Archive for the ‘Hot Articles’ Category

September’s HOT Article!

Article of the month for September, recommended by our referees, is free* to access for a limited time only!


An improved interolog mapping-based computational prediction of protein–protein interactions with increased network coverage
Edson Luiz Folador, Syed Shah Hassan, Ney Lemke, Debmalya Barh, Artur Silva, Rafaela Salgado Ferreira and Vasco Azevedo
Integr. Biol., 2014,6, 1080-1087
DOI: 10.1039/C4IB00136B

From themed collection Computational Integrative biology (IB)


Take a look at our Integrative Biology 2014 HOT Articles Collection!


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Non-linear EGFR pathway has linear response to ligand (say that five times fast)

The authors of the cover article for the August 2014 issue of Integrative Biology explore how extracellular signals are transmitted into the cells for the epidermal growth factor (EGF) pathway. In addition to shedding light on the complex nature of the EGFR pathway, this work provides insights that could be used to further understand mutations that cause cancerous cells to form. Signalling pathways, especially those involving growth factors, are often causes of the excessive growth and division rates of cancer cells

Cover Image, Integrative Biology August 2014

Extracellular signalling pathways are important for cell growth, division and death (apoptosis), but are difficult to study due to their transient nature and the presence of feedback loops. The epidermal growth factor (EGF) pathway also feeds into the MAPK signal cascade, so the quantitative responses of the cell to the initial signal is difficult to determine experimentally. Once the extracellular signal molecule (here EGF) binds to its receptor (EGFR), the cell acts on the signal, and then the original ligand is degraded. Further, the receptors themselves can be made and recycled during this process, adding another layer of complexity.

Figure 1A: The EGFR pathway

The researchers investigated the activation of the EGF receptor itself both experimentally and using a mathematical model (outlined in the paper). Using their mathematical model they predicted that the activation of EGFR (by phosphorylation) should be linearly related to the concentration of ligand EGF which binds to the cell. They then took serum starved cells, added varying concentrations of EGF and determined the amount of phosphorylated EGFR by high-throughput imaging of the immunofluorescence level. They determined that the activation level of the ligand was directly proportional to the ligand concentration, in agreement with the mathematical model.

Figure 4, bottom left panel: The linear relationship between receptor activation level and the amount of EGF added.

The study also showed that the activation of EGFR does not depend on the receptor turnover rate, the ligand binding affinity or the number of receptors available. The methods reported here could be used to describe other extracellular signalling pathways in future, leading to a greater understanding of these complicated and crucial systems.

Download the full article for free* until 21st October 2014!

The EGFR demonstrates linear signal transmission

Diego A. Oyarzun, Jo L. Bramhall, Fernando Lopez-Caamal, Frances M. Richards, Duncan I Jodrell, and Ben-Fillippo Krippendorff

DOI: 10.1039/c4ib00062e

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Free access to HOT articles

These HOT articles were recommended by our referees and are free to access for 4 weeks*

A biocompatible method of controlled retrieval of cell-encapsulating microgels from a culture plate
Kihak Gwon, Mihye Kim and Giyoong Tae  
Integr. Biol., 2014,6, 596-602
DOI: 10.1039/C4IB00006D

 Graphical abstract: A biocompatible method of controlled retrieval of cell-encapsulating microgels from a culture plate

The EGFR demonstrates linear signal transmission
Diego A. Oyarzún, Jo L. Bramhall, Fernando López-Caamal, Frances M. Richards, Duncan I. Jodrell and Ben-Fillippo Krippendorff  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C4IB00062E

Graphical abstract: The EGFR demonstrates linear signal transmission

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Free access to HOT Articles

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A biocompatible method of controlled retrieval of cell-encapsulating microgels from a culture plate
Kihak Gwon, Mihye Kim and Giyoong Tae  
Integr. Biol., 2014,6, 596-602
DOI: 10.1039/C4IB00006D

Graphical abstract: A biocompatible method of controlled retrieval of cell-encapsulating microgels from a culture plate

Sensory neurons and osteoblasts: close partners in a microfluidic platform
Estrela Neto, Cecília J. Alves, Daniela M. Sousa, Inês S. Alencastre, Ana H. Lourenço, Luís Leitão, Hyun R. Ryu, Noo L. Jeon, Rui Fernandes, Paulo Aguiar, Ramiro D. Almeida and Meriem Lamghari  
Integr. Biol., 2014,6, 586-595
DOI: 10.1039/C4IB00035H

Graphical abstract: Sensory neurons and osteoblasts: close partners in a microfluidic platform
 
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Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture
Rachel W. Kasinskas, Raja Venkatasubramanian and Neil S. Forbes  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C4IB00001C, Paper

Graphical abstract: Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture

A screen for short-range paracrine interactions
K. H. Spencer, M. Y. Kim, C. C. W. Hughes and E. E. Hui  
 Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40211H, Paper

Graphical abstract: A screen for short-range paracrine interactions
Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits
Xiaosai Yao, Atish D. Choudhury, Yvonne J. Yamanaka, Viktor A. Adalsteinsson, Todd M. Gierahn, Christina A. Williamson, Carla R. Lamb, Mary-Ellen Taplin, Mari Nakabayashi, Matthew S. Chabot, Tiantian Li, Gwo-Shu M. Lee, Jesse S. Boehm, Philip W. Kantoff, William C. Hahn, K. Dane Wittrup and J. Christopher Love  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40264A, Paper 

Graphical abstract: Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits

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The contractile strength of vascular smooth muscle myocytes is shape dependent
George J. C. Ye, Yvonne Aratyn-Schaus, Alexander P. Nesmith, Francesco S. Pasqualini, Patrick W. Alford and Kevin Kit Parker  
Integr. Biol., 2014,6, 152-163
DOI: 10.1039/C3IB40230D, Paper

Retrotaxis of human neutrophils during mechanical confinement inside microfluidic channels
Bashar Hamza, Elisabeth Wong, Sachin Patel, Hansang Cho, Joseph Martel and Daniel Irimia  
Integr. Biol., 2014,6, 175-183
DOI: 10.1039/C3IB40175H, Paper

Response of single leukemic cells to peptidase inhibitor therapy across time and dose using a microfluidic device
Michelle L. Kovarik, Alexandra J. Dickinson, Pourab Roy, Ranjit A. Poonnen, Jason P. Fine and Nancy L. Allbritton  
Integr. Biol., 2014,6, 164-174
DOI: 10.1039/C3IB40249E, Paper

Determination of glucose flux in live myoblasts by microfluidic nanosensing and mathematical modeling
Alessandro Zambon, Alice Zoso, Camilla Luni, Wolf B. Frommer and Nicola Elvassore  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40204E, Paper

Studies of the drug resistance response of sensitive and drug-resistant strains in a microfluidic system
Xiangdan Jiang, Yu Kang, Xingjie Pan, Jun Yu, Qi Ouyang and Chunxiong Luo  
Integr. Biol., 2014,6, 143-151
DOI: 10.1039/C3IB40164B, Paper

Topographical control of multiple cell adhesion molecules for traction force microscopy
Samuel R. Polio, Harikrishnan Parameswaran, Elizabeth P. Canovic, Carolynn M. Gaut, Diana Aksyonova, Dimitrije Stamenovic and Michael L. Smith  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40127H, Technical Innovation

Oscillatory shear stress induced calcium flickers in osteoblast cells
Bibhas Roy, Tamal Das, Debasish Mishra, Tapas K. Maiti and Suman Chakraborty  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40174J, Paper

The role of regucalcin in bone homeostasis: involvement as a novel cytokine
Masayoshi Yamaguchi  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40217G, Review Article

RhoA and Rac1 play independent roles in lysophosphatidic acid-induced ovarian cancer chemotaxis
Hyundoo Hwang, Eung-Kyun Kim, Juhee Park, Pann-Ghill Suh and Yoon-Kyoung Cho  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40183A, Paper 

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The mouse retina in 3D: quantification of vascular growth and remodeling
Florian Milde, Stephanie Lauw, Petros Koumoutsakos and M. Luisa Iruela-Arispe  
Integr. Biol., 2013,5, 1426-1438
DOI: 10.1039/C3IB40085A, Paper

Graphical abstract: The mouse retina in 3D: quantification of vascular growth and remodeling
Postulates on electromagnetic activity in biological systems and cancer
Jiří Pokorný, Jan Pokorný and Jitka Kobilková  
Integr. Biol., 2013,5, 1439-1446
DOI: 10.1039/C3IB40166A, Paper

Graphical abstract: Postulates on electromagnetic activity in biological systems and cancer
Local control of hepatic phenotype with growth factor-encoded surfaces
Dipali Patel, Amranul Haque, Caroline N. Jones, Nazgul Tuleouva, Elena Foster, Tam Vu, A. Hari Reddi and Alexander Revzin  
Integr. Biol., 2014,6, 44-52
DOI: 10.1039/C3IB40140E, Paper

Graphical abstract: Local control of hepatic phenotype with growth factor-encoded surfaces

Advances in magnetic tweezers for single molecule and cell biophysics
Devrim Kilinc and Gil U. Lee  
Integr. Biol., 2014,6, 27-34
DOI: 10.1039/C3IB40185E, Frontier

Graphical abstract: Advances in magnetic tweezers for single molecule and cell biophysics

Enhanced luminescence of CaMoO4:Eu by core@shell formation and its hyperthermia study after hybrid formation with Fe3O4: cytotoxicity assessment on human liver cancer cells and mesenchymal stem cells
A. K. Parchur, A. A. Ansari, B. P. Singh, T. N. Hasan, N. A. Syed, S. B. Rai and R. S. Ningthoujam  
Integr. Biol., 2014,6, 53-64
DOI: 10.1039/C3IB40148K, Paper

Graphical abstract: Enhanced luminescence of CaMoO4:Eu by core@shell formation and its hyperthermia study after hybrid formation with Fe3O4: cytotoxicity assessment on human liver cancer cells and mesenchymal stem cells

Microfluidic evaluation of red cells collected and stored in modified processing solutions used in blood banking
Yimeng Wang, Adam Giebink and Dana M. Spence  
Integr. Biol., 2014,6, 65-75
DOI: 10.1039/C3IB40187A, Paper

Graphical abstract: Microfluidic evaluation of red cells collected and stored in modified processing solutions used in blood banking
Probing the anti-aging role of polydatin in Caenorhabditis elegans on a chip
Hui Wen, Xinghua Gao and Jianhua Qin  
Integr. Biol., 2014,6, 35-43
DOI: 10.1039/C3IB40191J, Paper

Graphical abstract: Probing the anti-aging role of polydatin in Caenorhabditis elegans on a chip
Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids
Rebecca L. DiMarco, James Su, Kelley S. Yan, Ruby Dewi, Calvin J. Kuo and Sarah C. Heilshorn  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40188J, Paper

Graphical abstract: Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids
Cardiac tissue engineering: renewing the arsenal for the battle against heart disease
Vassilis Georgiadis, Richard A. Knight, Suwan N. Jayasinghe and Anastasis Stephanou  
Integr. Biol., 2014, Advance Article
DOI: 10.1039/C3IB40097B, Critical Review 

Graphical abstract: Cardiac tissue engineering: renewing the arsenal for the battle against heart disease
 

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Choose your own microtubule imaging adventure

Recent advances in fluorescent imaging and microscopy are allowing for better imaging of microtubule dynamics than ever before. Here, Dr. Ross and colleagues have collected the most effective techniques currently in use, and the major findings for each method to date. This comprehensive review was features as an Integrative Biology HOT article.

Fig. 1 of paper: Microtubule structure and dynamic instability

Microtubules are the stiffest of the three types of cytoskeletal filaments found in eukaryotic cells, and can be thought of as the “bones” of the cell. They are a crucial participant in cell division, and both push the chromosomes into alignment, and later pull them apart during anaphase. This involvement in cell division makes microtubules a target for several anti-cancer medications currently in use. In addition to being able to withstand and apply cellular forces, microtubules have been shown to undergo rapid switching between growth and shrinkage stages, called dynamic instability. The flexibility and structural properties of microtubules determines their functional roles in cells, and makes them a particularly compelling and challenging system to study. Imaging dynamic instability is therefore of paramount importance for elucidating the details of microtubule behavior in cells.

Transmitted light microscopy methods such as dark-field imaging and video-enhanced differential interference contrast (VE-DIC) led to the first observation of dynamic instability in 1986 by the Hotani group. They were able to observe individual microtubules growing and shrinking (at ~25 nm in diameter, microtubules are the smallest object that can be visualized).

Fluorescence microscopy can also be used both in living cells and in vitro, through different techniques and using different fluorescent labels. In cells, microtubules can be labeled with green fluorescent protein (GFP) and this has been used to image microtubule turnover, though there are limitations due to photobleaching under imaging conditions and spatial resolution in the crowded cellular environment.

For in vitro measurements, total internal reflection fluorescence (TIRF) microscopy is used. This technique provides better temporal resolution, and the ability to visualize microtubules and their associated proteins simultaneously with different fluorescent dyes. The determination that kinesin motors can either diffuse or walk towards the microtubule end was made using TIRF.

Another technique that has proven very useful is force microscopy. In this set-up the microtubule is fixed at one end and allowed to grow towards a barrier or trap. The force exerted by the microtubule during the growth or shrinkage stage can then be measured. This force has been determined to be on the pN scale, which is biologically relevant, and explains how microtubules can exert the necessary forces to align and then separate the chromosomes during cell division.

In future, techniques offering better resolution of microtubules both in living cells and in vitro could provide answers to many open questions, such as how the dynamics of microtubules are tuned in crowded living cells by both stabilizing and destabilizing associated proteins.

Modern methods to interrogate microtubule dynamics, Megan Bailey, Leslie Conway, Michael W. Gramlich, Taviare L. Hawkins and Jennifer L. Ross, Integr. Biol., 2013,5, 1324-1333. DOI: 10.1039/C3IB40124C

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Free to access HOT articles!

These HOT articles were recommended by our referees and are free to access for 4 weeks*

Modern methods to interrogate microtubule dynamics
Megan Bailey, Leslie Conway, Michael W. Gramlich, Taviare L. Hawkins and Jennifer L. Ross  
DOI: 10.1039/C3IB40124C

A co-culture device with a tunable stiffness to understand combinatorial cell–cell and cell–matrix interactions
Nikhil Rao, Gregory N. Grover, Ludovic G. Vincent, Samantha C. Evans, Yu Suk Choi, Katrina H. Spencer, Elliot E. Hui,  Adam J. Englerac and Karen L. Christman  
DOI: 10.1039/C3IB40078F

Cancer cell glycocalyx mediates mechanotransduction and flow-regulated invasion
Henry Qazi, Rocio Palomino, Zhong-Dong Shi, Lance L. Munn and John M. Tarbell  
DOI: 10.1039/C3IB40057C

Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-α
Ken S. Lau, Sarah B. Schrier, Jessica Gierut, Jesse Lyons, Douglas A. Lauffenburger and Kevin M. Haigis  
DOI: 10.1039/C3IB40062J

Directed cell migration in multi-cue environments
Laura Lara Rodriguez and Ian C. Schneider  
DOI: 10.1039/C3IB40137E

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Tumour cells: understanding the invasion strategy

Roger Kamm and colleagues from the Massachusetts Institute of Technology have taken us one step closer to understanding how cancer cells are sneaking into secondary invasion sites.

In their recent paper 1 published in Integrative Biology, Kamm et al produce a microfluidics-based platform for the study of tumour cell movement, which they use to analyse the process through which cancer cells spread throughout our body as they execute a complex invasion strategy.

Through this platform, Kamm and team showed that more aggressive tumour cells are better at getting out of our blood stream and into our tissues, and that within a group of tumour cells, subpopulations exist which differ in their tissue invasion capability. But what makes these cells good at moving through our bodies? 

 

Metastasis is a step in malignancy in which tumour cells move from their initial development site, enter the blood stream, and move through the vascular system to secondary invasion sites. Extravasation is the final step in metastasis: tumour cells work their way out of the vascular network by latching onto the endothelial cells lining our blood vessels, squeezing out through small pores and entering adjacent tissue.

As such an important step in metastasis, finding drug targets within the extravasation mechanism of tumour cells has potential to allow for a huge development in cancer therapy. But in order to do this, we must understand the key molecular players in extravasation.

In the past, studies have been low resolution in vivo and have not allowed for the elucidation of the molecular details of the process. Developments in the field of microfluidics have provided advancements. However, there are limitations both in the unknown effect of microfluidic components on extravasation mechanisms and in the physiological relevance. 3D microvascular networks are now being more widely used to study cell migration as they allow for more physiologically representative studies due to their formation through angio- and vasculogenesis (growth of new blood vessels).

In Kamm’s paper, the team combined these microvascular networks with microfluidic technology to study the entire process of extravasation in vitro; the model is high-resolution, high throughput and has increased physiological relevance over previous models.

First of all, human umbilical vein endothelial cells were used to ‘grow’ microvascular networks through vasculogenesis. Cell culturing within two gel-filled channels lead to spreading and organisation of endothelial cells into tubes, providing a micro-scale blood vessel network.

Once this model system was set up, changes in pressure were used to draw a suspension of tumour cells into the vascular network, in a process called seeding. Seeded tumour cells are shown below (green), in amongst the vascular network (red), in an image taken from Fig. 1 of Kamm’s paper. After seeding, tumour cells were left to their own devices for 30min before the channel was washed. After this, cells that had begun the extravasation process remained within the channel through mechanical or adhesive interactions; they had completed the ‘latching on’ step of extravasation.

 

Kamm found that sub-populations of tumour cells exist, which had varying extravasation capabilities. His research team also showed positive correlation between the metastatic potentials of different cells lines and their extravasation capabilities. This tells us that the more aggressive tumour cells are better at getting out of our blood vessels and into our tissues.

In addition to this, Kamm et al showed that elevated levels of TNF-α, a pro-inflammatory molecule, were associated with both an increase in endothelial permeability and extravasation rate, suggesting a correlation between the two.

In this work, Kamm and colleagues have made an excellent contribution to the study of tumour metastasis, and their microfluidic-based research platform is sure to continue to elucidate the molecular signatures behind the process. We look forward to future work by this research team!

This article by Kamm et al will be free to download* for the next two weeks, so pick it up for a thorough read.

  1. Mechanisms of tumour cell extravasation in an in vitro microvascular network platform. Roger D. Kamm, Michelle B. Chen, Jordan A. Whisler and Jessie S. Jeon. DOI: 10.1039/C3IB40149A.

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