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  • Biological network border detection
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-01
    Paulo E. P. Burke, Cesar H. Comin, Filipi N. Silva, Luciano da F. Costa
    更新日期:2017-11-15
  • EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON BREAST CANCER CELLS WITHIN A TUMOR-STROMA MICROFLUIDIC MODEL
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-14
    Nitish Peela, Eric S Barrientos, Danh Truong, Ghassan Mouneimne, Mehdi Nikkhah

    Metastatic cancer is regarded as one of the largest contributors to disease-related deaths world-wide. Poor patient prognosis and treatment outcome is tied to the lack of efficacious anti-cancer therapies, which is due in part to the lack of physiologically relevant in vitro screening systems that can mimic the native tumor microenvironment. Conventional drug screening platforms, which are often used in pharmaceutical industry, are either two-dimensional (2D) assays or three-dimensional (3D) hydrogel-based matrices that lack precise control over cell distribution as well as matrix architecture and organization. Despite the significance of in vivo models, these models are limited as it is difficult to control and analyze the influence of specific variables within their tumor microenvironment. Thus, there is still a crucial need to develop tumor models that enable precise control of microenvironmental cues (e,g. matrix composition, soluble factors, cellular organization) to assess the efficacy of anti-cancer drugs. Herein, we report the development and validation of a 3D microfluidic invasion platform for anti-cancer drug studies. Our platform allowed for compartmentalization of tumor and stromal entities adjacent to each other, thereby enabling pharmacokinetic drug transport to a cell-dense tumor region. We analyzed the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, on the behavior of SUM159 breast cancer cells. Many HDAC inhibitors, including SAHA, have been a subject of controversy with highly conflicting results for the treatment of solid tumors in vitro as well as in clinical trials. We found that SAHA significantly inhibited cellular migration/proliferation, and decreased microtubule polarization.

    更新日期:2017-11-15
  • A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-14
    Alyssa D Schwartz, Lauren E Barney, Lauren E Jansen, Thuy V Nguyen, Christopher L Hall, Aaron A Meyer, Shelly Peyton

    Traditional drug screening methods lack features of the tumor microenvironment that can contribute to resistance. There remains a gap in whether extracellular signals, such as stiffness, dimensionality, and cell-cell contacts act independently, or are integrated within a cell, to affect drug sensitizations or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and as spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. Transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance. However, a systems biology analysis of phospho-kinome data suggested that MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

    更新日期:2017-11-15
  • Bioreactor Model of Neuromuscular Junction with Electrical Stimulation for Pharmacological Potency Testing
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-14
    Surapon Charoensook, Damian Williams, Syandan Chakraborty, Kam Leong, Gordana Vunjak-Novakovic

    In vitro models of the neuromuscular junction (NMJ) are emerging as a valuable tool to study synaptogenesis, synaptic maintenance, and pathogenesis of neurodegenerative diseases. Many models have previously been developed using a variety of cell sources for skeletal muscle and motoneurons. These models can advanced by integrating beneficial features of the native developmental milieu of the NMJ. We created a functional in vitro model of NMJ by bioreactor cultivation of transdifferentiated myocytes and stem cell-derived motoneurons, in the presence of electrical stimulation. In conjunction with a coculture medium, electrical stimulation resulted in improved maturation and function of motoneurons and myocytes, as evidenced by mature cellular structures, increased expression of neuronal and muscular genes, clusterization of acetylcholine receptors (AChRs) in the vicinity of motoneurons, and the response to glutamate stimulation. To validate the model and demonstrate its utility for pharmacological testing, we documented the potency of drugs that affect key pathways during NMJ signal transduction: (i) acetylcholine (ACh) synthesis, (ii) ACh vesicular storage, (iii) ACh synaptic release, (iv) AChR activation, and (v) ACh inactivation in the synaptic cleft. The model properly responded to the drugs in a concentration-dependent manner. We thus propose that this in vitro model of NMJ could be used as a platform in pharmacological screening and controlled studies of neuromuscular diseases.

    更新日期:2017-11-15
  • RNA-mediated TILDA for improved cell capacity and enhanced detection of multiply-spliced HIV RNA
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-03
    Hannah M. Pezzi, Scott M. Berry, David J. Beebe, Rob Striker
    更新日期:2017-11-13
  • Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-30
    Sultan Doğanay, Maurice Youzong Lee, Alina Baum, Jessie Peh, Sun-Young Hwang, Joo-Yeon Yoo, Paul J. Hergenrother, Adolfo García-Sastre, Sua Myong, Taekjip Ha
    更新日期:2017-11-13
  • Three-dimensional morphometry of collagen fibrils in membranous bone
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-20
    Mana Hashimoto, Noriyuki Nagaoka, Kaori Tabata, Tomoyo Tanaka, Ryuta Osumi, Naoya Odagaki, Toru Hara, Hiroshi Kamioka
    更新日期:2017-11-13
  • Correction: A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-12
    Hagit Peretz-Soroka, Reuven Tirosh, Jolly Hipolito, Erwin Huebner, Murray Alexander, Jason Fiege, Francis Lin

    Correction for ‘A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay’ by Hagit Peretz-Soroka et al., Integr. Biol., 2017, DOI: 10.1039/c7ib00086c.

    更新日期:2017-11-13
  • Lipidomic profiles of Drosophila melanogaster and cactophilic fly species: models of human metabolic diseases
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-02
    Daniel Cázarez-García, Mariana Ramírez Loustalot-Laclette, Therese Ann Markow, Robert Winkler
    更新日期:2017-11-13
  • A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay
    Integr. Biol. (IF 3.252) Pub Date : 2017-09-29
    Hagit Peretz-Soroka, Reuven Tirosh, Jolly Hipolito, Erwin Huebner, Murray Alexander, Jason Fiege, Francis Lin
    更新日期:2017-11-13
  • Probing impaired neurogenesis in human brain organoids exposed to alcohol
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-09
    Jianhua Qin, Yujuan Zhu, Li Wang, Fangchao Yin, Yue Yu, Yaqing Wang, Matthew Shepard, Zhengping Zhuang

    The fetal brain is highly vulnerable to ethanol exposure, which can trigger various long-term neuronal disabilities and cognitive dysfunctions. However, a comprehensive understanding of fetal brain development under ethanol exposure is challenging due to the limitations of animal models. Here, we propose a human induced pluripotent stem cell (hiPSC)-based 3D brain organoid model, and explore the mechanisms underlying neural dysfunctions in prenatal alcohol exposure (PAE) in vitro. Brain organoids were examined to resemble brain organogenesis in vivo at early stages during gestation, with specific features of neuronal differentiation, brain regionalization, and cortical organization. With ethanol exposure, the brain organoids displayed attenuated neurite outgrowth and skewed neural maturation. Transcriptome analysis identified a series of new markedly altered genes and enriched pathways, such as GSX2, RSPO2, and Hippo signaling pathway. These genes or pathways, to our knowledge, were firstly reported to be involved in ethanol-induced impaired neurogenesis. Our new findings might facilitate better understanding of the various postnatal neural disorders observed in individuals with PAE.

    更新日期:2017-11-09
  • Modulation of cellular polarization and migration by ephrin/Eph signal-mediated boundary formation
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-02
    Sahar Javaherian, Elisa D’Arcangelo, Benjamin Slater, Camila Londono, Bin Xu, Alison P. McGuigan
    更新日期:2017-11-09
  • Effect of amino acid mutations on intra-dimer tubulin–tubulin binding strength of microtubules
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-31
    Ning Liu, Ramana Pidaparti, Xianqiao Wang
    更新日期:2017-11-08
  • Enhanced directional cell migration induced by vaccinia virus on a microfluidic-based multi-shear cell migration assay platform
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-30
    Cheng Wang, Na Xu, Yu-Jun Yang, Qiu-Mei Wu, Dai-Wen Pang, Zhi-Ling Zhang
    更新日期:2017-11-07
  • RNA-mediated TILDA for improved cell capacity and enhanced detection of multiply-spliced HIV RNA
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-03
    Hannah M. Pezzi, Scott M. Berry, David J. Beebe, Rob Striker
    更新日期:2017-11-03
  • Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-30
    Sultan Doğanay, Maurice Youzong Lee, Alina Baum, Jessie Peh, Sun-Young Hwang, Joo-Yeon Yoo, Paul J. Hergenrother, Adolfo García-Sastre, Sua Myong, Taekjip Ha
    更新日期:2017-11-03
  • Modulation of cellular polarization, migration and tension by ephrin/Eph signal-mediated boundary formation
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-02
    Sahar Javaherian, Elisa D’Arcangelo, Benjamin Slater, Camila Londono, Bin Xu, Alison McGuigan

    Compartment boundaries are essential for ensuring proper cell organization during embryo development and in adult tissues, yet the mechanisms underlying boundary establishment are not completely understood. A number of mechanisms, including (i) differential adhesion, (ii) differential tension, and (iii) cell signaling-mediated cell repulsion, are known to contribute and likely a context-dependent balance of each of these dictates boundary implementation. The ephrin/Eph signaling pathway is known to impact boundary formation in higher animals. In different contexts, ephrin/Eph signaling is known to modulate adhesive properties and migratory behavior of cells. Furthermore it has been proposed that ephrin/Eph signaling may modulate cellular tensile properties, leading to boundary implementation. It remains unclear however, whether, in different contexts, ephrin/Eph act through distinct dominant action modes (e.g. differential adhesion vs. cell repulsion), or whether ephrin/Eph signaling elicits multiple cellular changes simultaneously. Here, using micropatterning of cells over-expressing either EphB3 or ephrinB1, we assess the contribution of each these factors in one model. We show that in this system ephrinB1/EphB3-mediated boundaries are accompanied by modulation of tissue-level architecture and polarization of cell migration. These changes are associated with changes in cell shape and cytoskeletal organization also suggestive of altered cellular tension.

    更新日期:2017-11-03
  • Biological Networks Border Detection
    Integr. Biol. (IF 3.252) Pub Date : 2017-11-01
    Paulo Eduardo Pinto Burke, Cesar Henrique Comin, Filipi Nascimento, Luciano da Fontoura Costa

    Complex networks have been widely used to model biological systems. The concept of accessibility has been proposed recently as a means to organize the nodes of complex networks as belonging to its border or center. Such an approach paves the way to investigating how the functional and structural properties of nodes vary with their respective position in the networks. In this work, we approach such a problem in a biological context applying border detection to Protein-Protein Interaction networks from four organisms of Mycoplasma genus. We found evidence that the borderness of proteins bears a relation with their spatial organization and molecular function specificity.

    更新日期:2017-11-02
  • Three-dimensional morphometry of collagen fibrils in membranous bone
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-20
    Mana Hashimoto, Noriyuki Nagaoka, Kaori Tabata, Tomoyo Tanaka, Ryuta Osumi, Naoya Odagaki, Toru Hara, Hiroshi Kamioka
    更新日期:2017-11-01
  • Effect of Amino Acid Mutations on Intra-Dimer Tubulin-Tubulin Binding Strength of Microtubules
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-31
    Ning Liu, Ramana Pidaparti, Xianqiao Wang

    Energetic interactions inside αβ-tubulin dimers of a microtubule (MT) with atomic resolutions are of importance in determining the mechanical properties and structural stability of the MT as well as designing self-assembled functional structures from it. Here, we carry out several comprehensive atomistic simulations to investigate the interaction properties within αβ-tubulin dimers and effect of residue mutations on the intra-dimer tubulin-tubulin (IDTT) binding strength. Results indicate that the force-displacement responses of the dimer could be roughly divided into three stages involving increasing, decreasing, and fluctuating forces. Energetic analysis shows that electrostatic interactions dominate the IDTT binding strength. Further per-residue energetic analysis shows that the major part of the interface interaction energy (approximately 72% for α- tubulin and 62% for β-tubulin) come from amino acid residues with net charges, namely arginine (ARG), lysine (LYS), glutamic acid (GLU), aspartic acid (ASP). Residue mutations are completed for ARG105 on α-tubulin and ASP251 on β-tubulin to study the effect of mutations on the IDTT binding strength. Results indicate that stiffness, rupture force, and interface interaction energy of αβ-tubulin dimer can be improved by up to 28%, 13% and 28%, respectively. Overall, our results provide a thorough atomistic understanding of the IDTT binding strength within αβ-tubulin heterodimers and help pave the way for eventually designing and controlling the self-assembled functional structures from MTs.

    更新日期:2017-11-01
  • Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-30
    Sultan Doganay, Maurice Youzong Lee, Alina Baum, Jessie Peh, Sun-Young Hwang, Joo-Yeon Yoo, Paul J. Hergenrother, Adolfo Garcia-Sastre, Sua Myong, Taekjip Ha

    RIG-I-like receptors (RLRs) are cytoplasmic sensors of viral RNA that trigger the signaling cascade that leads to type I interferon (IFN) production. Transcriptional induction of RLRs by IFN is believed to play the role of positive feedback to further amplify viral sensing. We found that RLRs and several other IFN-stimulated genes (ISGs) are induced early in viral infection independent of IFN. Expression of these early ISGs requires IRF3/IRF7 and is highly correlated amongst them. Simultaneous detection of mRNA of IFNB1, viral replicase, and ISGs revealed distinct populations of IFNB1 expressing and non-expressing cells which are highly correlated with the levels of early ISGs but are uncorrelated with IFN-dependent ISGs and viral gene expression. Individual expression of RLRs made IFNB1 expression more robust and earlier, suggesting a causal relation between levels of RLR and induction of IFN.

    更新日期:2017-10-31
  • Enhanced Directional Cell Migration Induced by Vaccinia Virus on A Microfluidic-based Multi-shear Cell Migration Assay Platform
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-30
    Cheng Wang, Na Xu, Yu-Jun Yang, Qiumei Wu, Dai-Wen Pang, Zhi-Ling Zhang

    Virus-induced cell migration plays important roles in the direct and rapid spread of virus particles. As cell migration is also regulated by shear stress, it is necessary to explore the cell migration behavior influenced by multiple factors including virus and shear stress. In this report, a three-layer microfluidic chip with symmetric channels was designed and fabricated to investigate vaccinia virus-induced cell migration in different shear stress environments. Regular “exclusion zones” without cell damage were formed by microvalves. The results showed that infected cells were more elongated and tended to migrate along the flow direction compared to the random cell migration in static condition. Meanwhile, shear stress enhanced the natural directional persistence and accelerated the velocity of infected cell migration. Moreover, reduced peripheral lamellae and confined axial lamella to flow direction were responsible for the increased directionality of cell migration under shear stress. Interestingly, in the presence of shear stress, Golgi complex reoriented and relocated behind the nucleus and aligned to the flow direction in infected migratory cells accompanied by the rearrangement of cytoskeleton. Our report reveals the cell migration behavior in the multi-environment of virus and shear stress based on the microfluidic cell migration assay platform. It helps us to deeply understand the interactions between virus, host cells, and surrounding microenvironment.

    更新日期:2017-10-31
  • Three-dimensional morphometry of collagen fibrils in membranous bone
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-20
    Mana Hashimoto, Noriyuki Nagaoka, Kaori Tabata, Tomoyo Tanaka, Ryuta Osumi, Naoya Odagaki, Toru Hara, Hiroshi Kamioka

    The collagen network acts as a scaffold for calcification and its three-dimensional structure influences bone strength. It is therefore important to observe the collagen network in detail and three-dimensionally. In this study, we observed the collagen network of chick embryonic calvaria in membranous bone three-dimensionally by orthogonally arranged FIB-SEM. A 25×25-μm area of chick embryonic calvaria were observed at high resolution (25 nm/pixel). The inside of the bone (i.e. the primary calcified tissue), the bone cells (i.e. the osteoblasts and the osteocytes), the organelles, and the collagen fibrils were observed in detail. These structures were observed three-dimensionally using the Amira software program. In addition, the collagen fibrils of the bone were automatically extracted using the XTracing extension software program, and three-dimensional morphometry was performed. Almost all of the collagen fibrils ran along the longitudinal axis of the trabecular bone. We found that the regularity of the collagen fibril orientation was less remarkable in the osteoblast layer, which contained numerous osteoblasts. The collagen fibril orientation started to show regularity toward the central bone layer, which contained few bone cells.

    更新日期:2017-10-21
  • Lipidomic profiles of Drosophila melanogaster and cactophilic fly species: models of human metabolic diseases
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-02
    Daniel Cázarez-García, Mariana Ramírez Loustalot-Laclette, Therese Ann Markow, Robert Winkler
    更新日期:2017-10-18
  • Comparing Caenorhabditis elegans gentle and harsh touch response behavior using a multiplexed hydraulic microfluidic device
    Integr. Biol. (IF 3.252) Pub Date : 2017-09-05
    Patrick D. McClanahan, Joyce H. Xu, Christopher Fang-Yen
    更新日期:2017-10-16
  • Model-guided identification of novel gene amplification targets for improving succinate production in Escherichia coli NZN111
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-30
    Xingxing Jian, Ningchuan Li, Qian Chen, Qiang Hua
    更新日期:2017-10-16
  • A multiscale study of the role of dynamin in the regulation of glucose uptake
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-23
    Raphaël Trouillon, M. Cristina Letizia, Keir J. Menzies, Laurent Mouchiroud, Johan Auwerx, Kristina Schoonjans, Martin A. M. Gijs
    更新日期:2017-10-16
  • Membrane and genomic DNA dual-targeting of citrus flavonoid naringenin against Staphylococcus aureus
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-22
    Lang-Hong Wang, Man-Sheng Wang, Xin-An Zeng, Xi-Ming Xu, Charles S. Brennan
    更新日期:2017-10-16
  • Correction: A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-12
    Hagit Peretz-Soroka, Reuven Tirosh, Jolly Hipolito, Erwin Huebner, Murray Alexander, Jason Fiege, Francis Lin

    Correction for ‘A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay’ by Hagit Peretz-Soroka et al., Integr. Biol., 2017, DOI: 10.1039/c7ib00086c.

    更新日期:2017-10-12
  • Lipidomic profiles of Drosophila melanogaster and cactophilic fly species: models of human metabolic diseases
    Integr. Biol. (IF 3.252) Pub Date : 2017-10-02
    Daniel Cázarez-García, Mariana Ramírez Loustalot-Laclette, Therese Ann Markow, Robert Winkler

    The metabolic syndrome (MetS) is associated with serious diseases and represents an important threat for global public health. The common fruit fly (Drosophila melanogaster) has served as a model organism to study physiological processes of the MetS, because central metabolic pathways are conserved among species, and because the flies are easy to cultivate in a laboratory. In nature, D. melanogaster is a fruit generalist, feeding on diets rich in simple carbohydrates. Other Drosophilids, however, have specialized on distinct resources. Drosophila mojavensis, for example, is endemic to the Sonoran Desert, where it feeds on necrotic cacti which are low in carbohydrates. It’s close relative, Drosophila arizonae is cactophilic as well, but also is found breeding in fruits containing simple sugars. Previous studies have shown that high-sugar diets negatively affect the larval development of D. mojavensis and increase their triglyceride content, compared to D. melanogaster. More general metabolic profiles, in response to these different diets, however, have yet to be produced for any of the species. In addition, because D. arizonae appears somewhat intermediate to D. melanogaster and D. mojavensis in their development times and survival under the above mentioned diets, its general metabolic profiles also are of interest. Thus, in the present study we ask to what extent the general metabolism of these three different Drosophila species is affected by diets of distinct protein-sugar ratios. To obtain an un-biased view on possibly novel phenomena, we combined untargeted metabolomics with Random Forest data mining.

    更新日期:2017-10-02
  • A bioenergetic mechanism for amoeboid-like cell motility profiles tested in a microfluidic electrotaxis assay
    Integr. Biol. (IF 3.252) Pub Date : 2017-09-29
    Hagit Peretz-Soroka, Reuven Tirosh, Jolly Hipolito, Erwin Huebner, Murray Alexander, Jason Fiege, Francis Lin
    更新日期:2017-09-29
  • A microfluidic oxygen gradient demonstrates differential activation of the hypoxia-regulated transcription factors HIF-1α and HIF-2α
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-18
    Megan L. Rexius-Hall, Jalees Rehman, David T. Eddington
    更新日期:2017-09-18
  • Quantitative profiling of innate immune activation by viral infection in single cells
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-15
    Andrea C. Timm, Jay W. Warrick, John Yin
    更新日期:2017-09-18
  • A hollow fiber system for simple generation of human brain organoids
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-28
    Yujuan Zhu, Li Wang, Fangchao Yin, Yue Yu, Yaqing Wang, Hui Liu, Hui Wang, Ning Sun, Haitao Liu, Jianhua Qin
    更新日期:2017-09-18
  • Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-20
    Yuta Chonan, Sotaro Taki, Oltea Sampetrean, Hideyuki Saya, Ryo Sudo
    更新日期:2017-09-18
  • Engineering micromyocardium to delineate cellular and extracellular regulation of myocardial tissue contractility
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-12
    Nethika R. Ariyasinghe, Caitlin H. Reck, Alyssa A. Viscio, Andrew P. Petersen, Davi M. Lyra-Leite, Nathan Cho, Megan L. McCain
    更新日期:2017-09-18
  • Pheomelanin molecular vibration is associated with mitochondrial ROS production in melanocytes and systemic oxidative stress and damage
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-11
    Ismael Galván, Alberto Jorge, María García-Gil
    更新日期:2017-09-18
  • Comparing Caenorhabditis elegans gentle and harsh touch response behavior using a multiplexed hydraulic microfluidic device
    Integr. Biol. (IF 3.252) Pub Date : 2017-09-05
    Patrick D. McClanahan, Joyce H. Xu, Christopher Fang-Yen
    更新日期:2017-09-15
  • Model-guided identification of novel gene amplification targets for improving succinate production in Escherichia coli NZN111
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-30
    Xingxing Jian, Ningchuan Li, Qian Chen, Qiang Hua
    更新日期:2017-09-08
  • Comparing Caenorhabditis elegans gentle and harsh touch response behavior using a multiplexed hydraulic microfluidic device
    Integr. Biol. (IF 3.252) Pub Date : 2017-09-05
    Patrick McClanahan, Joyce Xu, Christopher Fang-Yen

    The roundworm Caenorhabditis elegans is an important model system for understanding the genetics and physiology of touch. Classical assays for C. elegans touch, which involve manually touching the animal with a probe and observing its response, are limited by low their low throughput and qualitative nature. To address these limitations, weWe developed a microfluidic device in which several dozen animals are subject to spatially localized mechanical stimuli with variable amplitude. The device contains 64 sinusoidal channels through which worms crawl, and hydraulic valves that deliver touch stimuli to the worms. We used this assay to characterize the behavioral responses to gentle touch stimuli and the less well studied harsh (nociceptive) touch stimuli. First, we measured the relative response thresholds of gentle and harsh touch. Next, we quantified differences in the receptive fields between wild type worms and a mutant with non-functioning posterior touch receptor neurons. We foundshowed that under gentle touch the receptive field of the anterior touch receptor neurons extends into the posterior half of the body. Finally, we found that the behavioral response to gentle touch does not depend on the locomotion of the animal immediately prior to the stimulus, but does depend on the location of the previous touch. Responses to harsh touch, on the other hand, did not depend on either previous velocity or stimulus location. Differences in gentle and harsh touch response characteristics may reflect the different innervation patterns of the respective mechanosensory cells. Our assay will facilitate studies of mechanosensation, sensory adaptation, and nociception.

    更新日期:2017-09-06
  • Membrane and genomic DNA dual-targeting of citrus flavonoid naringenin against Staphylococcus aureus
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-22
    Lang-Hong Wang, Man-Sheng Wang, Xin-An Zeng, Xi-Ming Xu, Charles S. Brennan
    更新日期:2017-09-04
  • Model-guided identification of novel gene amplification targets for improving succinate production in Escherichia coli NZN111
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-30
    Xingxing Jian, Ningchuan Li, Qian Chen, Qiang Hua

    Reconstruction and application of genome-scale metabolic models (GEMs) have facilitated metabolic engineering by providing a platform on which systematic computational analysis of metabolic networks can be performed. In this study, a GEM of Escherichia coli NZN111 was employed by the analysis of production and growth coupling (APGC) algorithm to identify genetic strategies for the overproduction of succinate. Through in silico simulation and reaction expression analysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), triosephosphate isomerase (TPI), and phosphoenolpyruvate carboxylase (PPC), encoded by gapA, pgk, tpiA, and ppc, respectively, were selected for experimental overexpression. The results showed that overexpressing any of these could improve both growth and succinate production. Specifically, overexpression of GAPDH or PGK showed a significant effect with up to 24% increase on succinate production. These results indicate that the APGC algorithm can be effectively used to guide genetic manipulation for strain design by identifying genome-wide gene amplification targets.

    更新日期:2017-08-31
  • A multiscale study of the role of dynamin in the regulation of glucose uptake
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-23
    Raphaël Trouillon, M. Cristina Letizia, Keir J. Menzies, Laurent Mouchiroud, Johan Auwerx, Kristina Schoonjans, Martin A. M. Gijs
    更新日期:2017-08-30
  • A microfluidic oxygen gradient demonstrates differential activation of the hypoxia-regulated transcription factors HIF-1α and HIF-2α
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-18
    Megan L. Rexius-Hall, Jalees Rehman, David T. Eddington
    更新日期:2017-08-25
  • A multiscale study of the role of dynamin in the regulation of glucose uptake
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-23
    Raphaël Trouillon, M. Cristina Letizia, Keir J. Menzies, Laurent Mouchiroud, Johan Auwerx, Kristina Schoonjans, Martin Gijs

    Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. The inability of cells to mobilize the specific glucose transporter GLUT4 is believed to be at least partially accountable for diseases, like diabetes, where cells do not respond to an insulin stimulus. In this work, a microchip is used to detect electrochemically glucose uptake from C2C12 myoblasts cultured on a patch of paper upon exposure to insulin. More importantly, the data suggest a new role for dynamin, a molecular motor which would be involved in GLUT4 translocation by facilitating exocytosis. It is also shown in vivo that dynamin is involved in the response to glucose in a completely distinct organism, namely the nematode Caenorhabditis elegans. The new mechanism for dynamin could therefore be more generally relevant in vivo and may play a role in insulin resistance.

    更新日期:2017-08-24
  • Quantitative profiling of innate immune activation by viral infection in single cells
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-15
    Andrea C. Timm, Jay W. Warrick, John Yin
    更新日期:2017-08-23
  • Membrane and genomic DNA dual-targeting of citrus flavonoid naringenin against Staphylococcus aureus
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-22
    Lang-Hong Wang, Man-Sheng Wang, Xin-An Zeng, Xi-Ming Xu, Charles Brennan

    The antimicrobial mechanism of naringenin, one of the citrus antibacterial flavonoids against foodborne Staphylococcus aureus ATCC 6538 was investigated in this work. Analysis of gas chromatography−mass spectrometry (GC−MS) and fluorescence showed that the relative low concentrations of naringenin caused perturbations in membrane fatty acid composition and conformation of membrane protein with changing the microenvironment of the phenylalanine, tyrosine and tryptophane residues. Exposure of naringenin at higher levels increased significantly membrane permeability and changed morphology of S. aureus cells. The genomic DNA-binding of naringenin was also quantitatively monitored using Uv-vis spectra with combination of multivariate curve resolution-alternating least (MCR−ALS) analysis, and the concentration and pure spectra profiles for the three reaction species (DNA, naringenin and DNA−naringenin) were obtained. Moreover, thermal behavior of DNA and docking studies revealed that naringenin preferentially bound to the A−T base pairs region of genomic DNA via groove mode, and atomic force microscopy and circular dichroism showed that naringenin induced mild secondary structure and obvious morphological variations of this biomacromolecule. These results suggested that naringenin exerts its antibacterial effects might be connected with disruption of the cytoplasmic membrane and DNA targeting effects of Staphylococcus aureus.

    更新日期:2017-08-23
  • A Microfluidic Oxygen Gradient Demonstrates Differential Activation of the Hypoxia-Regulated Transcription Factors HIF-1α and HIF-2α
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-18
    Megan L. Rexius-Hall, Jalees Rehman, David T Eddington

    Gas-perfused microchannels generated a linear oxygen gradient via diffusion across a 100 μm polydimethylsiloxane (PDMS) membrane. The device enabled exposure of a single monolayer of cells sharing culture media to a heterogeneous oxygen landscape, thus reflecting the oxygen gradients found at the microscale in the physiological setting and allowing for the real-time exchange of paracrine factors and metabolites between cells exposed to varying oxygen levels. By tuning the distance between two gas supply channels, the slope of the oxygen gradient was controlled. We studied the hypoxic activation of the transcription factors HIF-1α and HIF-2α in human endothelial cells within a spatial linear gradient of oxygen. Quantification of the nuclear to cytosolic ratio of HIF immunofluorescent staining demonstrated that the threshold for HIF-1α activation was below 2.5% O2 while HIF-2α was activated throughout the entire linear gradient. We show for the first time HIF-2α is subject to hyproxya, hypoxia by proxy, wherein hypoxic cells activate HIF in close proximity normoxic cells. These results underscore the differences between HIF-1α and HIF-2α regulation and suggest that a microfluidic oxygen gradient is a novel tool for identifying distinct hypoxic signaling activation and interactions between differentially oxygenated cells.

    更新日期:2017-08-18
  • Quantitative Profiling of Innate Immune Activation by Viral Infection in Single Cells
    Integr. Biol. (IF 3.252) Pub Date : 2017-08-15
    Andrea C Timm, Jay Warrick, John Yin

    Cells infected by viruses can exhibit diverse patterns of viral and cellular gene expression. The patterns arise in part from the stochastic or noisy reaction kinetics associated with the small number of genomes, enzymes, and other molecules that typically initiate virus replication and activate cellular anti-viral defenses. It is not known what features, if any, of the early viral or cellular gene expression correlate with later processes of viral replication or cell survival. Here we used two fluorescent reporters to visualize innate immune activation of human prostate cancer (PC3) cells against infection by vesicular stomatitis virus. The cells were engineered to express green-fluorescent protein under control of the promoter for IFIT2, an interferon-sensitive component of the anti-viral response, while red-fluorescent protein was expressed as a byproduct of virus infection. To isolate and quantitatively analyze single-cells, we used a unique microwell array device and open-source image processing software. Kinetic analysis of viral and cellular reporter profiles from hundreds of cells revealed novel relationships between gene expression and the outcome of infection. Specifically, the relative timing rather than the magnitude of the viral gene expression and innate immune activation correlated with the infection outcome. Earlier viral or anti-viral gene expression favored or hindered virus growth, respectively. Further, a correlation analysis of kinetic parameters estimated from these data showed a trade-off between robust antiviral signaling and cell death, as indicated by detectable cell lysis. More broadly, we demonstrate how the intrinsic heterogeneity of individual cell behaviors can be exploited to discover features of viral and host gene expression that correlate with single-cell outcomes, which will ultimately impact whether or not infections spread.

    更新日期:2017-08-15
  • Lmna knockout mouse embryonic fibroblasts are less contractile than their wild-type counterparts
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-07
    I. A. E. W. van Loosdregt, M. A. F. Kamps, C. W. J. Oomens, S. Loerakker, J. L. V. Broers, C. V. C. Bouten
    更新日期:2017-08-15
  • The Arp2/3 complex binding protein HS1 is required for efficient dendritic cell random migration and force generation
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-05
    Amy C. Bendell, Edward K. Williamson, Christopher S. Chen, Janis K. Burkhardt, Daniel A. Hammer
    更新日期:2017-08-15
  • Microengineered cultures containing human hepatic stellate cells and hepatocytes for drug development
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-03
    Matthew D. Davidson, David A. Kukla, Salman R. Khetani
    更新日期:2017-08-15
  • Exploring DNA–protein interactions on the single DNA molecule level using nanofluidic tools
    Integr. Biol. (IF 3.252) Pub Date : 2017-06-22
    Karolin Frykholm, Lena K. Nyberg, Fredrik Westerlund
    更新日期:2017-08-15
  • Demonstration of transgressive overyielding of algal mixed cultures in microdroplets
    Integr. Biol. (IF 3.252) Pub Date : 2017-06-15
    David N. Carruthers, Chang Kyu Byun, Bradley J. Cardinale, Xiaoxia Nina Lin
    更新日期:2017-08-15
  • 更新日期:2017-08-15
  • A hollow fiber system for simple generation of human brain organoids
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-28
    Yujuan Zhu, Li Wang, Fangchao Yin, Yue Yu, Yaqing Wang, Hui Liu, Hui Wang, Ning Sun, Haitao Liu, Jianhua Qin
    更新日期:2017-08-10
  • Hollow Fiber System for Simple Generation of Human Brain Organoids
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-28
    Jianhua Qin, Yujuan Zhu, Li Wang, Fangchao Yin, Yue Yu, Yaqing Wang, Hui Liu, Hui Wang, ning sun, haitao Liu

    3D organoids exhibit near-physiological morphogenesis and histology relying on the self-organization of human pluripotent stem cells (hPSCs), representing a new class of in vitro model for studying developmental biology and diseases. An engineered approach is highly desirable to generate sufficient organoids in a simple and efficient manner. Herein, we present a new strategy for simple formation of massive human brain organoids from hiPSCs within hollow fiber reactor system by combining fiber materials with developmental biology principle. A thin and finely adjustable calcium alginate (CaA) core-shell fiber was constructed using a multilayer coaxial laminar flow microfluidic system. The meter-long hollow fibers enabled neural differentiation of hiPSCs and simple formation of abundant brain organoids in a 3D matrix. The generated brain organoids displayed essential features of human brain organogenesis, including polarized neuroepithelium, cell type heterogeneity and discrete brain regions, resembling the early brain development. This approach is simple and easy to operate, which allows for simplified formation of massive brain organoids, overcoming the tedious procedures in conventional methods. In particular, the facile and scalable characteristics of hollow fibers are compatible with real-time observation and monitor, as well as flexible tissue manipulations for downstream biological analysis. It might also provide a new platform to advance stem cell-derived organoid models and their utilities in biomedical applications.

    更新日期:2017-08-03
  • Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-20
    Yuta Chonan, Sotaro Taki, Oltea Sampetrean, Hideyuki Saya, Ryo Sudo
    更新日期:2017-08-03
  • Engineering micromyocardium to delineate cellular and extracellular regulation of myocardial tissue contractility
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-12
    Nethika R. Ariyasinghe, Caitlin H. Reck, Alyssa A. Viscio, Andrew P. Petersen, Davi M. Lyra-Leite, Nathan Cho, Megan L. McCain
    更新日期:2017-08-03
  • Pheomelanin molecular vibration is associated with mitochondrial ROS production in melanocytes and systemic oxidative stress and damage
    Integr. Biol. (IF 3.252) Pub Date : 2017-07-11
    Ismael Galván, Alberto Jorge, María García-Gil
    更新日期:2017-08-03
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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