June 21, 2017

Researchers at the University of Michigan Life Sciences Institute have identified a new type of rapid-response defense mechanism that helps protect cells from environmental stress while giving slower, well-known protection systems time to act.

"It's like a first responder rushing to an alarm while the larger response team mobilizes," said Natsuko Jin, a postdoctoral research fellow in the lab of LSI faculty member Lois Weisman and lead author of a study scheduled to be published June 21 in the Journal of Cell Biology.

Generally, when cells are put under stress, adaptation mechanisms kick in. They trigger transcriptional machinery and, through gene expression, the cell produces new proteins to respond to the stress and keep itself alive.

In yeast, a single-cell organism often used to study fundamental cellular biology, a much faster type of response was also observedan immediate and short-lived spike in the production of a signaling lipid that is usually seen only in miniscule quantities.

When the scientists short-circuited the yeast's ability to generate this rapid response, the yeast succumbed to an environmental stress at catastrophic rates.

"This is the first time an early protection pathway that works faster than gene expression has been identified," Jin said. "Since many of the key players have been preserved by evolution up into people and other mammals, our investigations suggest this and other types of early protection pathways may exist more broadly, and they may respond to different types of cellular stress."

For this study, the yeast were put into an environment with a high concentration of saltwhat scientists call high osmolarity. Within a few minutes, each cell responds by setting off a signaling cascade that activates a key protein kinaseHog1which travels from the cell's cytoplasm into the nucleus, where it promotes changes in gene expression. These changes in gene expression take between 30 minutes and an hour to start to have an effect, and up to two hours to be fully activated.

Meanwhile, the researchers also observed a sharp, immediate spike in a signaling lipid known as PI3,5P2, which is produced by an organelle called the vacuole in yeast. The yeast vacuole is similar to the lysosome in complex organisms.

"Within one minute you see a five-fold elevation of this lipid," said Weisman, senior author on the study and professor of cell and developmental biology at the U-M Medical School. "Within five minutes, it's a 20-fold increase. Then, without us doing anything else to the cells, it plateaus and drops off."

When regular yeast were put into this high salt, or hyperosmotic, environment for four hours, most did just fine.

When the researchers used genetic manipulation to knock out the well-known, longer-term response pathway that produces Hog1, 30 percent of the cells died.

"Still, 70 percent did just fine," Weisman said.

But when they removed the cell's ability to produce PI3,5P2, 80 percent died.

"So we know it's doing something protective before the gene expression kicks in," she said. "If they don't have it, most die."

Exactly how PI3,5P2 conveys a benefit to the cell is not yet understood, Jin said. The current study examined the upstream regulators of the signaling lipid, and demonstrated they were distinct both in time and space from the action of the Hog1 pathway.

She also said that while the observation that PI3,5P2 spikes under hyperosmotic conditions dates back to the late 1990s, its role had previously been unclear. Jin's investigation started with the desire to understand what causes the spike and what physiological role it might play.

Explore further: Yeast study yields insights into cell-division cycle

Studies using yeast genetics have provided new, fundamental insights into the cell-division cycle, researchers at the University of Michigan Life Sciences Institute report.

In multicellular animals, cells communicate by emitting and receiving proteins, a process called signaling. One of the most common signaling pathways is the transforming growth factor b (Tgf-b) pathway, which functions in ...

Control of RNA lifespan is vital for the proper functioning of our cells. Marc Bhler's group at the Friedrich Miescher Institute for Biomedical Research (FMI) has discovered a novel mechanism determining the fate of RNA ...

Although all cells in an organism have the same DNA, cells function differently based on the genes they express. While most studies of gene expression focus on activities in the cell's nucleus, a new Cornell study finds that ...

Dr. Zhi-Liang Zheng, a biology professor and plant scientist in the Department of Biological Science, published a paper last month in the Proceedings of the National Academy of Sciences (PNAS) that demonstrates a connection ...

An MIT team has used an engineering approach to show that complex biological systems can be studied with simple models developed by measuring what goes into and out of the system.

The same mechanisms that quickly separate mixtures of oil and water are at play when controlling the organization in an unusual part of our DNA called heterochromatin, according to a new study by researchers at the Department ...

Researchers at the University of Michigan Life Sciences Institute have identified a new type of rapid-response defense mechanism that helps protect cells from environmental stress while giving slower, well-known protection ...

Gelada malesa close relative to baboonspay attention to the loud calls of a rival to gain information about his relative fighting ability compared to themselves, a new study indicated.

(Phys.org)A team of researchers from South Korea, the U.K. and the U.S. has used computational methods to follow chromosomal rearrangements in seven genomes. In their paper published in Proceedings of the National Academy ...

Humans possess many cognitive abilities not seen in other animals, such as a full-blown language capacity as well as reasoning and planning abilities. Despite these differences, however, it has been difficult to identify ...

Ever burn your tongue so badly that you were unable to taste your food for a few days? Luckily, a unique feature of taste cells is that they continually regenerate every 10 to 14 days. Now, a new study from the Monell Center ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Continued here:
Newly identified protection mechanism serves as first responder to cellular stress - Phys.Org

June 21, 2017 by Tom Fleischman

Integral membrane proteins, or IMPs, are a major class of proteins that play crucial roles in many cellular processes, including the catalysis of disulfide bonds, which are essential for the function and stability of many proteins such as antibodies, which have significant therapeutic potential.

But IMPs are intrinsically hydrophobic and thus have low solubility in watery environments. Their natural environment is within the lipid bilayer membrane of a cell, which makes it difficult to study their structure and function.

A previously reported method involving standard recombinant DNA techniques and some novel design principles enabled a team of Cornell chemical engineers to make large quantities of functional IMPs simply and inexpensively all without the use of harsh chemicals or detergents, which are typically used today. That team, led by Matt DeLisa, the William L. Lewis Professor of Engineering in the Robert Frederick Smith School of Chemical and Biomolecular Engineering, has now used that protein engineering method to convert a membrane-bound enzyme into a water-soluble biocatalyst that functions directly in the aqueous inner cell.

"You can redesign these tricky proteins, making them water-soluble, and perhaps really surprisingly, they can continue to catalyze their natural biological reactions," said DeLisa, principal investigator for "A water-soluble DsbB variant that catalyzes disulfide-bond formation in vivo," published June 19 in Nature Chemical Biology.

"To our knowledge, this is the first example of creating a water-soluble IMP that retains its natural catalytic activity but does so in an entirely new cellular environment," DeLisa said. "And because it's a genetically engineered construct, it can be expressed like any other soluble protein with very little effort or difficulty."

First author is Dario Mizrachi, former postdoctoral associate in chemical and biomolecular engineering who's now an assistant professor at Brigham Young University. Collaborators included Michael-Paul Robinson, doctoral student in chemical and biomolecular engineering, and Mehmet Berkmen of New England Biolabs.

The group's previous work detailed a method they called SIMPLEx (Solubilization of Integral Membrane Proteins with High Levels of Expression), for shielding IMPs from water and enabling the production of large quantities of these difficult-to-make proteins. Using recombinant DNA techniques, they stitched together an artificial membrane protein with an identity crisis one that maintains its biological function, but thinks it's soluble in water.

This latest work is the first application of that technique. The group used their identity-switched IMPs to make disulfide bonds, a type of post-translational modification that occurs in many proteins and influences nearly all aspects of normal cell biology and pathogenesis.

The group targeted the bacterial integral membrane enzyme DsbB, a central biocatalyst in disulfide bond formation, although DeLisa believes the technique is transferrable to myriad other membrane proteins.

Using the SIMPLEx method, the group converted membrane-bound DsbB into a water-soluble biocatalyst that could be readily expressed in the E. coli cytoplasm, where it spawned disulfide-bond formation in a range of protein targets.

Disulfide bonds are key players in many therapeutic proteins, such as monoclonal antibodies. Many cancer drugs employ these molecules, which can mimic or enhance the immune system's attack on tumor cells.

The ability to take the catalyst out of the lipid membrane and put it in the cytoplasm, DeLisa said, allows scientists to make these antibodies in potentially more favorable locations in the cell.

"We could make this pathway in the cytoplasm [or] we could move everything to a different subcellular compartment like the periplasm, or potentially take the entire pathway out of the cell and reconstitute it in a cell-free system," DeLisa said. "The point is, we create a tremendous amount of flexibility in terms of making these bonds by essentially turning a membrane protein into a soluble enzyme."

Explore further: New nanoparticle technology to decipher structure and function of membrane proteins

More information: Dario Mizrachi et al. A water-soluble DsbB variant that catalyzes disulfide-bond formation in vivo, Nature Chemical Biology (2017). DOI: 10.1038/nchembio.2409

Researchers at Karolinska Institutet, Sweden, have developed a nanoparticle technology that can be used to stabilise membrane proteins so that their structure can be studied in a lipid environment. The method, described in ...

A team of scientists from MIPT, Research Center Jlich (Germany), and Institut de Biologie Structurale (France) has developed a new approach to membrane protein crystallization. For the first time, the scientists have showed ...

Mention E. coli and what pops into most people's heads are bacteria, tainted food, a rush to the hospital basically, fear.

If you want to know if a compound is antibacterial, you can throw it into a petri dish to see if the bacteria cultured there die.

Monoclonal antibodies, proteins that bind to and destroy foreign invaders in our bodies, routinely are used as therapeutic agents to fight a wide range of maladies including breast cancer, leukemia, asthma, arthritis, psoriasis, ...

(PhysOrg.com) -- When viruses and bacteria invade the body, the immune system generates protective proteins called antibodies that bind to and destroy the invading pathogens.

Chemists at Case Western Reserve University have found a way to possibly store digital data in half the space current systems require.

Researchers are making progress in developing rechargeable batteries based on potassium, a potential alternative to lithium that's less expensive and far more plentiful, and also have shown how to derive carbon for battery ...

Integral membrane proteins, or IMPs, are a major class of proteins that play crucial roles in many cellular processes, including the catalysis of disulfide bonds, which are essential for the function and stability of many ...

Australian scientists have paved the way for carbon neutral fuel with the development of a new efficient catalyst that converts carbon dioxide (CO2) from the air into synthetic natural gas in a 'clean' process using solar ...

A growing number of pathogens are developing resistance to one or more antibiotics, threatening our ability to treat infectious diseases. According to a study published June 20th in Biophysical Journal, a simple new method ...

Combustion is often a rapid process, as in the case of fire. How can cells control the burning process so well? The question has long puzzled researchers. Using bacteria from hot springs, researchers from Stockholm University ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Read the rest here:
Changing the identity of cellular enzyme spawns new pathway - Phys.Org

June 21, 2017 Credit: European Bioinformatics Institute EMBL-EBI

A picture may be worth a thousand words, but only if you understand what you are looking at. The life sciences rely increasingly on 2-D, 3-D and 4-D image data, but its staggering heterogeneity and size make it extremely difficult to collate into a central resource, link to other data types and share with the research community.

To address this challenge, scientists at the University of Dundee, the European Bioinformatics Institute (EMBL-EBI), the University of Bristol and the University of Cambridge have launched a prototype repository for imaging data: the Image Data Resource (IDR). This free resource, described in Nature Methods, is the first general biological image repository that stores and integrates data from multiple modalities and laboratories.

The IDR also reveals the potential impact of sharing and reusing imaging data for the life sciences.

Pooling resources

"Imaging will only be truly transformative for science if we make the data publicly available," explains Alvis Brazma, a lead author and Senior Scientist at EMBL-EBI. "Scientists should be able to query existing data to identify commonalities and patterns. But to make this possible we need a robust platform where researchers can upload their imaging data and easily access data from other experiments. The Image Data Resource is the first step towards creating a public image data repository for the life sciences."

There are many resources worldwide in which people publish imaging data, but none of these repositories is both generic and linked to other relevant bio-molecular data. This means that for all the effort that goes into them, it is difficult to reuse these datasets in new studies.

There are many reasons why sharing imaging data has been so difficult until now most notably the heterogeneity and complexity of the image data, but also a critical mass of storage, compute and curation expertise.

"Imaging data is large, yes, but the real challenge is that it is heterogeneous and multidimensional," says Jason Swedlow, senior author of the study and Professor of Quantitative Cell Biology at the University of Dundee. "Curating, storing and analysing imaging data require significant effort and computing power. The creation of the IDR prototype was only possible thanks to a strong collaboration between several scientific organisations."

Nice picture but what does it mean?

IDR contains a broad range of imaging data, including high-content screening, super-resolution microscopy, time-lapse and digital pathology imaging. But it's not just the diversity of data types that makes the resource unique; it is the additional information available that creates the added value.

"IDR doesn't just show you an image or a video of a cell. It also tells you what the image is about, where it was taken, by whom and what conclusions can be drawn from it," continues Brazma.

The new resource integrates imaging data with molecular and phenotype data. IDR includes information on experimental protocols: parameters, analyses and the effects scientists have observed in cells and features, for example. This makes it possible for users to analyse gene networks potentially revealing previously unknown interactions on a scale that would not be possible for individual studies. That requires a staggering amount of storage and compute power. The IDR collaboration was able to launch their project successfully thanks to the Embassy Cloud resource and support at EMBL-EBI.

The Image Data Repository

The prototype public image repository contains a broad range of data, including:

Demonstrating success

The Swedlow group at Dundee and the Carazo Salas group at the University of Bristol used IDR to illustrate how shared imaging data can push the boundaries of research. Using data deposited in the IDR, they identified genes from different studies that, when mutated or removed, caused cells to elongate and stretch out. They put together information from several different studies and built a gene network, which gives a clear view on how these genes affect cell shape an important property to consider in metastatic cancer.

"Expanding the public archives to include imaging is of huge interest to the biotech industry and drug development companies. It offers potential to identify new therapies and targets, and broadens the scope of research by allowing scientists around the world to access each other's imaging datasets," adds Swedlow.

"Bioimaging technologies are currently revolutionising life science. Sharing the rapidly increasing amount of image data is the key to enabling ground-breaking future research," says Jan Ellenberg, Head of EMBL's Cell Biology and Biophysics Unit and Coordinator of Euro-BioImaging, the pan-European infrastructure for imaging technologies. "For this reason image data archiving and sharing is a high priority for EMBL, and for Euro-BioImaging's future general data services, which can build on the IDR pilot example."

Next steps

So far, the collaborators have proven that IDR is both possible and useful. The next step is to secure the support and investment needed to transform the prototype into a production-ready imaging infrastructure.

IDR's software and technology is open source, so it can be accessed and built into other image data publication systems. This promotes and extends publication and re-analysis of scientific data.

Explore further: 'Big Data' resource raises possibility of research revolution

More information: Eleanor Williams et al. Image Data Resource: a bioimage data integration and publication platform, Nature Methods (2017). DOI: 10.1038/nmeth.4326

Journal reference: Nature Methods

Provided by: European Bioinformatics Institute EMBL-EBI

A group of UK scientists involving researchers from the University of Bristol have demonstrated how aggregating image data from laboratories all around the world has the potential to revolutionise scientific research.

As the bioimaging revolution gives scientists ever-more detailed views on the inner workings of cells, there is growing demand for public infrastructure to store, share and link the massive datasets produced using high-resolution ...

The Chan Zuckerberg Initiative (CZI) has announced financial support for the Human Cell Atlas, which is using sequencing technology to redefine every cell in the body. Funding and engineering support from CZI will enable ...

Advances in genetic sequencing and other technologies have led to an explosion of biological data, and decades of openness (both spontaneous and enforced) mean that scientists routinely deposit data in online repositories. ...

The collaboration of two leading cell image resource centers now provides a more extensive and advanced facility for archiving, sharing, and analyzing microscope images in great detail. The American Society for Cell Biology ...

The Allen Institute for Cell Science today announces the launch of the Allen Cell Explorer: a one-of-a-kind portal and dynamic digital window into the human cell. The website combines large-scale 3D imaging data, the first ...

The same mechanisms that quickly separate mixtures of oil and water are at play when controlling the organization in an unusual part of our DNA called heterochromatin, according to a new study by researchers at the Department ...

Researchers at the University of Michigan Life Sciences Institute have identified a new type of rapid-response defense mechanism that helps protect cells from environmental stress while giving slower, well-known protection ...

Gelada malesa close relative to baboonspay attention to the loud calls of a rival to gain information about his relative fighting ability compared to themselves, a new study indicated.

(Phys.org)A team of researchers from South Korea, the U.K. and the U.S. has used computational methods to follow chromosomal rearrangements in seven genomes. In their paper published in Proceedings of the National Academy ...

Humans possess many cognitive abilities not seen in other animals, such as a full-blown language capacity as well as reasoning and planning abilities. Despite these differences, however, it has been difficult to identify ...

Ever burn your tongue so badly that you were unable to taste your food for a few days? Luckily, a unique feature of taste cells is that they continually regenerate every 10 to 14 days. Now, a new study from the Monell Center ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

See the rest here:
Open imaging data for biology - Phys.org - Phys.Org