. Overall, this study outlines a new cell culture system that leverages the low volume effects of microfluidic channels in a multiwell plate format. Beyond hepatocytes, such a system may be of use in the maintenance of other difficult-to-culture cells including stem cells and primary cancer cells.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"427-435"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00010c","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34865684","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":"Chemical genomic analysis of GPR35 signaling.","authors":"Heidi Haibei Hu,&nbsp;Huayun Deng,&nbsp;Shizhang Ling,&nbsp;Haiyan Sun,&nbsp;Terry Kenakin,&nbsp;Xinmiao Liang,&nbsp;Ye Fang","doi":"10.1039/c7ib00005g","DOIUrl":"https://doi.org/10.1039/c7ib00005g","url":null,"abstract":"<p><p>GPR35, a family A orphan G protein-coupled receptor, has been implicated in inflammatory, neurological, and cardiovascular diseases. However, not much is known about the signaling and functions of GPR35. We performed a label-free kinome short hairpin RNA screen and identified a putative signaling network of GPR35 in HT-29 cells, some of which was validated using gene expression, biochemical and cellular assays. The results showed that GPR35 induced hypoxia-inducible factor 1α, and was involved in synaptic transmission, sensory perception, the immune system, and morphogenetic processes. Collectively, our data suggest that GPR35 may play an important role in response to hypoxic stress and be a potential target for the treatment of inflammatory, cardiovascular, and neurological disorders.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"451-463"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00005g","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34928719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blue light effect on retinal pigment epithelial cells by display devices.","authors":"Jiyoung Moon,&nbsp;Jieun Yun,&nbsp;Yeo Dae Yoon,&nbsp;Sang-Il Park,&nbsp;Young-Jun Seo,&nbsp;Won-Sang Park,&nbsp;Hye Yong Chu,&nbsp;Keun Hong Park,&nbsp;Myung Yeol Lee,&nbsp;Chang Woo Lee,&nbsp;Soo Jin Oh,&nbsp;Young-Shin Kwak,&nbsp;Young Pyo Jang,&nbsp;Jong Soon Kang","doi":"10.1039/c7ib00032d","DOIUrl":"https://doi.org/10.1039/c7ib00032d","url":null,"abstract":"<p><p>Blue light has high photochemical energy and induces cell apoptosis in retinal pigment epithelial cells. Due to its phototoxicity, retinal hazard by blue light stimulation has been well demonstrated using high intensity light sources. However, it has not been studied whether blue light in the displays, emitting low intensity light, such as those used in today's smartphones, monitors, and TVs, also causes apoptosis in retinal pigment epithelial cells. We attempted to examine the blue light effect on human adult retinal epithelial cells using display devices with different blue light wavelength ranges, the peaks of which specifically appear at 449 nm, 458 nm, and 470 nm. When blue light was illuminated on A2E-loaded ARPE-19 cells using these displays, the display with a blue light peak at a shorter wavelength resulted in an increased production of reactive oxygen species (ROS). Moreover, the reduction of cell viability and induction of caspase-3/7 activity were more evident in A2E-loaded ARPE-19 cells after illumination by the display with a blue light peak at a shorter wavelength, especially at 449 nm. Additionally, white light was tested to examine the effect of blue light in a mixed color illumination with red and green lights. Consistent with the results obtained using only blue light, white light illuminated by display devices with a blue light peak at a shorter wavelength also triggered increased cell death and apoptosis compared to that illuminated by display devices with a blue light peak at longer wavelength. These results show that even at the low intensity utilized in the display devices, blue light can induce ROS production and apoptosis in retinal cells. Our results also suggest that the blue light hazard of display devices might be highly reduced if the display devices contain less short wavelength blue light.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"436-443"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00032d","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34893370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein self-assembly following in situ expression in artificial and mammalian cells.","authors":"Urszula M Migas,&nbsp;Michelle K Quinn,&nbsp;Jennifer J McManus","doi":"10.1039/c6ib00240d","DOIUrl":"https://doi.org/10.1039/c6ib00240d","url":null,"abstract":"<p><p>The self-assembly of proteins has been widely studied in controlled in vitro conditions, and more recently in biological environments. The self-assembly of proteins in biology can be a feature of the pathogenesis of protein condensation disease, or can occur during normal physiological function, for example during the formation of intracellular non-membrane bound organelles. To determine the mechanisms for the assembly process fully, controlled in vitro experiments using purified protein solutions are often required. However, making direct connections between insights gathered from controlled experiments and those in complex biological environments remains a challenge. Using the P23T mutant of human γD-crystallin, a protein associated with congenital cataract, we have demonstrated that the equilibrium solubility boundary and solution behavior measured using phase diagrams of purified protein solutions is consistent with the assembly of the protein expressed in cell-free expression medium in artificial cells (without fluorescent labelling) and condensates formed in mammalian cells, thereby directly connecting in vitro measurements with those performed under physiological conditions.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"444-450"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c6ib00240d","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34907968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative meta-modeling identifies endocytic vesicles, late endosome and the nucleus as the cellular compartments primarily directing RTK signaling.","authors":"Jared C Weddell,&nbsp;Princess I Imoukhuede","doi":"10.1039/c7ib00011a","DOIUrl":"https://doi.org/10.1039/c7ib00011a","url":null,"abstract":"<p><p>Recently, intracellular receptor signaling has been identified as a key component mediating cell responses for various receptor tyrosine kinases (RTKs). However, the extent each endocytic compartment (endocytic vesicle, early endosome, recycling endosome, late endosome, lysosome and nucleus) contributes to receptor signaling has not been quantified. Furthermore, our understanding of endocytosis and receptor signaling is complicated by cell- or receptor-specific endocytosis mechanisms. Therefore, towards understanding the differential endocytic compartment signaling roles, and identifying how to achieve signal transduction control for RTKs, we delineate how endocytosis regulates RTK signaling. We achieve this via a meta-analysis across eight RTKs, integrating computational modeling with experimentally derived cell (compartment volume, trafficking kinetics and pH) and ligand-receptor (ligand/receptor concentration and interaction kinetics) physiology. Our simulations predict the abundance of signaling from eight RTKs, identifying the following hierarchy in RTK signaling: PDGFRβ > IGFR1 > EGFR > PDGFRα > VEGFR1 > VEGFR2 > Tie2 > FGFR1. We find that endocytic vesicles are the primary cell signaling compartment; over 43% of total receptor signaling occurs within the endocytic vesicle compartment for these eight RTKs. Mechanistically, we found that high RTK signaling within endocytic vesicles may be attributed to their low volume (5.3 × 10^-19 L) which facilitates an enriched ligand concentration (3.2 μM per ligand molecule within the endocytic vesicle). Under the analyzed physiological conditions, we identified extracellular ligand concentration as the most sensitive parameter to change; hence the most significant one to modify when regulating absolute compartment signaling. We also found that the late endosome and nucleus compartments are important contributors to receptor signaling, where 26% and 18%, respectively, of average receptor signaling occurs across the eight RTKs. Conversely, we found very low membrane-based receptor signaling, exhibiting <1% of the total receptor signaling for these eight RTKs. Moreover, we found that nuclear translocation, mechanistically, requires late endosomal transport; when we blocked receptor trafficking from late endosomes to the nucleus we found a 57% reduction in nuclear translocation. In summary, our research has elucidated the significance of endocytic vesicles, late endosomes and the nucleus in RTK signal propagation.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":" ","pages":"464-484"},"PeriodicalIF":2.5,"publicationDate":"2017-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/c7ib00011a","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34938283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}