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Roche NimbleGen Unveil the Secrets of Insidious Potato Blight

November 2009. A large international team of researchers recently published the 240-megabase DNA sequence of Phytophthora infestans, a robust parasitic water mold responsible for the Irish potato famine of the 1840s, in Nature (1). Breeders have not been able to produce potato cultivars that remain resistant to this insidious blight, aptly named as the plant (phyto) destroyer (phthora). This fungal-like pathogen is an oomycete, an eukaryote related to algae and diatoms that is transferred by wind-borne spores that spread rapidly and germinate on wet leaves, killing entire fields of potatoes, tomatoes, and other plants within a few weeks. Conservative estimates of potato crop losses attributed to late blight are about 16% (US$ 7.7 billion) of the global potato crop (US$ 47.2 billion) each year (2). The sequencing of this mold and subsequent genomic analyses will now help reveal details of its biologic and pathogenic processes, allowing more rapid development of reliable, environmentally benign, and economically feasible management tactics as well as insight into new breeding strategies.
Yearly potato production (300 Mt) substantially contributes to worldwide food security, surpassed only by wheat (630 Mt) and rice (608 Mt)(2). While it is important to identify the problem genes responsible for infection, it is equally important to identify the genes that develop resistance.
Brian J. Haas, a primary contributor from the Broad Institute of MIT and Harvard, noted that “NimbleGen services generated the data that made it possible for us to identify key genes in pathogenesis, as described in our recent Nature publication on the potato blight genome. In particular we identified a large number of so-called effector genes that are critical to pathogenesis that had been previously unknown and are extremely challenging to predict because of their small size and unusual structure.”
Senior author Chad Nusbaum, co-director of the Broad Institute’s Genome Sequencing and Analysis Program, added that “NimbleGen services generated data that made it possible for us to identify these genes in a timely and cost-competitive manner.”
The authors capitalized on Roche NimbleGen’s flexible array design capability to use the data from the newly sequenced genome to build a custom gene expression microarray, which helped measure gene level changes between the vegetative stage and infection stage. Nearly 3% of approximately 18,000 genes analyzed on the NimbleGen Gene Expression microarray are induced at least twofold during infection. Some of the induced genes belong to gene families with functions previously known to be involved in infection, such as RXLR genes, which may maintain virulence by suppressing host cell death. Understanding the P. infestans genes responsible for potato blight, and having unraveled its genetic code, will lead to methods for controlling the infection to improve food production and reduce the impact on worldwide crop losses.


(1) BJ Haas, S Kamoun, et al., Nature 2009 September 17; 241: 393–398; doi: 10.1038/nature08358
(2) AJ Haverkort, PC Struik, et al., Potato Res 2009 August 8; 52:249-264; doi: 10.1007/s11540-009-9136-3

 

 

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xCELLigence System for Cell Analysis

xCelligence RTCA DPThe extent to which protein targets are modulated by drugs or small molecule compounds depends on a number of factors, including the expression levels of the target, the effective concentration of the compound, and the time needed for the compound to perturb the target. One of the limitations of current multidimensional phenotypic profiling approaches is that typically a single time point is chosen to assess the effect of compounds. The conclusion, regarding the compounds´ mechanism of action, is based on the time point at which the samples are processed.

To address these restrictions, researchers Abassi et al. (1) have devised a live cell morphological profiling approach for dynamic monitoring of the effect of small molecule compounds that was based on impedance measurement of cells with the xCELLigence RTCA System of Roche Applied Science (SIX: RO, ROG; OTCQX: RHHBY). The approach was tested by screening a library containing FDA approved drugs, experimental compounds, and natural compounds. Compounds with similar activity produced similar impedance-based Time-dependent Cell Response Profiles (TCRPs). The compounds were clustered then based on TCRP similarity.

The researchers identified novel mechanisms for existing drugs, confirmed previously reported calcium modulating activity for COX-2 inhibitor celecoxib, and discovered an additional mechanism for the experimental compound monastrol. They also recognized and characterized a new antimitotic agent. This approach will also help to detect the off target effect of a given compound.

The TCRP technique described by Abassi et al. can overcome the limitations of current approaches, because the profile generated is time dependent. In combination with measurement of cell number, morphology, and adhesion, the TCR technique allows greater expansion of the ‘‘biological space’’ at which compounds are screened. It provides ample opportunity to detect and identify biological activity associated with small molecules.

In conclusion, these findings indicate that the time-dependant resolution, provided by the TCRP approach, can be used in conjunction with phenotypic profiling approaches to obtain additional data associated with small molecule compounds. TCRP approach provides predictive mechanistic information for small molecule compounds.

The non-invasive and label-free xCELLigence analysis method, originally invented by ACEA Biosciences in San Diego, USA is based on measuring the impedance of cells. The technique utilizes an electronic readout of impedance to non-invasively quantify cellular status in real-time. Cells are seeded in E-Plate microtiter plates, which are integrated with microelectronic sensor arrays. The interaction of cells with the microelectrode surface generates a cell-electrode impedance response, which not only indicates cell viability but also correlates with the number of the cells seeded in the well. In conjunction with its user-friendly data collection and analysis capabilities, the xCELLigence System makes a unique platform for continuous, real-time cell-based assays and provides a huge opportunity for cellular and molecular biology.

 

For more information on the technology, please visit www.roche-applied-science.com.

Literature:

(1) Abassi YA et al.: Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects. Chem Biol 2009; 16:712-723.

 

More information: www.xCELLigence.roche.com.

All trademarks used or mentioned in this release are protected by law.XCELLIGENCE is a trademark of Roche.E-PLATE and ACEA BIOSCIENCES are registered trademarks of ACEA Biosciences, Inc. in the US.

 

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