Timing is everything: Bacterial attachment mimics just-in-time industrial model

ScienceDaily (Nov. 30, 2011) — n the human world of manufacturing, many companies are now applying an on-demand, just-in-time strategy to conserve resources, reduce costs and promote production of goods precisely when and where they are most needed. A recent study from Indiana University Bloomington scientists reveals that bacteria have evolved a similar just-in-time strategy to constrain production of an extremely sticky cement to exactly the appropriate time and place, avoiding wasteful and problematic production of the material.

Indiana University biologists and two physicists at Brown University with IU connections have shown that certain bacteria wait until the last minute to synthesize the glue that allows them to attach permanently to surfaces. Binding efficiently to surfaces is extremely important to bacteria in the environment and for bacterial disease agents during the infection process.

The researchers found that bacteria -- including the freshwater bacterium Caulobacter crescentus and the agricultural pathogen Agrobacterium tumefaciens -- first connect to a surface with the cellular equivalents of propellers and cables and that this initial, reversible contact stimulates the synthesis of a sticky glue. This holdfast adhesin, which is composed of polysaccharide sugar molecules, is then released only at the site of surface contact to irreversibly attach the bacteria to host surfaces.

The study, "Surface contact stimulates the just-in-time deployment of bacterial adhesins," was published earlier this month in Molecular Microbiology . It describes how single bacterial cells use their flagella (the propellers) and pili (the cables) to facilitate the timely release of adhesive polysaccharides upon initial contact with other surfaces.

Microbiologists are generally interested in bacterial adhesion and formation of complex microbial communities called biofilms that can clog pipes, slow down ships and establish antibiotic-resistant infections. Efficient surface attachment strategies are advantageous to bacteria as they can increase nutrient access and resistance to environmental stress, including host defenses.

"For bacteria, surface attachment by single cells is the first step to important processes such as biofilm formation and host infection," said IU microbiologist Pamela Brown, one of the project's lead authors. "What we found is that the interaction of bacterial cells with a surface using their flagellum and pili stimulates the on-the-spot production of polysaccharide adhesins, propelling the transition from transient to permanent attachment."

The new findings also suggest that pathogenic bacteria may carefully time adhesin release to protect themselves from premature exposure to a host's immune system during infection.

The team used cutting-edge, high-resolution video microscopy to observe the single-cell attachment process in real time in the presence of a fluorescent stain that decorates the adhesive polysaccharide. They found that when Caulobacter cells are propelled to a surface by their rotating propeller-like single flagellum, the flagellar motor stopped immediately upon contact with the surface. Inhibition of flagellar rotation was quickly followed by the production of the holdfast polysaccharide adhesin, specifically from the cell pole containing the now inactive flagellum, and in contact with the surface.

"We knew that cable-like pili are present at the same pole of the cell as the flagellum, and we hypothesized that they played a key role in the process by interacting with the surface, thereby preventing the free rotation of the flagellum," said IU microbiologist Yves Brun, the project's principal investigator. Indeed, when the team made a mutation that abolished the pili, the cells became tethered to the surface by their flagellum, but its rotation continued and the cell eventually detached.

The team hypothesizes that just-in-time adhesin production may be a general phenomenon since they obtained similar results with two other bacterial species, Agrobacterium tumefaciens and Asticcacaulis biprosthecum.

"What is striking is that we found that this mechanism does more than stimulate binding to inert surfaces. It also operates when the plant pathogen Agrobacterium tumefaciens binds to host tissue," said IU microbiologist Clay Fuqua, who recently discovered the holdfast-type adhesin used by this bacterium to attach to plant tissue. "We think that the ability to rapidly deploy this permanent adhesin may be advantageous for swimming cells attempting to colonize a favorable environment."

Since pathogens such as Escherichia coli and Pseudomonas aeruginosa also attach by their pole prior to their transition from reversible to irreversible attachment, the authors hypothesize that this mechanism could also be at play during the infection process.

"Once we know more about the details of this mechanism, we may be able to design drugs that prevent this adhesin stimulation, therefore reducing the efficiency of infections," Brown said.

Research from Brun's laboratory and that of Brown University physicist Jay Tang on bacterial glues published in 2006 received international attention after they showed that the holdfast "glue" released by the tiny Caulobacter cells was the strongest in nature with a pulling force of 1 micronewton, equivalent to holding three or four cars with glue spread on the surface of a quarter.

"For such a strong adhesive, it may be important to avoid producing it too early because it might lose its efficiency, or it might get the cells irreversibly bound to the wrong surface. The analogy to the human world is amazing: You don't apply glue hours before you want to use it because it cures and hardens," Brun said.

Timing is everything, and with just-in-time adhesive production, cells have a better chance for efficient surface interaction and colonization because the two main factors in reducing adhesion -- curing and coating of glue with small particles -- are inhibitory mechanisms that require time to decrease adhesiveness. The on-the-spot production of adhesins circumvents this problem.

Funding for this research was provided by the National Institutes of Health, the Indiana University Faculty Research Support Program and the Indiana METACyt Initiative of IU.

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The above story is reprinted from materials provided by Indiana University.

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Journal Reference:

Guanglai Li, Pamela J. B. Brown, Jay X. Tang, Jing Xu, Ellen M. Quardokus, Clay Fuqua, Yves V. Brun. Surface contact stimulates the just-in-time deployment of bacterial adhesins. Molecular Microbiology, 2011; DOI: 10.1111/j.1365-2958.2011.07909.x

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More accurate tropical cyclone prediction model developed

ScienceDaily (Nov. 18, 2011) — Researchers at the Naval Research Laboratory Marine Meteorology Division (MMD), Monterey, Calif., have developed the Coupled Ocean/Atmosphere Mesoscale Prediction System Tropical Cyclone (COAMPS-TC™) model, achieving a significant research milestone in predictions of tropical cyclone intensity and structure.

While the predictions of the paths or tracks of hurricanes, more generally referred to as tropical cyclones (TC), have steadily improved over the last few decades, improvements in the predictions of storm intensity have proven much more difficult.

"Over the past two years, the COAMPS-TC model has shown to be the most accurate emerging research model for predicting tropical cyclone intensity," said Dr. Jim Doyle, research meteorologist, NRL Monterey. "There is no better example of these difficult challenges than the intensity predictions for Hurricane Irene this past August."

Producing very accurate intensity predictions during a real-time experimental demonstration of Hurricane Irene, COAMPS-TC intensity errors were six knots on average for a series of three-day forecasts, a clear improvement over the official National Hurricane Center (NHC) forecast and other operational models that ranged from 20-30 knots.

The successful predictions have demonstrated that Numerical Weather Prediction (NWP) models can outperform operational statistical-dynamic models that are based on climatology and previous behavior. It is further believed that NWP models, which explicitly predict the location, dynamics and intensity of a storm, will eventually provide the most promising approach to achieve accurate TC intensity and structure prediction.

Advancing further methodologies used for vortex initialization, data assimilation and representation of physical processes, COAMPS-TC is expected to become fully-operational in 2013 at the Navy's Fleet Numerical Meteorology and Oceanography Center (FNMOC) in Monterey. Considerable advancements have been made to several components of the modeling system including the data assimilation of conventional and special TC synthetic observations, vortex initialization, and representation of key TC physical processes such as air-sea fluxes, clouds and convection.

The COAMPS-TC project will potentially signal a paradigm shift in TC forecasting and is already making a strong impression on the forecasting community. Focusing on the development and transition of a fully coupled air-ocean-wave prediction system, the COAMPS-TC model includes nonhydrostatic atmospheric dynamics, multiple nested moving grids that follow the center of the storm and improved boundary layer and cloud physical parameterizations.

COAMPS-TC was first tested in real-time in support of two field campaigns sponsored by the Office of Naval Research (ONR). The Tropical Cyclone Structure-08 (TCS-08) conducted as part of The Observing System Research and Predictability Experiment (THORPEX) Pacific Asian Regional Campaign (T-PARC) in 2008 and the Impact of Typhoons on the Ocean in the Pacific (ITOP) in 2010, both of which took place in the Western Pacific. Additionally, COAMPS-TC advancements and real-time demonstrations in the Eastern Pacific and Western Atlantic have taken place through collaboration with the National Oceanic and Atmospheric Administration (NOAA) as part of the Hurricane Forecast Improvement Project (HFIP) -- a community-wide effort focused on improving operational hurricane prediction.

In June 2011, COAMPS-TC was one of nine worldwide winners of the inaugural High Performance Computing (HPC) Excellence Award presented at the ISC-11 International Supercomputing Conference in Hamburg, Germany -- an award presented annually to recognize noteworthy achievements by users of HPC technologies. As a result, COAMPS-TC was recognized for achieving 'a significantly improved model for tropical cyclone forecasting.' COAMPS-TC development benefited significantly from the Department of Defense HPC Modernization Program Office (HPCMO) computational assets at the Navy Defense Supercomputing Resource Center (DSRC) at Mississippi's Stennis Space Center.

Increasingly-sophisticated developmental versions of COAMPS-TC will continue to be demonstrated in real-time and in support of the Joint Typhoon Warning Center and the National Hurricane Center. A key additional enhancement will be a fully coupled ocean-atmosphere version in which the NRL Costal Ocean Model (NCOM) and the Wave Watch III (WWIII) will provide the ocean circulation and wave components, respectively.

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Yeast model connects Alzheimer's disease risk and amyloid beta toxicity

ScienceDaily (Oct. 27, 2011) — In a development that sheds new light on the pathology of Alzheimer's disease (AD), a team of Whitehead Institute scientists has identified connections between genetic risk factors for the disease and the effects of a peptide toxic to nerve cells in the brains of AD patients.

The scientists, working in and in collaboration with the lab of Whitehead Member Susan Lindquist, established these previously unknown links in an unexpected way. They used a very simple cell type -- yeast cells -- to investigate the harmful effects of amyloid beta (Aß), a peptide whose accumulation in amyloid plaques is a hallmark of AD. This new yeast model of Aß toxicity, which they further validated in the worm C. elegans and in rat neurons, enables researchers to identify and test potential genetic modifiers of this toxicity.

"As we tackle other diseases and extend our lifetimes, Alzheimer's and related diseases will be the most devastating personal challenge for our families and one the most crushing burdens on our economy," says Lindquist, who is also a professor of biology at Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute. "We have to try new approaches and find out-of the-box solutions."

In a multi-step process, reported in the journal Science, the researchers were able to introduce the form of Aß most closely associated with AD into yeast in a manner that mimics its presence in human cells. The resulting toxicity in yeast reflects aspects of the mechanism by which this protein damages neurons. This became clear when a screen of the yeast genome for genes that affect Aß toxicity identified a dozen genes that have clear human homologs, including several that have previously been linked to AD risk by genome-wide association studies (GWAS) but with no known mechanistic connection.

With these genetic candidates in hand, the team set out to answer two key questions: Would the genes identified in yeast actually affect Aß toxicity in neurons? And if so, how?

To address the first issue, in a collaboration with Guy Caldwell's lab at the University of Alabama, researchers created lines of C. elegans worms expressing the toxic form of Aß specifically in a subset of neurons particularly vulnerable in AD. This resulted in an age-dependent loss of these neurons. Introducing the genes identified in the yeast that suppressed Aß toxicity into the worms counteracted this toxicity. One of these modifiers is the homolog of PICALM, one of the most highly validated human AD risk factors. To address whether PICALM could also suppress Aß toxicity in mammalian neurons, the group exposed cultured rat neurons to toxic Aß species. Expressing PICALM in these neurons increased their survival.

The question of how these AD risk genes were actually impacting Aß toxicity in neurons remained. The researchers had noted that many of the genes were associated with a key cellular protein-trafficking process known as endocytosis. This is the pathway that nerve cells use to move around the vital signaling molecules with which they connect circuits in the brain. They theorized that perhaps Aß was doing its damage by disrupting this process. Returning to yeast, they discovered that, in fact, the trafficking of signaling molecules in yeast was adversely affected by Aß. Here again, introducing genes identified as suppressors of Aß toxicity helped restore proper functioning.

Much remains to be learned, but the work provides a new and promising avenue to explore the mechanisms of genes identified in studies of disease susceptibility.

"We now have the sequencing power to detect all these important disease risk alleles, but that doesn't tell us what they're actually doing, how they lead to disease," says Sebastian Treusch, a former graduate student in the Lindquist lab and now a postdoctoral research associate at Princeton University.

Jessica Goodman, a postdoctoral fellow in the Lindquist lab, says the yeast model provides a link between genetic data and efforts to understand AD from the biochemical and neurological perspectives.

"Our yeast model bridges the gap between these two fields," Goodman adds. "It enables us to figure out the mechanisms of these risk factors which were previously unknown."

Members of the Lindquist lab intend to fully exploit the yeast model, using it to identify novel AD risk genes, perhaps in a first step to determining if identified genes have mutations in AD patient samples. The work will undoubtedly take the lab into uncharted territory.

Notes staff scientist Kent Matlack: "We know that Aß is toxic, and so far, the majority of efforts in the area of Aß have been focused on ways to prevent it from forming in the first place. But we need to look at everything, including ways to reduce or prevent its toxicity. That's the focus of the model. Any genes that we find that we can connect to humans will go into an area of research that has been less explored so far."

This work was supported by an HHMI Collaborative Innovation Award, an NRSA fellowship, the Cure Alzheimer's Fund, the National Institutes of Health, the Kempe foundation, and Alzheimerfonden.

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The above story is reprinted from materials provided by Whitehead Institute for Biomedical Research. The original article was written by Matt Fearer.

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Journal Reference:

Sebastian Treusch, Shusei Hamamichi, Jessica L. Goodman, Kent E. S. Matlack, Chee Yeun Chung, Valeriya Baru, Joshua M. Shulman, Antonio Parrado, Brooke J. Bevis, Julie S. Valastyan, Haesun Han, Malin Lindhagen-Persson, Eric M. Reiman, Denis A. Evans, David A. Bennett, Anders Olofsson, Philip L. Dejager, Rudolph E. Tanzi, Kim A. Caldwell, Guy A. Caldwell, Susan Lindquist. Functional Links Between Aß Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast. Science, 2011; DOI: 10.1126/science.1213210

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