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Archive - Feb 9, 2018

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Stem Cell Research Provides Hope for Tasmanian Devils with Deadly, Transmissible Cancer

Morris Animal Foundation-funded researcher Dr. Deanne Whitworth, and her colleagues at the University of Queensland in Australia, have taken the first step toward developing an effective treatment for devil facial tumor disease (DFTD), which is decimating Tasmanian devils in the wild. The team's findings were published in the January 15, 2018 issue of Stem Cells and Development. The article is titled “Induced Pluripotent Stem Cells from a Marsupial, the Tasmanian Devil (Sarcophilus harrisii): Insight into the Evolution of Mammalian Pluripotency.” The University of Queensland team has been exploring the possibility of using stem-cell therapy to eradicate tumor cells from Tasmanian devils suffering from DFTD, a deadly transmissible cancer unique to this species. But first they had to find ways to grow and maintain marsupial stem cells, a feat that has not been achieved until now. Dr. Whitworth and her team successfully generated induced pluripotent Tasmanian devil stem cells in the laboratory. The team generated the cells as a first step toward developing a novel and effective treatment for devil facial tumor disease. "Since its discovery in 1996, DFTD has decimated 95 percent of the devil population," said Dr. Whitworth. "It is estimated that within 20 to 30 years, the devil will be extinct in the wild. Our work is moving us closer to finding a strategy to prevent the spread of DFTD and to cure animals already infected with the disease." Induced pluripotent stem cells are cells that have been reprogrammed back to an embryonic stem-cell-like state. The generation of these special cells from humans and other mammals has paved the way for the expanding field of stem cell research and new therapies.

Liver Cells with Whole Genome Duplications Protect Against Cancer in Mice

Researchers at the Children's Medical Center Research Institute (CRI) at the University of Texas (UT) Southwestern have discovered that cells in the liver with whole genome duplications, known as polyploid cells, can protect the liver against cancer. The study, published online on February 8, 2018 in Developmental Cell, addresses a long-standing mystery in liver biology and could stimulate new ideas to prevent cancer. The article is titled “The Polyploid State Plays a Tumor-Suppressive Role in the Liver.” Most human cells are diploid, carrying only one set of matched chromosomes that contain each person's genome. Polyploid cells carry two or more sets of chromosomes. Although rare in most human tissues, these cells are prevalent in the hearts, blood, and livers of mammals. Polyploidization also increases significantly when the liver is exposed to injury or stress from fatty liver disease or environmental toxins that could cause liver cancer later in life. It is unknown, however, whether these increases in polyploidization have functional importance. Previous research into the exact function of polyploid liver cells has been limited, in part because it has been difficult to change the number of sets of chromosomes in a cell, or ploidy, without introducing permanent mutations in genes that may also affect other cellular activities, such as division, regeneration, or cancer development. Because of this, there were many ideas as to why the liver is polyploid, but little experimental evidence. CRI researchers have discovered a new approach. "Our lab has developed new methods to transiently and reversibly alter ploidy for the first time. This was an important advance because it allowed us to separate the effects of ploidy from the effects of genes that change ploidy.

New Study Provides First 3D Visualization of Dynein-Dynactin Complex Bound to Microtubules

On the cellular highway, motor proteins called dyneins rule the road. Dyneins "walk" along structures called microtubules to deliver cellular cargo, such as signaling molecules and organelles, to different parts of a cell. Without dynein on the job, cells cannot divide and people can develop neurological diseases. Now, a new study, which was published on February 7, 2018 in Nature Structural & Molecular Biology, provides the first three-dimensional (3D) visualization of the dynein-dynactin complex bound to microtubules. The article is titled “Cryo-Electron Tomography Reveals That Dynactin Recruits a Team of Dyneins for Processive Motility.” The study leaders from The Scripps Research Institute (TSRI) report that a protein called dynactin hitches two dyneins together, like a yoke locking together a pair of draft horses. "If you want a team of horses to move in one direction, you need to line them up," says Gabriel C. Lander, PhD, a TSRI Associate Professor and senior author of the study. "That's exactly what dynactin is doing to dynein molecules." Understanding how the dynein-dynactin complex is assembled and organized provides a critical foundation to explain the underlying causes of several dynein-related neurodegenerative diseases such as spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) disease. Researchers knew that dynactin is required for dynein to move cargo, but they struggled to get a complete picture of how the different parts of the complex worked together. "We knew that dynein only becomes active when it binds with a partner called dynactin. The problem was that, historically, it was difficult to solve this structure because it is very flexible and dynamic," explains Danielle Grotjahn, a TSRI graduate student and co-first author of the study.

Clock Protein Rev-erbα Represses Transcription by Loosening Chromosome Loops

It is well known that the human body functions on a 24-hour, or circadian, schedule. The up-and-down daily cycles of a long-studied clock protein called Rev-erb coordinates the ebb and flow of gene expression by tightening and loosening loops in chromosomes, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings were published online on February 8, 2018 in Science. The article is titled “Rev-erbα Dynamically Modulates Chromatin Looping to Control Circadian Gene Transcription.” Over the last 15-plus years, a team led by the new study's senior author Mitchell A. Lazar, MD, PhD, Director of Penn's Institute for Diabetes, Obesity, and Metabolism, has been teasing out the versatile role of Rev-erb in maintaining daily cycles of the body's molecular clock, metabolism, and even brain health. "Many studies, including this one, point to a link between the human internal clock and such metabolic disorders as obesity and diabetes," Dr. Lazar said. "Proteins such as Rev-erb are the gears of the clock and understanding their role is important for investigating these and many other diseases." Human physiology works on a 24-hour cycle of gene expression (when the chromosome coding region is translated by RNA and then transcribed to make protein) and is controlled by the body's molecular clock. Core clock proteins activate or repress protein complexes that physically loop one part of a chromosome to become adjacent to a distant part of the same chromosome. The Penn team showed that daily oscillations of Rev-erb control gene expression in the mouse liver via interactions between on-and-off regions on the same chromosome.

Scientists Describe On-Off Switch for Inflammasomes; Finding May Advance Understanding of Inflammation in Many Diseases, Including Alzheimer’s

A discovery by Queensland scientists in Australia could be the key to stopping damage caused by uncontrolled inflammation in a range of common diseases including liver disease, Alzheimer's, and gout. University of Queensland (UQ) researchers have uncovered how an inflammation process automatically switches off in healthy cells, and are now investigating ways to stop it manually when it goes awry. UQ's Institute for Molecular Bioscience (IMB) researcher Associate Professor Kate Schroder (photo) said this inflammation pathway drove many different diseases. "Now that we understand how this pathway naturally turns off in health, we can investigate why it doesn't turn off in disease -- so it's very exciting," Dr. Schroder said. Her work at IMB's Centre for Inflammation and Disease Research focuses on inflammasomes, which are machine-like protein complexes at the heart of inflammation and disease. "These complexes form when an infection, injury, or other disturbance is detected by the immune system, and they send messages to immune cells to tell them to respond," Dr. Schroder said. "If the disturbance can't be cleared, such as in the case of amyloid plaques in Alzheimer's, these molecular machines continue to fire, resulting in neurodegenerative damage from the sustained inflammation." Dr. Schroder's team, led by Dr. Dave Boucher, discovered that inflammasomes normally work with an in-built timer switch, to ensure they only fire for a specific length of time once triggered. "The inflammasome initiates the inflammation process by activating a protein that functions like a pair of scissors, and cuts itself and other proteins," Dr. Schroder said.