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Integrative Biology: Quantitative Biosciences From Nano to Macro

Zhixiong Zhang, Lili Chen, Brock Humphries, Riley Brien, Max S Wicha, Kathryn E Luker, Gary D Luker, Yu-Chih Chen, Euisik Yoon
Metastasis is the cause of death in most patients of breast cancer and other solid malignancies. Identification of cancer cells with highly migratory capability to metastasize relies on markers for epithelial-to-mesenchymal transition (EMT), a process increasing cell migration and metastasis. Marker-based approaches are limited by inconsistences among patients, types of cancer, and partial EMT states. Alternatively, we analyzed cancer cell migration behavior using computer vision. Using a microfluidic single-cell migration chip and high-content imaging, we extracted morphological features and recorded migratory direction and speed of breast cancer cells...
November 13, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Mahboubeh S Noori, Evan S Streator, Grady E Carlson, David S Drozek, Monica M Burdick, Douglas J Goetz
Esophageal cancer has a 5 year survival rate of ∼20%. This dismal prognosis is due, in part, to the fact that esophageal cancer often presents at a late stage. Thus, there is a critical need for assays that enable the early detection of cancerous tissue within the esophagus. The luminal surface of the esophagus expresses signature molecule(s) at sites of transformation providing an avenue for the development of in situ assays that detect neoplastic growth within the esophagus. An attractive approach, receiving increased attention, is the endoscopic administration of particles conjugated with ligands to signature molecules present on transforming tissue...
November 6, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Jacob A VanderBurgh, Halie Hotchkiss, Archit Potharazu, Paul V Taufalele, Cynthia A Reinhart-King
Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates...
November 1, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Mayank, Navneet Kaur, Narinder Singh
Mutations in the BRAF gene are well known for their oncogenic effects. Point mutations in V599 are particularly oncogenic and are considered important for therapeutic purposes. Along with wild type, other V599 mutated BRAF variants viz. V599E, V599D and V599R are reported and crystals of the former two with inhibitor (BAY43-9006) are further detailed. Both wild-type and mutated BRAF forms show similar interaction patterns with BAY43-9006, but the 599th residue did not show any involvement in the interactions...
September 19, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
R C H Driessen, O M J A Stassen, M Sjöqvist, F Suarez Rodriguez, J Grolleman, C V C Bouten, C M Sahlgren
Notch signaling and blood flow regulate vascular formation and maturation, but how shear stress affects the different components of the Notch pathway in endothelial cells is poorly understood. We show that laminar shear stress results in a ligand specific gene expression profile in endothelial cells (HUVEC). JAG1 expression increases while DLL4 expression decreases. Jagged1 shows a unique response by clustering intracellularly six to nine hours after the onset of flow. The formation of the Jagged1 clusters requires protein production, ER export and endocytosis...
November 12, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Juan Wang, Joseph Koelbl, Anuraag Boddupalli, Zhiqi Yao, Kaitlin M Bratlie, Ian C Schneider
Contact guidance or bidirectional migration along aligned fibers modulates many physiological and pathological processes such as wound healing and cancer invasion. Aligned 2D collagen fibrils epitaxially grown on mica substrates replicate many features of contact guidance seen in aligned 3D collagen fiber networks. However, these 2D collagen self-assembled substrates are difficult to image through, do not have known or tunable mechanical properties and cells degrade and mechanically detach collagen fibrils from the surface, leading to an inability to assess contact guidance over long times...
November 12, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Pahweenvaj Ratnatilaka Na Bhuket, Jittima Amie Luckanagul, Pornchai Rojsitthisak, Qian Wang
The unique characteristics of enveloped viruses including nanometer size, consistent morphology, narrow size distribution, versatile functionality and biocompatibility have attracted attention from scientists to develop enveloped viruses for biomedical applications. The biomedical applications of the viral-based nanoparticles include vaccine development, imaging and targeted drug delivery. The modification of the structural elements of enveloped viruses is necessary for the desired functions. Here, we review the chemical approaches that have been utilized to develop bionanomaterials based on enveloped viruses for biomedical applications...
November 12, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Guillaume Perry, Wenjin Xiao, Gavin I Welsh, Adam W Perriman, Rachel Lennon
Improvements in the physiological relevance of cell-based assays have been enabled by the development of various interdisciplinary methods. However, due to their complexity, in vivo structures such as basement membranes (BMs), which regulate the phenotype of adherent cells, are still difficult to mimic in vitro. The reconstruction of a physiologically relevant BM is crucially important to develop cell-based assays with the capacity for drug screening and disease modelling. Here, we review the biophysical and biochemical properties of BMs in vivo and their interactions with neighbouring cells...
November 12, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Ramesh Prasad, Prosenjit Sen
Endothelial cell protein C receptor (EPCR), the cellular receptor for protein C (PC), facilitates PC activation through the thrombin/thrombomodulin complex and regulates thrombin generation. Under pathophysiological conditions like sepsis, the interactions between EPCR and PC become impaired. Previous studies have demonstrated that the EPCR contains a phospholipid in the antigen-binding groove that is responsible for the structural stability of the EPCR and for PC recognition. However, an understanding at the atomic level during ligand recognition is not fully developed...
November 12, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Ningwei Li, Tianfa Xie, Yubing Sun
Recently, researchers have been attempting to control pluripotent stem cell fate or generate self-organized tissues from stem cells. Advances in bioengineering enable generation of organotypic structures, which capture the cellular components, spatial cell organization and even some functions of tissues or organs in development. However, only a few engineering tools have been utilized to regulate the formation and organization of spatially complex tissues derived from stem cells. Here, we provide a review of recent progress in the culture of organotypic structures in vitro, focusing on how microengineering approaches including geometric confinement, extracellular matrix (ECM) property modulation, spatially controlled biochemical factors, and external forces, can be utilized to generate organotypic structures...
October 15, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Catarina Costa Moura, Stuart A Lanham, Tual Monfort, Konstantinos N Bourdakos, Rahul S Tare, Richard O C Oreffo, Sumeet Mahajan
The unique properties of skeletal stem cells have attracted significant attention in the development of strategies for skeletal regeneration. However, there remains a crucial unmet need to develop quantitative tools to elucidate skeletal cell development and monitor the formation of regenerated tissues using non-destructive techniques in 3D. Label-free methods such as coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG) and two-photon excited auto-fluorescence (TPEAF) microscopy are minimally invasive, non-destructive, and present new powerful alternatives to conventional imaging techniques...
October 15, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Vivi Andasari, Dongyuan Lü, Maciej Swat, Shiliang Feng, Fabian Spill, Li Chen, Xiangdong Luo, Muhammad Zaman, Mian Long
It is widely agreed that keratinocyte migration plays a crucial role in wound re-epithelialization. Defects in this function contribute to wound reoccurrence causing significant clinical problems. Several in vitro studies have shown that the speed of migrating keratinocytes can be regulated by epidermal growth factor (EGF) which affects keratinocyte's integrin expression. The relationship between integrin expression (through cell-matrix adhesion) stimulated by EGF and keratinocyte migration speed is not linear since increased adhesion, due to increased integrin expression, has been experimentally shown to slow down cell migration due to the biphasic dependence of cell speed on adhesion...
October 15, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Dana Mackey, Eilís Kelly, Robert Nooney, Richard O'Kennedy
The orientation and activity of antibodies immobilized on solid surfaces are of direct relevance to many immunosensing applications. We therefore investigate a mathematical model which estimates the fraction of antibodies which are available for reaction in a randomly adsorbed sample. Numerical simulations are presented which highlight the separate effects of antibody orientation, accessibility and loss of binding ability on the amount of captured antigen. The assay response can then be expressed as a function of total antibody density and used for optimizing the surface coverage strategy under various conditions...
October 15, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Henrik S Thoke, Luis A Bagatolli, Lars F Olsen
Water is involved in all aspects of biological activity, both as a solvent and as a reactant. It is hypothesized that intracellular water is in a highly structured state due to the high concentrations of macromolecules in the cell and that this may change the activity of intracellular enzymes due to altered binding affinities and allosteric regulations. Here we first investigate the kinetics of two glycolytic enzymes in artificially crowded aqueous solutions and show that crowding does indeed change their kinetics...
October 15, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Y Onishi, Y Eshita, R-C Ji, T Kobayashi, M Onishi, M Mizuno, J Yoshida, N Kubota
A DEAE-dextran-MMA copolymer (DDMC)-paclitaxel (PTX) conjugate was prepared using PTX as the guest and DDMC as the host. The resistance of B16F10 melanoma cells to PTX was confirmed, while the DDMC-PTX conjugate showed excellent anticancer activity that followed the Hill equation. The robustness in the tumor microenvironment of the allosteric system was confirmed via BIBO stability. This feedback control system, explained via a transfer function, was very stable and showed the sustainability of the system via a loop, and it showed superior anti-cancer activity without drug resistance from cancer cells...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Alexandra L Crampton, Katherine A Cummins, David K Wood
A critical role of vascular endothelium is as a semi-permeable barrier, dynamically regulating the flux of solutes between blood and the surrounding tissue. Existing platforms that quantify endothelial function in vitro are either significantly throughput limited or overlook physiologically relevant extracellular matrix (ECM) interactions and thus do not recapitulate in vivo function. Leveraging droplet microfluidics, we developed a scalable platform to measure endothelial function in nanoliter-volume, ECM-based microtissues...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Ivan de Carlos Cáceres, Daniel A Porto, Ivan Gallotta, Pamela Santonicola, Josue Rodríguez-Cordero, Elia Di Schiavi, Hang Lu
Spinal muscular atrophy (SMA) is a degenerative disorder that selectively deteriorates motor neurons due to a deficiency of survival motor neuron protein (SMN). The illness is the leading genetic cause of death in infants and is difficult to study in complex biological systems such as humans. A simpler model system, such as the nematode C. elegans, can be used to study potential mechanisms underlying this disease; C. elegans expresses the smn-1 gene, a homologue of SMN; powerful genetic tools in C. elegans research can be used to discover novel genes whose effect on SMN remains unknown or uncharacterized...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Laura Bernardi, Costanza Giampietro, Vita Marina, Martina Genta, Edoardo Mazza, Aldo Ferrari
Mature epithelial monolayers share the ability to coherently respond to external mechanical stimuli. Tissue remodeling requires cell shape changes and coordinated movements. Human endothelia provide an exquisite example of such emerging collective activities. As part of their function in maintaining body homeostasis under variable hemodynamic loadings, endothelial ensembles must dynamically adapt to wall shear stress and cyclic deformation. While the alignment of several types of cells, including fibroblasts, osteoblasts and epithelial tissues, in response to various flow conditions or wall shear stress levels has been described in detail, less is known about collective endothelial remodeling under pure wall deformation...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Julian Michael Rocha, Charles Joseph Richardson, Mingxing Zhang, Caroline Maureen Darch, Eugene Cai, Andreas Diepold, Andreas Gahlmann
In bacterial type 3 secretion, substrate proteins are actively transported from the bacterial cytoplasm into the host cell cytoplasm by a large membrane-embedded machinery called the injectisome. Injectisomes transport secretion substrates in response to specific environmental signals, but the molecular details by which the cytosolic secretion substrates are selected and transported through the type 3 secretion pathway remain unclear. Secretion activity and substrate selectivity are thought to be controlled by a sorting platform consisting of the proteins SctK, SctQ, SctL, and SctN, which together localize to the cytoplasmic side of membrane-embedded injectisomes...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Kathryn E Worley, Jennifer Rico-Varela, Dominic Ho, Leo Q Wan
Birth defects are a common occurrence in the United States and worldwide. Currently, evaluation of potential developmental toxicants (i.e., teratogens) relies heavily on animal-based models which do not always adequately mimic human development. In order to address this, researchers are developing in vitro human-based models which utilize human pluripotent stem cells (hPSCs) to assess the teratogenic potential of chemical substances. The field of human developmental toxicity assays includes a variety of platforms including monolayer, micropattern, embryoid body, and 3D organoid cultures...
September 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
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