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Mapping out the mystery of blood stem cells

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Princess Margaret scientists have revealed how stem cells are able to generate new blood cells throughout our life by looking at vast, uncharted regions of our genetic material that hold important clues to subtle biological changes in these cells.

The finding, obtained from studying normal blood, can be used to enhance methods for stem cell transplantation, and may also shed light into processes that occur in cancer cells that allow them to survive chemotherapy and relapse into cancer growth many years after treatment.

Using state-of-the art sequencing technology to perform genome-wide profiling of the epigenetic landscape of human stem cells, the research revealed important information about how genes are regulated through the three-dimensional folding of chromatin.

Chromatin is composed of DNA and proteins, the latter which package DNA into compact structures, and is found in the nucleus of cells. Changes in chromatin structure are linked to DNA replication, repair and gene expression (turning genes on or off).

The research by Princess Margaret Cancer Centre Senior Scientists Drs. Mathieu Lupien and John Dick is published in Cell Stem Cell, Wednesday, November 25, 2020.

“We don’t have a comprehensive view of what makes a stem cell function in a specific way or what makes it tick,” says Dr. Dick, who is also a Professor in the Department of Molecular Genetics, University of Toronto.

“Stem cells are normally dormant but they need to occasionally become activated to keep the blood system going. Understanding this transition into activation is key to be able to harness the power of stem cells for therapy, but also to understand how malignant cells change this balance.

“Stem cells are powerful, potent and rare. But it’s a knife’s edge as to whether they get activated to replenish new blood cells on demand, or go rogue to divide rapidly and develop mutations, or lie dormant quietly, in a pristine state.”

Understanding what turns that knife’s edge into these various stem cell states has perplexed scientists for decades. Now, with this research, we have a better understanding of what defines a stem cell and makes it function in a particular way.

“We are exploring uncharted territory,” says Dr. Mathieu Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto. “We had to look into the origami of the genome of cells to understand why some can self-renew throughout our life while others lose that ability. We had to look beyond what genetics alone can tell us.”

In this research, scientists focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Hidden amongst this noncoding DNA – which comprise about 98% of the genome – are crucial elements that not only control the activity of thousands of genes, but also play a role in many diseases.

The researchers examined two distinct human hematopoietic stem cells or immature cells that go through several steps in order to develop into different types of blood cells, such as white or red blood cells, or platelets.

They looked at long-term hematopoietic stem cells (HSCs) and short-term HSCs found in the bone marrow of humans. The researchers wanted to map out the cellular machinery involved in the “dormancy” state of long-term cells, with their continuous self-renewing ability, as compared to the more primed, activated and “ready-to-go” short-term cells which can transition quickly into various blood cells.

The researchers found differences in the three-dimensional chromatin structures between the two stem cell types, which is significant since the ways in which chromatin is arranged or folded and looped impacts how genes and other parts of our genome are expressed and regulated.

Using state-of-the-art 3D mapping techniques, the scientists were able to analyze and link the long-term stem cell types with the activity of the chromatin folding protein CTCF and its ability to regulate the expression of 300 genes to control long-term, self-renewal.

“Until now, we have not had a comprehensive view of what makes a stem cell function in a particular way,” says Dr. Dick, adding that the 300 genes represent what scientists now think is the “essence” of a long-term stem cell.

He adds that long-term dormant cells are a “protection” against malignancy, because they can survive for long periods and evade treatment, potentially causing relapse many years later.

However, a short-term stem cell that is poised to become active, dividing and reproducing more quickly than a long-term one, can gather up many more mutations, and sometimes these can progress to blood cancers, he adds.

“This research gives us insight into aspects of how cancer starts and how some cancer cells can retain stem-cell like properties that allow them to survive long-term,” says Dr. Dick.

He adds that a deeper understanding of stem cells can also help with stem cells transplants for the treatment of blood cancers in the future, by potentially stimulating and growing these cells ex vivo (out of the body) for improved transplantation.

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The research was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research (CIHR), Medicine by Design, University of Toronto, Canadian Cancer Society Research Institute, and the Terry Fox Research Institute.

Competing Interests

Dr. John Dick served on the SAB at Trillium Therapeutics, and has ownership interest (including patents) in Trillium Therapeutics. He also reports receiving a commercial research grant from Celgene.

About Princess Margaret Cancer Centre

Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca

Source: https://bioengineer.org/mapping-out-the-mystery-of-blood-stem-cells/

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Nuclear war could trigger big El Niño and decrease seafood

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A nuclear war could trigger an unprecedented El Niño-like warming episode in the equatorial Pacific Ocean, slashing algal populations by 40 percent and likely lowering the fish catch, according to a Rutgers-led study.

The research, published in the journal Communications Earth & Environment, shows that turning to the oceans for food if land-based farming fails after a nuclear war is unlikely to be a successful strategy – at least in the equatorial Pacific.

“In our computer simulations, we see a 40 percent reduction in phytoplankton (algae) biomass in the equatorial Pacific, which would likely have downstream effects on larger marine organisms that people eat,” said lead author Joshua Coupe, a post-doctoral research associate in the Department of Environmental Sciences in the School of Environmental and Biological Sciences at Rutgers University-New Brunswick. “Previous research has shown that global cooling following a nuclear war could lead to crop failure on land, and our study shows we probably can’t rely on seafood to help feed people, at least in that area of the world.”

Scientists studied climate change in six nuclear war scenarios, focusing on the equatorial Pacific Ocean. The scenarios include a major conflict between the United States and Russia and five smaller wars between India and Pakistan. Such wars could ignite enormous fires that inject millions of tons of soot (black carbon) into the upper atmosphere, blocking sunlight and disrupting Earth’s climate.

With an Earth system model to simulate the six scenarios, the scientists showed that a large-scale nuclear war could trigger an unprecedented El Niño-like event lasting up to seven years. The El Niño-Southern Oscillation is the largest naturally occurring phenomenon that affects Pacific Ocean circulation, alternating between warm El Niño and cold La Niña events and profoundly influencing marine productivity and fisheries.

During a “nuclear Niño,” scientists found that precipitation over the Maritime Continent (the area between the Indian and Pacific oceans and surrounding seas) and equatorial Africa would be shut down, largely because of a cooler climate.

More importantly, a nuclear Niño would shut down upwelling of deeper, colder waters along the equator in the Pacific Ocean, reducing the upward movement of nutrients that phytoplankton – the base of the marine food web – need to survive. Moreover, the diminished sunlight after a nuclear war would drastically reduce photosynthesis, stressing and potentially killing many phytoplankton.

“Turning to the sea for food after a nuclear war that dramatically reduces crop production on land seems like it would be a good idea,” said co-author Alan Robock, a Distinguished Professor in the Department of Environmental Sciences at Rutgers-New Brunswick. “But that would not be a reliable source of the protein we need, and we must prevent nuclear conflict if we want to safeguard our food and Earth’s environment.”

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Scientists at the University of California, Santa Barbara; University of Colorado, Boulder; Australian Antarctic Partnership Program; University of Texas, Rio Grande Valley; and National Center for Atmospheric Research contributed to the study.

https://www.rutgers.edu/news/nuclear-war-could-trigger-big-el-nino-and-decrease-seafood

Source: https://bioengineer.org/nuclear-war-could-trigger-big-el-nino-and-decrease-seafood/

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Regulating the ribosomal RNA production line

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Cryo-electron microscopy study allows researchers to visualize structural changes in an E. coli enzyme synthesizing ribosomal RNA that shift it between turbo- and slow-modes depending on the bacteria’s growth rate

The enzyme that makes RNA from a DNA template is altered to slow the production of ribosomal RNA (rRNA), the most abundant type of RNA within cells, when resources are scarce and the bacteria Escherichia coli needs to slow its growth. Researchers used cryo-electron microscopy (cryo-EM) to capture the structures of the RNA polymerase while in complex with DNA and showed how its activity is changed in response to poor-growth conditions. A paper describing the research led by Penn State scientists appears January 22, 2020 in the journal Nature Communications.

“RNA polymerase is an enzyme that produces a variety of RNAs using information encoded in DNA,” said Katsuhiko Murakami, professor of biochemistry and molecular biology at Penn State and the leader of the research team. “This is one of the key steps in the central dogma of molecular biology: transferring genetic information from DNA to RNA, which in turn often codes for protein. It’s required for life and the process is basically shared from bacteria to humans. We are interested in understanding how the structure of RNA polymerase is changed for modulating its activity and function, but it’s been difficult to capture using traditional methods like X-ray crystallography, which requires crystallizing a sample to determine its structure.”

RNA polymerase functions by binding to specific DNA sequences called “promoters” found near the beginning of genes that are going to be made into RNA. To understand the structure and function of the polymerase during this interaction, researchers need to capture the polymerase while it is bound to the promoter DNA, but the interaction can be very unstable at some promoters. Crystallography can only capture RNA polymerase bound to a promoter if the complex is very stable, but for ribosomal RNA promoters this interaction tends to be unstable so that the polymerase can quickly escape to begin making the RNA. To see these interactions the researchers turned to cryo-EM, a method that allows them to visualize the structure of macromolecules in solution.

“When you talk about RNA, most people think about messenger RNA (mRNA), which is the template for making proteins,” said Murakami. “But the most abundant type of RNA in cells doesn’t actually code for protein. Ribosomal RNA is the major structural component of the ribosome, which is the cellular machinery that builds proteins using messenger RNAs as templates. Ribosomal RNA synthesis accounts for up to 70 percent of total RNA synthesis in E. coli cells.”

When a cell divides, which E. coli can do every twenty minutes in nutrient-rich growth conditions, it needs to provide the two resulting daughter cells with enough ribosomes to function, so it is continually making ribosomal RNAs.

“If you do some back-of-the-envelope calculations, an E. coli cell needs to make around 70,000 ribosomes every 20 minutes,” said Murakami. “This means RNA polymerase starts ribosomal RNA synthesis every 1.7 seconds from each ribosomal RNA promoter. So, the polymerase has to bind the ribosomal RNA promoter transiently in order to quickly move onto the ribosomal RNA synthesis step. This is not an ideal for a crystallographic approach, but in a cryo-EM study, we could capture this interaction and, in fact, see different several stages of the interaction in a single sample.”

The researchers were able to determine the three-dimensional structures of the RNA polymerase-promoter complex at two different stages. One when the DNA was still “closed,” before the two strands of the DNA molecule are separated allowing access to the template strand (they refer to this as a closed complex), and one when the DNA was “open” (called an open complex) and primed for RNA synthesis to begin.

“We found a large conformational change in part of the polymerase called the ? (sigma) factor when it binds to promoter DNA, which has never been observed before” said Murakami. “This change opens a gate that allows the DNA to enter a cleft in the polymerase and form the open complex quickly.”

When E. coli needs to slow its growth due to limited resources, two molecules–a global transcription regulator called DksA and a bacterial signaling molecule called ppGpp, bind directly with the polymerase to reduce production of ribosomal RNA. The research team investigated how the binding of these two factors alters the conformation of the polymerase and affects its activity in a promoter-specific manner.

“DksA and ppGpp binding to the polymerase alters its conformation, which prevents the opening of a gate and therefor the polymerase has to follow an alternative pathway to form the open complex,” said Murakami. “This is not an ideal pathway for the ribosomal RNA promoter and thus slow its activity. It’s exciting to see these conformational changes to the polymerase that have direct functional consequences. We couldn’t do this without the cryo-EM, so I’m very thankful to have access to this technology here at Penn State for optimizing experimental conditions for preparing cryo-EM specimens before sending them to the National Cryo-EM Facility at NCI/NIH for high-resolution data collections. We are going to be able to continue to analyze cellular components and complexes that were previously inaccessible.”

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In addition to Murakami, the research team includes Yeonoh Shin and M. Zuhaib Qayyum at Penn State and Danil Pupov, Daria Esyunina, and Andrey Kulbachinskiy at the Russian Academy of Sciences. The research was funded by the U.S. National Institutes of Health, the Russian Science Foundation, and the Russian Foundation for Basic Research. Additional support was provided by the National Cancer Institute’s National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research.

Source: https://bioengineer.org/regulating-the-ribosomal-rna-production-line/

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A professor from RUDN University developed new liquid crystals

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A professor from RUDN University together with his Indian colleagues synthesized and studied new dibenzophenazine-based liquid crystals that could potentially be used in optoelectronics and solar panels. The results of the study were published in the Journal of Molecular Liquids.

Liquid crystals are an intermediate phase between a liquid and a solid body. They are ordered like regular chrystals but at the same time have a flow like liquids. It is this duality that allows them to be used in organic LEDs and LCDs. Unlike other liquid crystals, discotic ones (DLC) are capable of self-assembly into ordered structures. This makes them a promising material for industrial electronics, namely, for the production of displays. A professor from RUDN University together with his Indian colleagues synthesized and described new dibenzophenazine-based DLCs.

“Discotic liquid crystals are interesting because of their ability to form self-assembled ordered columnar structures. In such structures, an electric charge can move along the column, which makes them useful for optoelectronic devices such as organic LEDs, organic field-effect transistors (OFET), photoelectric solar elements, and sensors,” said Prof. Viktor Belyaev, a Ph.D. in Technical Sciences from the Department of Mechanics and Mechatronics at RUDN University.

DLCs consist of disc-shaped molecules aligned in columns. In the center of each disc, there is an aromatic ring (a cyclical organic fragment) surrounded by chains of other organic fragments. Due to this aromatic center, a DLC can transfer a charge along the axis of a column. Prof. Belyaev developed discotic liquid crystals with an aromatic compound called dibenzophenazine in the center. As for the chains that surrounded it, the team tried three different types of fragments. The molecular structure of the new DLCs was studied using spectral, X-ray diffraction, and elementary analysis. Then, the team tested the three groups of DLCs in a set of experiments.

The experiments showed that alkoxy thiol chains increased the polarity of the molecules in liquid crystals thus improving the internal structure of the columns and making them more even. All new DLCs were able to withstand temperatures up to 330?. However, the crystals that consisted of smaller molecules (i.e. the ones with their aromatic center surrounded by alkyl thiols) lost their intermediary status and transitioned from the liquid crystal to the liquid form at lower temperatures (55.1 ?) that the crystals from the other two groups. This is due to the size of the molecules in the columns: the bigger they are, the more stable is the liquid crystal state.

“The new discotic liquid crystals could play an important role in organic optoelectronic devices and solar panels,” added Prof. Viktor Belyaev from RUDN University.

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Source: https://bioengineer.org/a-professor-from-rudn-university-developed-new-liquid-crystals/

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New technique builds super-hard metals from nanoparticles

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PROVIDENCE, R.I. [Brown University] — Metallurgists have all kinds of ways to make a chunk of metal harder. They can bend it, twist it, run it between two rollers or pound it with a hammer. These methods work by breaking up the metal’s grain structure — the microscopic crystalline domains that form a bulk piece of metal. Smaller grains make for harder metals.

Now, a group of Brown University researchers has found a way to customize metallic grain structures from the bottom up. In a paper published in the journal Chem, the researchers show a method for smashing individual metal nanoclusters together to form solid macro-scale hunks of solid metal. Mechanical testing of the metals manufactured using the technique showed that they were up to four times harder than naturally occurring metal structures.

“Hammering and other hardening methods are all top-down ways of altering grain structure, and it’s very hard to control the grain size you end up with,” said Ou Chen, an assistant professor of chemistry at Brown and corresponding author of the new research. “What we’ve done is create nanoparticle building blocks that fuse together when you squeeze them. This way we can have uniform grain sizes that can be precisely tuned for enhanced properties.”

For this study, the researchers made centimeter-scale “coins” using nanoparticles of gold, silver, palladium and other metals. Items of this size could be useful for making high-performance coating materials, electrodes or thermoelectric generators (devices that convert heat fluxes into electricity). But the researchers think the process could easily be scaled up to make super-hard metal coatings or larger industrial components.

The key to the process, Chen says, is the chemical treatment given to the nanoparticle building blocks. Metal nanoparticles are typically covered with organic molecules called ligands, which generally prevent the formation of metal-metal bonds between particles. Chen and his team found a way to strip those ligands away chemically, allowing the clusters to fuse together with just a bit of pressure.

The metal coins made with the technique were substantially harder than standard metal, the research showed. The gold coins, for example, were two to four times harder than normal. Other properties like electrical conduction and light reflectance were virtually identical to standard metals, the researchers found.

The optical properties of the gold coins were fascinating, Chen says, as there was a dramatic color change when the nanoparticles were compressed into bulk metal.

“Because of what’s known as the plasmonic effect, gold nanoparticles are actually purplish-black in color,” Chen said. “But when we applied pressure, we see these purplish clusters suddenly turn to a bright gold color. That’s one of the ways we knew we had actually formed bulk gold.”

In theory, Chen says, the technique could be used to make any kind of metal. In fact, Chen and his team showed that they could make an exotic form of metal known as a metallic glass. Metallic glasses are amorphous, meaning they lack the regularly repeating crystalline structure of normal metals. That gives rise to remarkable properties. Metallic glasses are more easily molded than traditional metals, can be much stronger and more crack-resistant, and exhibit superconductivity at low temperatures.

“Making metallic glass from a single component is notoriously hard to do, so most metallic glasses are alloys,” Chen said. “But we were able to start with amorphous palladium nanoparticles and use our technique to make a palladium metallic glass.”

Chen says he’s hopeful that the technique could one day be widely used for commercial products. The chemical treatment used on the nanoclusters is fairly simple, and the pressures used to squeeze them together are well within the range of standard industrial equipment. Chen has patented the technique and hopes to continue studying it.

“We think there’s a lot of potential here, both for industry and for the scientific research community,” Chen said.

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Chen’s coauthors on the paper were Yasutaka Nagaoka, Masayuki Suda, Insun Yoon, Na Chen, Hanjun Yang, Yuzi Liu, Brendan A. Anzures, Stephen W. Parman, Zhongwu Wang, Michael Grünwald and Hiroshi M. Yamamoto. The research was supported by the National Science Foundation (CMMI-1934314, DMR-1332208, DMR-1848499) and the U.S. Department of Energy (DE-AC02-06CH11357).

Source: https://bioengineer.org/new-technique-builds-super-hard-metals-from-nanoparticles/

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