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Cell Biology

Azacitidine in Combination With Trametinib May Be Effective for … – The ASCO Post

By The ASCO Post StaffPosted: 4/7/2023 11:01:00 AM Last Updated: 4/7/2023 10:47:27 AM

Researchers have found that the hypomethylating agent azacitidine plus the MEK inhibitor trametinib may be a promising new combination to treat patients with juvenile myelomonocytic leukemia (JMML), according to a preclinical study published by Pasupuleti et al in Molecular Therapy.

Background

JMML is caused by a specific genetic mutation that results in the overactivity of the RAS/MAPK cellular pathway. There are currently limited therapies available to treat patients with JMML, and other drug treatments have been ineffective.

The most common treatments for [patients with] JMML today are bone marrow transplants, but unfortunately, nearly 50% of those transplant recipients relapse, explained senior study author Reuben Kapur, PhD, the Frieda and Albrecht Kipp Professor of Pediatrics and Director of the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, as well as CoLeader of the Hematopoiesis and Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Chemotherapy and other medications have also been used, but their responses have not been great. We hypothesized that a combination of targeted medications could be a better option than whats available, and were thrilled our preclinical studies have shown that to be the case, he added.

Study Methods and Results

In the novel study, the researchers evaluated the efficacy of the combination of azacitidine and trametinib in a JMML model and found that it may have been capable of reducing some of the cancerous features of the disease. The researchers noted that the novel drug combination worked by decreasing the number of cancerous blood stem cells in the model and reducing the activity of the RAS/MAPK pathway.

Our research findings demonstrated the combination of two drug therapies reduced the number of cancerous stem cells and enlargement of the spleen, and improved blood cell abnormalities often seen in [patients with] JMML, explained lead study author Santhosh Kumar Pasupuleti, PhD, MSc, Assistant Research Professor of Pediatrics in the Program in Hematologic Malignancies and Stem Cell Biology at the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, and an associate member of Hematopoiesis & Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. These results provide hope for improved therapeutic options for [patients with] JMML and highlight the potential of combination treatments in combating rare [pediatric] diseases.

Conclusions

A clinical trial funded by the National Institutes of Health (NIH) has been recently approved to further study azacitidine and trametinib combination treatment in patients with JMML whose previous lines of therapy have failed. The clinical trial will be led by Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. Dr. Stieglitz recently conducted a separate clinical trial that found trametinib to be effective but not curative on its own in patients with JMML who did not respond to regular chemotherapy.

Based on the information we learned, we will now test the combination of trametinib and azacitidine in patients with newly diagnosed JMML in the hope that the combination will be more effective than either drug alone, said costudy author Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. Importantly, certain lower-risk [patients with] JMML in the upcoming trial will receive this combination of targeted treatments in place of more intense treatment [with] stem cell transplantation. We anticipate this [National Institutes of Health]sponsored trial of targeted agents will decrease side effects and increase the number of patients who achieve remission compared [with] conventional treatments.

Disclosure: For full disclosures of the study authors, visit cell.com.

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Azacitidine in Combination With Trametinib May Be Effective for ... - The ASCO Post

Cell Biology

Biology’s unsolved chicken-or-egg problem: Where did life come from? – Big Think

Biology has a chicken-or-egg problem. Two types of molecules are essential for life. Cells contain protein molecules, which perform most of the biochemical and physical functions. Cells also contain DNA and RNA molecules, which carry the blueprint information for making more cells. When life first arose on Earth 3.5 billion years ago, which came first: function or information? Its a major unsolved problem of how biology arose from prebiotic chemistry.

Some people think that life first got started call it Day One from RNA, because some RNA molecules can do double-duty and act like proteins. But, we believe proteins came first. The proteins-first perspective helps to solve another major mystery: Where did Darwinian evolution come from? We want to know not only what form of matter arose on Day One, but also why that matter would persist and adapt and go forward into Day Two, Day Three, and beyond.

Darwinian evolution is biologys planet-wide unrelenting drive to adapt, innovate, and change. Through survival of the fittest, organisms compete to win resources, beget other organisms, and adapt to their environments. Ever since Charles Darwin 160 years ago, we know much about how evolution works, but we have no idea how it got started. Evolution must have had a beginning. It is not a universal law, like the principles of physics or chemistry, which have operated since the beginning of the Universe. As far as we know, evolution has only been running since biology first arose about 3.5 billion years ago, a billion years after earth was formed.

Why would proteins come first? Proteins are most of a cells mass, so the differential growth rates that are the grist for the mill of cell evolution are largely a matter of differential protein production. And, proteins are the maker molecules that catalyze those growth reactions. Importantly, proteins are unique in having sequence > structure > function relationships. Most other polymers, including most RNAs, do not.

Proteins form specific folded structures, which are the bases for the molecular functions that create the actions and behaviors of the cell. Think of a proteins 20 amino acids as falling into roughly two classes: oil-like hydrophobic monomers and water-like polar monomers. Proteins fold up; that is, protein strings ball up in water into specific compact shapes because of the basic physics that oil avoids water that is, oily amino acids fold to be inside the ball, away from the surrounding water outside the protein. This makes proteins great catalysts. Folded proteins are miniature solids. Being a solid is exactly whats needed to catalyze chemical reactions, because catalyst atoms need to hold their places long enough to assist the reaction. Further, a 20-amino-acid alphabet spans a range of chemistries, so they catalyze a range of reactions.

But how did protein-making get started? First, we know from experiments that the amino acid building blocks of proteins plausibly could have existed on the early Earth. We also know there were simple catalysts that could initially link together amino acids into peptides minerals and clays or air-water surfaces will do. Short proteins, called peptides, are even found on some meteorites.

So, lets call the first catalyst the Founding Rock rock simply implying a site fixed in space, and founding implying that it was the first catalyst, before proteins themselves were catalysts, free-floating and capturable inside cells. However, proteins made on the Founding Rock would have been too short and possessed neither functions nor propagation principles nor specific informational sequences. How might these bio-like properties emerge from simple peptides? Emergence is when a small change in some parameter turns a simple behavior into a more complex one.

Our computer modeling tells a plausible story: A few of those little random peptides ball up in water from oil-water forces, creating stable folded surfaces, becoming primitive catalysts, and helping to elongate other chains. Foldcats are what we call such chains. Those sequences will be rare, extremely so. But, as is true in many such matters of statistical physics, the question is not how improbable the states are, but rather how cooperative they are. How might one molecular action enhance the next one, like a snowball growing as it rolls down a hill? It doesnt matter which was the first snowflake. It matters only what is the process of becoming a snowball. The foldcat hypothesis explains snowballing cooperativity and the tipping point going from chemistry to biology, and from molecules falling apart to their persistent growth.

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How might this all work? The few long chains that are made on the Founding Rock catalyze the making of even longer chains, producing additional stable and diverse catalysts. Thats because long chains fold more tightly, protecting their cores from chemical degradation. Short chains degrade faster. Longer chains win recycled amino acid monomers, slurping up more resources. Winner peptide molecules take all, as a beginning to Darwinian evolution.

A skeptic might claim that this violates the Second Law of Thermodynamics, but this is not correct. Long story short: While the Second Law says that dead matter tends toward equilibrium and degradation, the Second Law doesnt apply to things that are plugged in things like TV sets, that are driven away from equilibrium. In the foldcat hypothesis, whats plugged in is the peptide synthesis on the Founding Rock in the presence of plentiful amino acids. Thats the driver. It would generate huge amounts of junk peptides, and a very small number of foldable longer chains. But, thats all that is needed to get the snowball rolling.

In short, we believe that function (proteins) came before information (RNA). We know of no alternative, that is, no driving force for an information-first process. Rather than genes using proteins to make new genes, we believe that proteins use genes to make new proteins. And, the foldcat mechanism simply shows how the middleman the genes were simply not needed at first. Peptides made proteins as the first step toward the origin of life.

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Biology's unsolved chicken-or-egg problem: Where did life come from? - Big Think

Cell Biology

New finding in roundworms upends classical thinking about animal cell differentiation – News-Medical.Net

Researchers have spotted how specific proteins within the chromosomes of roundworms enable their offspring to produce specialized cells generations later, a startling finding that upends classical thinking that hereditary information for cell differentiation is mostly ingrained within DNA and other genetic factors.

The Johns Hopkins University team reports for the first time the mechanisms by which a protein known as histone H3 controls when and how worm embryos produce both highly specific cells and pluripotent cells, cells that can turn certain genes on and off to produce varying kinds of body tissue. The details are published today in Science Advances.

The new research could shed light on how mutations associated with these proteins influence various diseases. In children and young adults, for example, histone H3 is closely associated with various cancers.

These mutations are highly prevalent in different cancers, so understanding their normal role in regulating cell fate and potentially differentiation of tissues may help us understand why some of them are more prevalent in certain diseases. The histones that we're looking at are some of the most mutated proteins in cancer and other diseases."

Ryan J. Gleason, lead author, postdoctoral fellow in biology at Johns Hopkins

Histones are the building blocks of chromatin, the structural support of chromosomes within a cell's nucleus. While histone H3 is particularly abundant in multicellular organisms such as plants and animals, unicellular organisms teem with a nearly identical variant of H3. That's why scientists think the difference in rations of H3 and its variant hold crucial clues in the mystery of why pluripotent cells are so versatile during early development.

The researchers revealed that as C. elegans roundworm embryos grew, increasing H3 levels in their systems restricted the potential or "plasticity" of their pluripotent cells. When the team changed the worm's genome to lower the amount of H3, they successfully prolonged the window of time for pluripotency that is normally lost in older embryos.

"As cells differentiate, you start to get a hundredfold histone H3 being expressed at that time period, which coincides with that lineage-specific regulation," Gleason said. "When you lower the amount of H3 during embryogenesis, we were able to change the normal path of development to adopt alternative paths of cell fate."

In pluripotent cells, histones help switch certain genes on and off to commit to specific cell types, be they neurons, muscles, or other tissue. Highly regulated by histones, genes act as a voice that tell cells how to develop. How quiet or loud a gene is determines a cell's fate.

The new findings come from the gene-editing technique CRISPR, which helped the team track the role the two histones played as the worm's offspring developed. CRISPR has made it much easier for scientists in the last decade to study the nuts and bolts of changing genetic material and spot what that does to animal, plant, and microbe traits, Gleason said.

Even though the C. elegans roundworm gives finer insights into how these pluripotent cells evolve, further research is needed to zero in on how histones might also underpin embryogenesis in humans and animals composed of hundreds of types of cells, said Xin Chen, a Johns Hopkins biology professor and co-investigator.

"Even though we are using this small worm to make these discoveries, really this finding should not be specific to one animal," Chen said. "It's hard to imagine the findings are only going to be applicable to one histone or one animal but, of course, more research needs to be done."

The team includes Yanrui Guo of Johns Hopkins, Christopher S. Semancik of Tufts University, Cindy Ow of University of California, San Francisco, and Gitanjali Lakshminarayanan of Dana-Farber Cancer Institute.

Source:

Journal reference:

Gleason, R. J., et al. (2023) Developmentally programmed histone H3 expression regulates cellular plasticity at the parental-to-early embryo transition. Science Advances. doi.org/10.1126/sciadv.adh0411.

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New finding in roundworms upends classical thinking about animal cell differentiation - News-Medical.Net

Cell Biology

Inland Empire stem-cell therapy gets $2.9 million booster – UC Riverside

A new UC Riverside training program will help undergraduates transition into regenerative medicine careers, infusing the Inland Empire wraith expertise in cutting-edge trauma and disease treatments.

Guadalupe Ruiz,RAMP diversity and outreach director, left, and Huinan Hannah Liu, bioengineering professor and RAMP principal investigator. (Stan Lim/UCR)

The Research Training and Mentorship Program to Inspire Diverse Undergraduates toward Regenerative Medicine Careers, or RAMP, has received $2.9 million to work with multiple groups of students over the next five years. The grant comes from the California Institute for Regenerative Medicine, the states stem cell agency.

The overall goal of the program is to develop therapies for cells and tissues damaged by injury, trauma, or disease, including brain cells. Laboratory work will include tissue engineering but also research into techniques where the body uses its own biological systems, sometimes with help of engineered materials to rebuild tissues and organs.

UCR already had parts of a stem-cell career training pipeline in place. The university hosts STRIDE, a program offering local high school students opportunities to participate in laboratory research projects. In addition, the TRANSCEND program, directed by UCR molecular biology professor Prue Talbot, helps increase the number and diversity of Ph.D. and postdoctoral scientists trained in stem cell biology.

The missing link was undergraduates, said Huinan Hannah Liu, UCR bioengineering professor and RAMP principal investigator. RAMP is a linker molecule between those two programs.Interested undergrads are encouraged to apply.

Liu got involved with the program because her laboratory works on ways to improve cellular nutrient delivery and waste transport. A lot of metabolic waste in a cell impedes regeneration, Liu said. Nothing thrives in an environment full of waste.

Sometimes called the body's master cells, stem cells develop into blood, brain, bones, and all of the body's organs. They have the potential to repair, restore, replace, and regenerate cells. (luismmolina/iStock/Getty)

Her focus mirrors the first of three sub-specialties from which RAMP students will be able to choose. Faculty from UCRs Marlan and Rosemary Bourns College of Engineering will work with students to engineer materials that serve as scaffolds for growing cells and tissues.

Students can also choose to work with faculty from the College of Natural and Agricultural Sciences, who have expertise in cell biology. They understand the biological mechanisms behind tissue development, and the pathology of different disease stages, Liu said. Their collaboration with engineering faculty will be critical.

Faculty from UCRs School of Medicine will also work with students on ways to differentiate stem cells toward various cell types, and research the mechanisms of how cells and tissues function in the body. They can determine, for example, whether the body will accept an engineered cell, Liu said.

Moving forward, Liu is hopeful that RAMP will attract more clinical faculty, who can help do studies to test whether engineered materials, cells and tissues are safe before translating the work to human subjects.

Another key component of the program will be reaching out to patients and local communities to make them aware of new treatment options available to them. As they see the need in our area, Im hopeful these students will remain long term and help heal our diverse, underserved Inland Empire communities, Liu said.

(Cover image: stem cells: luismmolina/iStock/Getty)

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Inland Empire stem-cell therapy gets $2.9 million booster - UC Riverside

Cell Biology

Researchers clear the way for well-rounded view of cellular defects – Phys.org

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Amrinder Nain is an associate professor in the Virginia Tech Department of Mechanical Engineering, but he doesn't build cars or robots. The mechanics he champions are the tiny building blocks of life and how they behave and move.

Cellular dynamics research studies living cells and their life, death, division, and multiplication. Over the past several years, Nain has taken many journeys down the microscopic roads where cells live. His past work has analyzed how cells move and even included projects with colleagues to measure cell forces and nucleus shapes and to electrify cells and observe how they heal.

His latest collaboration investigates how cells divide, particularly in the fibrous environment of living tissue. Cells are typically studied in a flat environment, and the difference between flat and fibrous landscapes opens new windows into the behavior of cells and the diseases that impact them. The findings were published in the Proceedings of the National Academy of Sciences on Feb. 27.

Cell division, called mitosis, is essential for developmental, repair, and disease biology. A cell, at its most fundamental level, duplicates its chromosomes, which are then separated and distributed equally between two daughter cells, each with its own complete set of genetic information. As new cells perform the same function over and over, they form organs, heal wounds, and replace dead cells, sustaining the cycle of healthy tissues and organs.

But cell division doesn't always happen this smoothly. Sometimes, cells divide unevenly, or chromosomes can become unevenly split. When those misfires occur, the resulting cell will continue to duplicate copies of its faulty self, creating genetic defects that could cause widespread problems in a living body. These abnormalities account for many prenatal birth defects and can contribute to the origins of cancer.

Better understanding cellular mitosis increases our chances of diagnosing, treating, and preventing those mitotic defects. Nain's discovery puts valuable information in the hands of researchers by painting a complete picture of what's going on at the cellular level within the body's fibrous environment.

At the microscopic level, cells move by way of an extracellular matrix (ECM), a three-dimensional lattice of organic material that provides the framework for cells to form organs by underlaying a strong foundation that holds them together.

Nain's foundational research focuses on re-creating and studying that lattice, and his team's past studies on cellular motion have shown how cells travel along it. For a single fiber, a cell pulls itself along at each end, walking the fiber like a tightrope. Two fibers running parallel allow the cell to double those connections.

A dividing cell also makes use of the fibers around it. For a single fiber, each end of the cell adheres and pulls to create the division. If a cell is in an environment with multiple fibers, it will likely attach to those as well. The ECM may cross above and below the cell, providing a three-dimensional web onto which cells connect.

The number of fibers available for cells to attach to affects the timing of cell division and the types of defects a cell may produce. Cells take longer to divide on single fibers, and mitotic errors change with more attachments, creating a complex picture of the myriad ways in which a cell might fail.

This discovery affects future research because the complex view of cell division errors has not been previously investigated in fibrous environments. Schematic of a rounded cell body attached to a single fiber and held by actin retraction fiber cables (red) connecting adhesion clusters (green) with the cell cortex (blue). Credit: Amrinder Nain

"Cellular biology has predominantly been studied on a Petri dish, which is a flat, two-dimensional surface," said Nain. "Flat 2D is limited in physiological output because there are very few places in the body where the environment can be considered two-dimensional."

The team found that observing cells in the 3D environment of an ECM yielded new results beyond the capability of 2D Petri dishes. In this work, the team asked a central question: How does the shape of a cell affect its dividing behavior?

Cell shape depends on how a cell adheres to underlying substrates. For example, on a flat, two-dimensional Petri dish, a cell resembles a pancake. In a fibrous environment such as an ECM, shapes range from elongated aerofoils to kites, depending on the number of fibers and their architecture. While a cell might adhere above and below the fiber plane on suspended fibers, a flat surface causes the cell to flatten out and form connections outward. That flattening causes the cell to behave differently when it balls up and undergoes division.

As a rounded cell body divides, it's held in place by organic cables that attach the cell body, or cortex, to the fibers. On single fibers, near-perfect spherical cell bodies are held in place by two sets of cables, giving maximum freedom for the rounded cell body to move in 3D. As the number of fibers in the lattice increases, so does the number of places to which a cell can adhere. This results in multiple cable complexes that limit 3D movement of the rounded cell body.

This simple mechanical effect highlights the significant difference between the Petri dish and the ECM. On a Petri dish, monopolar spindle defects, which represent incomplete spindle pole (or centrosome) separation, do not often occur. However, when a cell is in a single-fiber environment with two cable attachment sites, monopolar spindle defects increase.

These results turn cell study quite literally on its head: In the environment of a Petri dish, some defects that occur during cellular mitosis cannot happen in the same way as they do in a living body.

"While bipolar division, the most common and error-free division mode, dominates division outcomes in fibrous environments, our work shows a switch in monopolar and multipolar defects by changing the number of fibers cells attach to," said Nain. "It offers a glimpse into how cell division might occur in actual living tissues."

Nain hopes that the fresh perspective provided by this foundational experimental-computational work will yield insights on how to treat disease and genetic disorders.

"With fiber networks, we provide more detail on a comprehensive in vivo picture, filling in some missing information and using our multi-disciplinary approach, we would like to ask some precise questions in mitotic biology as we move forward," he said.

More information: Aniket Jana et al, Mitotic outcomes and errors in fibrous environments, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2120536120

Journal information: Proceedings of the National Academy of Sciences

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Researchers clear the way for well-rounded view of cellular defects - Phys.org

Cell Biology

We were dancing around the lab cellular identity discovery has potential to impact cancer treatments – Newswise

Newswise A team of scientists led by those in Trinity College Dublin has discovered new mechanisms involved in establishing cellular identity, a process that ensures the billions of different cells in our bodies do the correct job. This new discovery in stem cells a result so surprising that the team initially believed it to be an error in the lab has potential translational impacts in cancer biology and associated targeted treatments.

The research focuses on the workings of Polycomb protein complexes, PRC1 and PRC2, which are studied by Professor Adrian Bracken and his team, based in Trinitys School of Genetics and Microbiology. PhD student,Ellen Tuck, describes these proteins as strict librarians inside cells. PRC1 and PRC2 block access to certain areas of the genetic library, such that a neuron cell wont have access to muscle genes, and it doesnt get confused in its cellular identity.

A puzzle regarding PRC2 has intrigued the Bracken lab and other scientists in the field for years: two forms (PRC2.1 and PRC2.2) exist in the cell but the Bracken labpreviously showedthat the two forms of PRC2 target the same regions of DNA and do the same job. So why do we need two versions?

The new discovery from the lab takes an exciting step towards answering this conundrum, as the team found that PRC2.1 and PRC2.2 recruit different forms of the PRC1 complex to DNA, thereby finally explaining why two versions are needed.

This took us by complete surprise. We initially thought there must have been a technical issue with the experiment, but multiple replications confirmed that we had in fact stumbled upon a fascinating new process that reshapes our understanding of the hierarchical workflow of Polycomb complexes.We were dancing around the lab,saidDr Eleanor Glancy, recalling the evening the team finally realised what the data were telling them.

Successful PhD graduate of the Bracken lab, Dr Eleanor Glancy, together with Postdoctoral researcher, Dr Cheng Wang, spearheaded the work, with important collaborative support from scientists in Italy and the Netherlands. The team has published the work today in leading journal,Molecular Cell.

This research by Trinity scientists represents a massive contribution to the field of chromatin and epigenetics research and has further impact in cancer biology research as the genes encoding Polycomb proteins are frequently mutated in cancers.

Professor Brackensaid:My team currently studies the effects of these mutations in childhood brain cancers and adult lymphomas, seeking to understand what biological mechanisms go awry and how we can target these complexes with more effective treatments. A firm and comprehensive understanding of the workings of these complexes is critical to figuring out new ways to target them in cancer settings. Therefore, this work led by Dr Glancy and Dr Wang in my lab will be built upon here and by other researchers worldwide to advance our approach to many cancers.

The team worked through the COVID-19 pandemic shutdown, social distancing measures, failed hypotheses, failed experiments and tight deadlines, maintaining belief and determination, to ultimately make a significant advance in our biological knowledge.

More information about the Bracken lab and their research can be found on theirwebsite.

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We were dancing around the lab cellular identity discovery has potential to impact cancer treatments - Newswise

Cell Biology

Environmental stressors’ effect on gene expression explored in lecture – Environmental Factor Newsletter

Anita Hopper, Ph.D., shared insights into how transfer ribonucleic acid (tRNA) responds to environmental stressors during the NIEHS Distinguished Lecture held March 14. The Ohio State University professor described how different tRNAs, which play a key role in protein synthesis, move around within cells and alter gene expression.

Robin Stanley, Ph.D., who leads the Nucleolar Integrity Group and holds a secondary appointment in the NIEHS Genome Integrity and Structural Biology Laboratory, hosted the lecture.

Over the years, work from the Hopper lab has beautifully established that tRNA trafficking inside the cell is bi-directional, Stanley said. Using yeast as a model system, her lab has identified the major cellular players involved and established that tRNA trafficking dynamically responds to environmental stress, leading to the regulation of gene expression.

According to Hopper, who is a member of the National Academy of Sciences, the American Association for the Advancement of Science, and member and past president of the RNA Society, researchers are still working to untangle the production, alternative functions and cell biology of tRNAs.

I am enthralled with the complexity and regulation of this molecule, Hopper said. It serves as a conduit from genome to the proteome. Any misstep in the production of tRNAs can cause a variety of diseases, both mitochondrial and neurological.

During the lecture, Hopper discussed the movement of tRNAs from a cells nucleus to cytoplasm, which is an essential step in every living organism, including humans. Although scientists knew of one cellular pathway that delivered tRNAs after transcription in the nucleus to the cytoplasm, it was not essential in all living organisms. The Hopper lab recently discovered two parallel pathways involving Mex67-Mtr2 and Crm1, respectively, through which tRNA is shuffled from nucleus to cytoplasm.

A subset of tRNAs contain introns segments of nucleic acid that interrupt the mature gene sequence. These introns need to be removed before a tRNA can function in protein synthesis. Failure to remove introns is one way that tRNA can become nonfunctional.

Cells make an enormous number of intron-containing tRNAs, Hopper explained. About 600,000 molecules of free introns are generated every cell cycle and you almost never see them. They are very efficiently turned over.

Still-attached introns are just one way that tRNA can become problematic. To synthesize proteins accurately, tRNAs must themselves form completely correctly within the cell. If not functioning properly, they misfold, decrease stability, and cause errors in decoding the genome.

Malformed tRNA occasionally move from the nucleus to cytoplasm prematurely. One of Hoppers mentees, Emily Kramer, found that retrograde movement back to the nucleus serves an important role in tRNA quality control.

One of my favorite ideas is that when they return to the nucleus, maybe they are given a second chance, Hopper said. They get their end processed and end up whole.

In addition to her research contributions, Hopper is known for her commitment to mentoring future scientists.

Throughout her career, Dr. Hopper has been an outstanding mentor and role model to budding RNA scientists both in her own lab and the larger RNA community, Stanley said. She has been an incredibly active member of the RNA Society, who honored her with the Societys Lifetime Service Award in 2009 and the Lifetime Achievement Award in 2015.

Citation: Kramer EB, Hopper AK. 2013. Retrograde transfer RNA nuclear import provides a new level of tRNA quality control in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 110(52):21042-7.

(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison.)

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Environmental stressors' effect on gene expression explored in lecture - Environmental Factor Newsletter

Cell Biology

Traumatic brain injury interferes with immune system cells’ recycling … – Science Daily

Each year about 1.5 million people in the U.S. survive a traumatic brain injury due to a fall, car accident, or a sports injury, which can cause immediate and long-term disability.

University of Maryland School of Medicine (UMSOM) researchers wanted to better understand what happens in the brain during injury, so they conducted a study in mice to determine how different types of brain cells in mice react to severe trauma. In a new study published in the January issue of Autophagy, they found that after traumatic brain injury, the brain's immune system cells' internal recycling function slowed dramatically, allowing waste products to build up and interfere with recovery from injury.

The researchers also found that treating mice that had traumatic brain injury with a drug to promote cellular recycling improved the mice's ability to recover from injury and solve a water maze, a measure of memory function in mice.

"Many drugs and potential solutions have been proposed to treat traumatic brain injury, but none have ever worked in practice," said lead researcher Marta Lipinski, PhD, Associate Professor of Anesthesiology and Anatomy & Neurobiology at UMSOM and a member of the Shock, Trauma, and Anesthesiology Research (STAR) Center at the University of Maryland Medical Center (UMMC). "It could be that designing drugs for patients that promote this cellular recycling might reverse or prevent damage from traumatic brain injury as we saw in our animal studies. We are continuing to learn more about the molecular and cell biology mechanisms in trauma, so we can use a more guided approach for developing solutions."

The body's cells regularly recycle their own worn-out or damaged parts that accrue through normal wear and tear, infection, or injury in a process known as autophagy. Most cells in the brain use that process for cleaning up their own waste and recycling it on a smaller scale. In a previous study, Dr. Lipinski's group showed that traumatic brain injury reduced the ability of neurons -- the cells that send electrical impulses -- to recycle their own damaged parts, which then led to these neurons dying off. However, some cells in the brain can perform greater feats of recycling, such as the resident immune cells in the brain known as microglia, which can engulf, digest, and recycle entire damaged or dead cells in the tissue.

After a traumatic brain injury, white blood cells -- normally excluded by the blood-brain barrier -- can also get into the brain and work alongside the microglia cells to eat and remove damaged cells. For this new study, Dr. Lipinski's team focused on the immune cells -- microglia and white blood cells -- in the brain after traumatic brain injury and found that, like the neurons, their recycling function was also suppressed.

"Dr. Lipinski's discovery of the recycling function suppression in both neurons and immune cells demonstrates how important it is for neuroscientists to fully understand the complex system involved in a traumatic brain injury," said Dean Mark Gladwin, MD, who is Vice President for Medical Affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor at UMSOM. "Developing effective drugs for traumatic brain injury treatment requires a deeper understanding of these cell-to-cell interactions and what impact each cell type has on the brain's ecosystem."

To demonstrate the full impact of the recycling process on traumatic brain injury and recovery, Dr. Lipinski and her team blocked one of the essential proteins needed to carry out the immune cell's recycling function in the brains of mice with a brain injury. These mice experienced an even greater suppression of their cell recycling processes, resulting in more inflammation in their brain. They even performed worse, as measured by their ability to solve the water maze, than the mice with only brain injury. These findings suggested that the recycling function of the immune cells in the brain is essential for recovery after brain trauma. Conversely, boosting it may possibly lessen the impact of the trauma.

To test that, the researchers used a drug, rapamycin (normally used as a cancer drug or to prevent organ rejection), to promote cellular recycling in the brains of mice who had traumatic brain injury. The researchers found that with the treatment, the mice had lower levels of inflammation in the brain and these mice did better in navigating the water maze.

"The drug we used in our study blocks a set of proteins that are important for regenerating the body's cells, so it cannot be used for extended time periods," said Dr. Lipinski. "We need to continue this line of research to identify the exact mechanism of how autophagy protects against neurological damage in order to find more targeted drugs that increase this process without targeting the vital proteins needed by the brain to regenerate."

This study was funded by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) (R01NS094527, R01NS091218, R01NS115876).

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Traumatic brain injury interferes with immune system cells' recycling ... - Science Daily

Cell Biology

RNA therapy restores gene function in monkeys modeling … – Spectrum – Autism Research News

Relative success: A gene therapy now in clinical trials works in macaques and targets a UBE3A antisense transcript shared by people.

Tim Laman / Minden Pictures

A drug injected into the spinal canal of monkeys activates expression of the paternal copy of UBE3A a gene linked to Angelman syndrome in their brain, raising hopes for the success of a human clinical trial currently underway.

Angelman syndrome is a debilitating condition marked by seizures, intellectual disability, deficits in communication and coordination, and sometimes autism. The syndrome arises primarily from an absence of E3A ubiquitin-protein ligase (UBE3A) in a childs brain. People typically inherit working copies of the UBE3A gene from both parents but develop Angelman if the maternal copy is missing or contains mutations.

Thats because a process called imprinting usually silences the paternal copy. Researchers have long sought a way to restore UBE3A levels by unsilencing it a strategy that three competing companies are pursuing using short strands of RNA known as antisense oligonucleotides, or ASOs.

One of these ASOs from Ultragenyx, a biotechnology company in Novato, California was able to increase UBE3A levels by 40 percent in the brains of crab-eating macaque monkeys, according to a report published in Science Translational Medicine on 22 March. Ultragenyx began testing the drug in people in a Phase 1/2 clinical trial in 2020.

This study shows the potency of that lead compound in a non-human primate, which is probably as close to a human situation as we can get in an animal model, says Ype Elgersma, professor of neuroscience and head of the ENCORE expertise center at Erasmus University in Rotterdam, the Netherlands, who was not involved in the study.

To achieve such results, however, the researchers had to use three 5-milligram doses injected at two-week intervals, Elgersma notes, which is much higher than the dose currently used in the clinical trial. The human trial had initially tested higher doses but was temporarily halted and modified after all of the participants experienced leg weakness a side effect that may be inherent to injecting higher doses of ASOs into the spinal canal. Interim results from the trial suggest that a lower dose is safe, and the participants showed improvements in certain areas.

But Elgersma asks, Will the current dose used in the clinical trial be high enough to induce sufficient levels of UBE3A in Angelman syndrome patients?

The new study not only demonstrates the promise of the ASO candidate in monkeys, but also provides one of the most detailed looks to date at the imprinting mechanism that silences the paternal copy of UBE3A in the brain, the so-called UBE3A antisense transcript.

The antisense transcript breaks all the rules of what we teach in genetics, says lead author Scott Dindot, associate professor of genetics at Texas A&M University in College Station and executive director of molecular genetics at Ultragenyx.

The UBE3A antisense transcript represents just one end of a massive, complex piece of RNA that contains both coding and noncoding regions that serve various functions in the cell. I was determined to figure this [locus] out, he says.

One of the first surprises Dindot discovered on his quest was that the UBE3A antisense transcript in mice is completely different from that in monkeys and humans. If you were developing an ASO in mice, it wasnt going to work in humans, he says.

Dindot and his collaborators used this knowledge to their advantage to home in on one or more ASOs that would halt transcription of the UBE3A antisense and thereby reactivate the paternal copy of UBE3A. Dindot identified a sweet spot in the UBE3A antisense transcript called cluster 2 that is evolutionarily conserved in placental mammals, reasoning that it had a high likelihood of stopping transcription.

He and his colleagues then generated six candidate oligonucleotides, including three for which the sequence is identical in humans and crab-eating macaques. Those sequences could be tested in both a primate model and in human neuron cell cultures before entering clinical trials. Their lead candidate among the three proved more effective at blocking the UBE3A antisense than did topotecan, a chemotherapy drug that has also been explored for that purpose.

This is the first comprehensive picture of what the antisense really looks like at a sequence level and what regions one would want to target, says Mark Zylka, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who was not involved in the work but whose lab has been employing a CRISPR-based strategy to boost UBE3A levels in mice.

The next step, Zylka says, will be to see whether one companys molecule or all three of them ends up succeeding in human trials. Its good to have multiple products against a single thing, because you dont know short-term and long-term what the side effects might be, he says.

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Cell Biology

Lab-grown fat could give cultured meat real flavor and texture – EurekAlert

Researchers have successfully bulk-produced fat tissue in the lab that has a similar texture and make-up to naturally occurring fats from animals.

The results, described in a study published today in eLife, could be applied to the production of cultured meat grown entirely from cells, giving it a more realistic texture and flavour.

Cultivated meat has been making waves in the news lately, with reports from startup companies around the world developing cell-grown chicken, beef, pork and fish mostly in early stages of development, not ready for large-scale production and with a couple of exceptions, not yet approved for commercial sale. Most of those products in development are in the form of an unstructured mixture of cells like chicken nuggets rather than a slice of chicken breast. What is lacking is the texture of real meat, created by muscle fibres, connective tissue and fat and its the fat that gives meat flavour.

In fact, consumer testing with natural beef of different fat content showed that the highest scores were registered for beef containing 36% fat.

However, producing cultured fat tissue in sufficient quantities has been a major challenge because, as the fat grows into a mass, the cells in the middle become starved of oxygen and nutrients. In nature, blood vessels and capillaries deliver oxygen and nutrients throughout the tissue. Researchers still have no way to replicate that vascular network at a large scale in lab grown tissue, so they can only grow muscle or fat to a few millimetres in size.

To get around this limitation, the researchers grew fat cells from mice and pigs first in a flat, two-dimensional layer, then harvested those cells and aggregated them into a three-dimensional mass with a binder such as alginate and mTG, which are both already used in some foods.

Our goal was to develop a relatively simple method of producing bulk fat. Since fat tissue is predominantly cells with few other structural components, we thought that aggregating the cells after growth would be sufficient to reproduce the taste, nutrition and texture profile of natural animal fat, says first author John Yuen Jr, a graduate student at the Tufts University Center for Cellular Architecture (TUCCA), Massachusetts, US. This can work when creating the tissue solely for food, since theres no requirement to keep the cells alive once we gather the fat in bulk.

The aggregated fat cells immediately had the appearance of fat tissue, but to see if they truly reproduced the features of native fat from animals, the team carried out a series of further experiments.

First, they explored the texture, by compressing the fat tissue and seeing how much pressure it could withstand compared to natural animal fat. They found that cell-grown fat bound with sodium alginate was able to withstand a similar amount of pressure to fat from livestock and poultry, but the cell-grown fat that was bound with mTG behaved more like rendered fat similar to lard or tallow. This suggests it could be possible to fine-tune the texture of cultured fat, so it best resembles the real-life texture of fat within meat, using different types and amounts of binders.

Cooking releases hundreds of compounds that add flavour to the meat, and most of those compounds originate from fat, including lipids and their component fatty acids. The team therefore examined the composition of molecules from the cell-grown fat and found that the mix of fatty acids from cultured mouse fat differed from native mouse fat. However, the cultured pig fat had a much closer fatty acid profile to the native tissue. The teams preliminary research suggests it might be possible to supplement growing fat cells with the required lipids to ensure that they more closely match the composition of natural meat.

This method of aggregating cultured fat cells with binding agents can be translated to large-scale production of cultured fat tissue in bioreactors a key obstacle in the development of cultured meat, says senior author David Kaplan, Stern Family professor of Biomedical Engineering at Tufts University and director of TUCCA. We continue to look at every aspect of cultured meat production with an eye toward enabling mass production of meat that looks, tastes and feels like the real thing.

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About eLife

eLife transforms research communication to create a future where a diverse, global community of scientists and researchers produces open and trusted results for the benefit of all. Independent, not-for-profit and supported by funders, we improve the way science is practised and shared. In support of our goal, weve launched a new publishing model that ends the accept/reject decision after peer review. Instead, papers invited for review will be published as a Reviewed Preprint that contains public peer reviews and an eLife assessment. We also continue to publish research that was accepted after peer review as part of our traditional process. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

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Aggregating in vitro-grown adipocytes to produce macroscale cell-cultured fat tissue with tunable lipid compositions for food applications

4-Apr-2023

No competing interests declared

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Lab-grown fat could give cultured meat real flavor and texture - EurekAlert