When I imagine the inner workings of a robot, I think hard, cold mechanics running on physics: shafts, wheels, gears. Human bodies, in contrast, are more of a contained molecular soup operating on the principles of biochemistry.

Yet similar to robots, our cells are also attuned to mechanical forcesjust at a much smaller scale. Tiny pushes and pulls, for example, can urge stem cells to continue dividing, or nudge them into maturity to replace broken tissues. Chemistry isnt king when it comes to governing our bodies; physical forces are similarly powerful. The problem is how to tap into them.

In a new perspectives article in Science, Dr. Khalid Salaita and graduate student Aaron Blanchard from Emory University in Atlanta point to DNA as the solution. The team painted a futuristic picture of DNA mechanotechnology, in which we use DNA machines to control our biology. Rather than a toxic chemotherapy drip, for example, a cancer patient may one day be injected with DNA nanodevices that help their immune cells better grab ontoand snuff outcancerous ones.

For a long time, said Salaita, scientists have been good at making micro devices, hundreds of times smaller than the width of a human hair. Its been more challenging to make functional nano devices, thousands of times smaller than that. But using DNA as the component parts is making it possible to build extremely elaborate nano devices because the DNA parts self-assemble.

Just as the steam engine propelled civilization through the first industrial revolution, DNA devices may fundamentally change medicine, biological research, and the development of biomaterials, further merging man and machine.

When picturing a tiny, whirling machine surveying the body, DNA probably isnt the first candidate that comes to mind. Made up of long chains of four lettersA, T, C, and GDNA is normally secluded inside a tiny porous cage in every cell, in the shape of long chains wrapped around a protein core.

Yet several properties make DNA a fascinating substrate for making mechano-machines, the authors said. One is its predictability: like soulmates, A always binds to T, and C with G. This chemical linking in turn forms the famous double helix structure. By giving the letters little chemical additions, or swapping them out altogether with unnatural synthetic letters, scientists have been able to form entirely new DNA assemblies, folded into various 3D structures.

Rather than an unbreakable, immutable chain, DNA components are more like Japanese origami paper, or Lego blocks. While they cant make every single shapetry building a completely spherical Death Star out of Legothe chemistry is flexible enough that scientists can tweak its structure, stiffness, and coiling by shifting around the letters or replacing them with entirely new ones.

In the late fall of 1980, Dr. Nadrian Seeman was relaxing at the campus pub at New York University when he noticed a mind-bending woodcut, Depth, by MC Escher. With a spark of insight, he realized that he could form similar lattice shapes using DNA, which would make it a lot easier for him to study the molecules shape. More than a decade later, his lab engineered the first artificial 3D nanostructurea cube made out of DNA molecules. The field of DNA nanotechnology was born.

Originally considered a novelty, technologists rushed to make increasingly complex shapes, such as smiley faces, snowflakes, a tiny world map, and more recently, the worlds smallest playable tic-tac-toe set. It wasnt just fun. Along the way, scientists uncovered sophisticated principles and engineering techniques to shape DNA strands into their desired structures, forming a blueprint of DNA engineering.

Then came the DNA revolution. Reading and writing the molecule from scratch became increasingly cheaper, making it easier to experiment with brand-new designs. Additional chemical or fluorescent tags or other modifications gave scientists a direct view of their creations. Rather than a fringe academic pursuit, DNA origami became accessible to most labs, and the number of devices rapidly explodeddevices that can sense, transmit, and generate mechanical forces inside cells.

If you put together these three main components of mechanical devices, you begin to get hammers and cogs and wheels and you can start building nano machines, said Salaita.

Salaita is among several dozen labs demoing the practical uses of DNA devices.

For example, our cells are full of long-haul driver proteins that carry nutrients and other cargo throughout their interior by following specific highways (it eerily looks like a person walking down a tightrope). Just as too much traffic damages our roadways, changes in our cells logistical players can also harm the cells skeleton. Here, scientists have used DNA handles to measure force-induced changes like stretching, unfolding, and rupture of molecules involved in our cells distribution system to look for signs of trouble.

Then there are DNA tension sensors, which act like scales and other force gauges in our macroscopic world. Made up of a stretchable DNA spring to extend with force, and a fluorescent ruler that measures the extension, each sensor is anchored at one end (generally, the glass bottom of a Petri dish) and binds to a cell at the other. If the pulling force exceeds a certain threshold, the spring unfolds and quenches the fluorescent light in the ruler, giving scientists a warning that the cellular tugging is too strong.

The work may sound abstruse, but its implications are plenty. One is for CAR-T, the revolutionary cancer treatment that uses gene therapy to amp up immune cells with better graspers to target tumor cells. The kiss of death between graspers and tumors are extremely difficult to measure because its light and fleeting. Using a DNA tension sensor, the team was able to track the force during the interaction, which could help scientists engineer better CAR-T therapies. A similar construct, the DNA tension gauge tether, irreversibly ruptures under too much force. The gauge is used to track how stem cells develop into brain cells under mechanical forces, and how immune cells track down and recognize foreign invasion.

[Immune] T cells are constantly sampling cells throughout your body using these mechanical tugs. They bind and pull on proteins on a cells surface and, if the bond is strong, thats a signal that the T cell has found a foreign agent, explained Salaita. DNA devices provide an unprecedented look at these forces in the immune system, which in turn could predict how strongly the body will mount an immune response.

To the authors, however, the most promising emerging DNA devices dont just observethey can also generate forces. DNA walkers, for example, uses DNA feet to transport (and sort) molecular cargo while walking down a track also made of DNA strands. When the feet bind to the track (A to T, C to G), it releases energy that propel the walker forward.

Even more exciting are self-assembling DNA machines. The field has DNA-based devices that transmit, sense and generate mechanical forces, the authors said. But eventually, their integration will produce nanomachines that exert mechanical control over living systems.

As costs keep dropping, the authors believe well witness even more creative and sophisticated DNA nanomachines.

Several hiccups do stand in the way. Like other biomolecules, foreign DNA can be chopped up by the bodys immune system as an invader. However, the team believes that the limitation wont be a problem in the next few years as biochemistry develops chemically-modified artificial DNA letters that resist the bodys scissors.

Another problem is that the DNA devices can generate very little forceless than a billionth the weight of a paperclip, which is a little too low to efficiently control forces in our cells. The authors have a solution here too: coupling many force-generating DNA units together, or engineer translators that can turn electrical energy into mechanical forcesimilar to the way our muscles work.

Fundamentally, any advancements in DNA mechanotechnology wont just benefit medicine; they will also feed back into the design of nanomaterials. The techniques, tools and design principlesare not specific to DNA, the authors said. Add in computer-aided design templates, similar to those used in 3D printing, and potentially anyone can dream up a nano-machine design and make it a reality, said Salaita.

Image Credit: Emory University. DNA mechanotechnology expands the opportunities for research involving biomedicine and materials sciences, says Khalid Salaita, right, professor of chemistry at Emory University and co-author of the article, along with Aaron Blanchard, left, a graduate student in the Salaita Lab.

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Newswise A new study examined the effects of local anesthetics combined with standard chemotherapy for treatment of incurable triple-negative (TN) breast cancer, as well as melanoma. The results suggest that the combined treatment can lower the effective chemotherapy dosage, reduce side effects, improve tumor cell apoptosis, and reduce tumor cell migration.

Researchers at the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University, Philadelphia, and the University of L'Aquila, Italy, and the University of Siena, Italy, examined the effects of two anesthetics, ropivacaine and levobupivacaine, on two different human cancer cell lines, MDA-MB-231, triple-negative breast cancer, and A375, melanoma. This discovery may have important implications for the design of new drugs and therapeutic interventions for these recurrent and incurable tumors.

The findings were published September 20, 2019 in the Journal of Cellular Physiology.

Researchers are pursuing possible strategies for defeating TN breast cancer and melanoma by interfering with cell proliferation and apoptosis induction because these forms of cancer are notoriously difficult to treat. Building on the previously indicated effect of anesthetics in breast cancer cells and in other types of cancer in counteracting cell cycle progression, this study explores more in-depth how anesthetics may be used in cancer therapy, and the authors suggest further study is warranted.

Our studies point towards a possible way to counteract tumor growth and recurrence by interfering with cell cycle progression, apoptosis induction, and migration, says Annamaria Cimini of the University of L'Aquila, lead author of the study.

"The design of new protocols with regional anesthetics may provide new perspectives for breast and melanoma therapies reducing cancer recurrence after surgery by counteracting their metastatic potential and resistance, says Antonio Giordano, MD, PhD, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine.

About the Sbarro Health Research Organization

The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visitwww.shro.org

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Treatment for Incurable Breast Cancer, Melanoma Improved by Adding Local Anesthetics - Newswise

Were not saying that discovering molecular drivers of cancer or cancer-causing genes doesnt deserve the Nobel Prize in medicine or physiology. But for Dr. Brian Druker (whose work led to the targeted leukemia drug Gleevec), Dr. Dennis Slamon (Herceptin), and Mary-Claire King (the BRCA breast- and ovarian-cancer gene), 2019 is probably not their year to be summoned to Stockholm: The 2018 medicine Nobel honored immuno-oncology, and according to STATs Nobel crystal ball, cancer wont win two years in a row.

With the naming of the science Nobels fast approaching the medicine prize will be announced on Oct. 7, physics on Oct. 8, chemistry on Oct. 9 polls, betting pools, and number crunching are in full swing, using approaches from toting up how many predictor prizes a scientist has won to calculating the periodicity of awards, meaning how many years pass before a specific subfield is honored again.

Past laureates, who get to submit nominations every year after their own anointing, have their favorites and, sometimes, their hunches, wrong though they usually are. As 2018 chemistry winner Frances Arnold of the California Institute of Technology said, Its not helpful to second-guess these things!

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Indeed, the Nobels are known for some head-scratching choices over the decades, though less in the science prizes than in peace and literature. Nevertheless, some experts have developed systems that do pretty well. Since 2002, David Pendlebury of Clarivate Analytics has made 50 correct predictions (though usually not in the right year) by analyzing how often a scientists key papers are cited by peers.

Using that strategy, Pendlebury thinks the chemistry Nobel could go toinventors of DNA sequencing techniques: Marvin Caruthers of the University of Colorado, Leroy Hood of the Institute for Systems Biology, and Michael Hunkapiller, CEO of DNA sequencing goliath Pacific Biosciences.Without their [1980s] inventions, Pendlebury said, there would be no map of the human genome.More on that below.

In medicine, Pendlebury likes the chances of Hans Clevers of the Netherlands Utrecht University for research on the Wnt signaling pathway. Wnt controls how stem cells differentiate and how some cancers develop. If Wnt wins, then the private biotech Samumed (valuation: $12 billion) can say its investigational Wnt-targeting drugs are based on Nobel-winning research.

Pendlebury also has his eyes on John Kappler and Philippa Marrack of National Jewish Health in Denver for discovering T-cell tolerance, a mechanism by which the thymus eliminates T cells that would attack the self. That advanced understanding of autoimmune diseases such as rheumatoid arthritis and lupus, and is so basic and important one wonders, Why no Nobel yet?

In 2019, the answer might be, because the 2018 prize honored the hybrid of immunology and cancer, so immunology might have to wait another decade for its next turn. Thats sad news for Jacques Miller, who has never received a Nobel for discovering the function of the thymus and the fact that immune cells include T and B cells in the 1960s. Look how many Nobels were given for immunology based on Millers work, said MITs Phillip Sharp, who shared the 1993 medicine Nobel. There is just a lot of good science that will never get recognized.

If immunology and cancer are off the table, it opens a lane for optogenetics, the revolutionary mashup of genetic engineering and neuroscience. Here, Pendlebury likes Ernst Bamberg of the Max Planck Institute of Biophysics in Germany, Karl Deisseroth of Stanford University, and Gero Miesenbck of the University of Oxford in the U.K. Honoring optogenetics would be wonderful on many levels, starting with the power of the technique to identify neural circuits involved in virtually any function and disease. (The Nobel committees like techniques that enable others to make cool discoveries, Sharp said.)

Even more fun, a prize for optogenetics could open the floodgates of controversy. The key discoveries have so many fathers (alas, optogenetics has no mothers) that picking any three, the maximum for a Nobel, would likely trigger weeks (maybe years!) of carping about who got left out. As it happens, on Thursday the $500,000 Warren Alpert Prize will honor optogenetics, but the winners are Deisseroth, Miesenbck, MITs Edward Boyden (Deisseroths former postdoc), and Peter Hegemann of Germanys Humboldt University. If science had cage matches, we could root for one between Bamberg, Boyden, and Hegemann for the third slot in an optogenetics Nobel.

Records of Nobel committee deliberations remain secret for 50 years, so its anyones guess if theyre influenced by other big prizes. But the latter do seem to have predictive value. Thats one reason David Allis of Rockefeller University and Michael Grunstein of Hebrew University, who in the 1990s discovered one way genes are activated and quieted (through proteins called histones), are favorites (again) for a medicine Nobel. Theyve shared a slew of awards, including a 2018 Lasker and a 2016 Gruber Prize in Genetics, so 2019 could (finally) be their year, especially since there hasnt been a Nobel for gene expression since 2006, and the Allis/Grunstein discovery basically launched the hot field of epigenetics.

Sharp points to another scientist who made seminal contributions to the understanding of genes off/on switches: Yale Universitys Joan Steitz, who in 1979 discovered small noncoding RNAs that control gene expression.

For his crystal ball, biologist Jason Sheltzer of Cold Spring Harbor Laboratory looks at periodicity, a strategy that helped him correctly predict last years medicine win for immune-oncology pioneer James Allison. Fields like infectious disease, immunology, and cancer win every 10 to 20 years, and so are probably off the table for 2019. But the last Nobel for DNA sequencing was way back in 1980, Sheltzer points out, and since then we have seen the complete sequencing of the human genome, one of humanitys towering achievements.

The problem is, hundreds of scientists worked on the Human Genome Project. Last year the Nobels honored the organizers of the project that discovered gravitational waves, so with similar reasoning the medicine or chemistry prize might go to Dr. Francis Collins, now director of the National Institutes of Health and the guy who herded all those cats to get the genome project done, and/or to the Broad Institutes Eric Lander, whose lab churned out much of the sequence. A third might be Craig Venter, the outsider whose private sequencing efforts raced the Collins/Lander government project to a bitter draw.

But if this trio wins, Pendleburys DNA-sequencing three (Caruthers, Hood, and Hunkapiller) wont. To complicate things even further, among the leading vote getters in an online poll for the chemistry Nobel is Shankar Balasubramanian of Cambridge University, who helped developed next-generation DNA sequencing. The Nobel committees grapple with questions of credit all the time: who did it, who did it first, who had the greatest impact, said chemist Peter Dorhout, past president of the American Chemical Society. I wouldnt want to be them.

For that and other messy reasons, when asked if sequencing has a shot at a Nobel, Sharp didnt hesitate: No, he told STAT.

Gene editing, on the other hand, last won in 1993, so it could be time for a new editing prize, Sheltzer tweeted. CRISPR in particular, [Jennifer] Doudna [of the University of California, Berkeley] will win for either chemistry or medicine.

The wisdom of the crowd agrees with him. Sigma Xi, the scientific research honor society, has been asking members to vote for most likely laureates in bracketology-style matchups. Doudna made the final four in chemistry. (Sigma Xi will announce the winner of its contest Thursday.) The other three finalists: Harvards Stuart Schreiber for research on signal transduction and master regulators of cell function such as the gene mTOR, now a hot target for cancer and other drugs; John Goodenough of the University of Texas for inventing lithium-ion batteries, and Stanfords Carolyn Bertozzi for basically developing bio-orthogonal chemistry, in which reporter molecules label biomolecules within cells.

Since STAT covers only life sciences, we have nothing to say about Goodenoughs chances (but thank you for making smartphones, digital cameras, and Teslas possible!), and agree that Schreiber and Bertozzi are stars. But the Doudna pick is a minefield. If she wins it alone, there will be hurt egos galore, starting with her collaborator Emmanuelle Charpentier of the Max Planck Institute for Infection Biology and including Virginijus iknys of Vilnius University. iknys is often called the forgotten man of CRISPR because Doudna and Charpentier had been running the table of prizes for their work turning a bacterial immune system into a DNA editor until he shared last years $1 million Kavli Prize in nanoscience.

If the Nobel committees prefer to keep firestorms of controversy for the peace prize (Greta Thunberg or Donald Trump?), they have many safe but stellar choices. Pierre Chambon and Ronald Evans have never won for discovering nuclear hormone receptors, where molecules as different as steroids and vitamins dock to make a whole suite of physiological reactions happen, Sharp points out. He also thinks Victor Ambros of the University of Massachusetts and Harvards Gary Ruvkun could bounce up this year for discovering microRNAs DNA-regulating molecules that turn out to control embryonic development, cancer, cell differentiation, and more. The pair has also snared a pile of predictor awards, including a Lasker, a Gairdner, a Breakthrough, and a Gruber Genetics Prize.

To all the many scientists whose work deserves a Nobel but who will not get an early-morning call from Stockholm next week, Sharp offers this quasi-consolation: Life is not fair.

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What's in the cards for this year's Nobel Prizes? - STAT

Does stress affect your appetite or your mood? Many people have experienced stressful situations that trigger a particular mood and also change certain feelings toward food. The laboratory of Dr. Yong Xu, and his colleagues looked into the possibility of crosstalk between stress, eating and mood in animal models and found quite interesting brain connections.

This study was initiated by first author Dr. Na Qu of Wuhan Mental Health Center, China, when she was visiting my lab, said Xu, associate professor of pediatrics and of molecular and cellular biology at Baylor College of Medicine.

Qu, a practicing psychiatrist who also conducts basic brain research, was interested in investigating whether there was a neurological basis for the association between depression and other psychiatric disorders, and alterations in metabolism, such as obesity or lack of appetite, she had observed in a number of her patients.

Xu, Qu and their colleagues worked with a mouse model of depression induced by chronic stress and observed that depressed animals ate less and lost weight. Then, they applied a number of experimental techniques to identify the neuronal circuits that changed activity when the animals were depressed.

We found that POMC neurons in the hypothalamus, which are essential for regulating body weight and feeding behavior, extend physical connections into another region of the brain that has numerous dopamine neurons that are implicated in the regulation of mood, said Xu, who also is a researcher at the USDA/ARS Childrens Nutrition Research Center at Baylor and Texas Childrens Hospital. We know that a decrease in dopamine may trigger depression.

In addition to the physical connection between the feeding and the mood centers of the brain, the researchers also discovered that when they triggered depression in mice, the POMC neurons were activated and this led to inhibition of the dopamine neurons. Interestingly, when the researchers inhibited the neuronal circuit connecting the feeding and the mood centers, the animals ate more, gained weight and looked less depressed.

We have discovered that a form of chronic stress triggers a neuronal circuit that starts in a population of cells that are known to regulate metabolism and feeding behavior and ends in a group of neurons that are famous for their regulation of mood, Xu said.

Stress-triggered activation of the feeding center led to inhibition of dopamine-producing neurons in the mood center.

Xu, Qu and their colleagues propose that their findings provide a new biological basis that may explain some of the connections between mood alterations and changes in metabolism observed in people, and may provide solutions in the future.

Our findings only explain one scenario, when depression is associated with poor appetite. But in other cases depression has been linked to overeating. We are interested in investigating this second association between mood and eating behavior to identify the neuronal circuits that may explain that response, Xu said.

Learn more about this study in the journal Molecular Psychiatry.

Other contributors to this work include Yanlin He, Chunmei Wang, Pingwen Xu, Yongjie Yang, Xing Cai, Hesong Liu, Kaifan Yu, Zhou Pei, Ilirjana Hyseni, Zheng Sun, Makoto Fukuda, Yi Li and Qing Tian. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Huazhong University of Science and Technology and China University of Geosciences.

This work received financial support from grants from the National Institutes of Health (K99DK107008,606 R01DK111436, R01ES027544, R21CA215591), USDA/CRIS (6250-51000-059-04S), American Diabetes Association (1-17-PDF-138), American Heart Association awards (17GRNT32960003, 16GRNT30970064 and 16POST27260254), National Natural Science Foundation of China (81400886), Hubei Province health and family planning scientific research project (WJ2015Q033) and Population and Family Planning Commission of Wuhan (WX14B34). Further support was provided by award and fellowships from Wuhan Young & Middle-Aged Talents, Health and Family Planning Commission of Wuhan Municipality and China Scholarship Council (File NO.201608420019).

By Ana Mara Rodrguez, Ph.D.

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Exploring the stress-mood-appetite connection - Baylor College of Medicine News

Twenty million Americans suffer from peripheral nerve injuries, which can be caused by traumas such as combat wounds and motorcycle crashes as well as medical disorders including diabetes. These injuries can have a devastating impact on quality of life, resulting in loss of sensation, motor function and long-lasting nerve pain. The body is capable of regenerating damaged nerves, but this process is slow and incomplete.

Now, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have discovered a molecular process that controls the rate at which nerves grow both during embryonic development and recovery from injury throughout life.

The study, led by senior author Samantha Butler and published in the Journal of Neuroscience, used experiments with mice to show that it is possible to accelerate peripheral nerve growth by manipulating this molecular process. The finding could inform the development of therapies that reduce the time it takes for people to recover from nerve injuries.

The human bodys nervous system is comprised of two components: the central nervous system, which includes the brain and spinal cord; and the peripheral nervous system, which encompasses all other nerves in the body. Peripheral nerves extend over long distances to connect limbs, glands and organs to the brain and spinal cord, sending signals that control movement via motor neurons, and relaying information such as pain, touch and temperature via sensory neurons.

Unlike the nerves in the brain and spinal cord, which are protected by the skull and vertebrae, the nerves of the peripheral nervous system have no such protection, leaving them vulnerable to injury. While the body has a mechanism to help peripheral nerves reestablish connections after injury, this process is slow; damaged nerves regrow at an average rate of just one millimeter per day.

The glacial pace of this recovery can take a tremendous toll on peoples lives, as they may have to live with impaired movement and sensation for many months or years.

People with severe peripheral nerve injuries often lose sensation, which makes them susceptible to further injury, and they lose mobility, which can lead to muscle atrophy, said Butler, who holds the Eleanor I. Leslie Chair in Pioneering Brain Research in the neurobiology department at the David Geffen School of Medicine at UCLA. The process of nerve regrowth can be extremely painful and if muscles have atrophied it requires a lot of physical therapy to regain function. My lab seeks methods to accelerate this healing process.

In a 2010 study in mice, Butler and her colleagues discovered they could control the rate at which nerves grow in the spinal cord during embryonic development by manipulating the activity of a gene called LIM domain kinase 1, or Limk1. Limk1 controls the rate of nerve growth by regulating the activity of a protein called cofilin. Cofilin plays a key role in a process known as actin polymerization, or treadmilling, which enables nerves to extend thread-like projections over long distances to form neural networks.

Butlers new paper builds on these findings by showing that Limk1 and cofilin also control the rate of growth of peripheral nerves during both development and regeneration.

We discovered that one of the first things a nerve does after injury is switch on all these early developmental molecules that controlled how it grew in the first place, said Butler, who is a member of the UCLA Broad Stem Cell Research Center. Its somewhat similar to how an adult in crisis might reach out to their childhood friends to renew themselves.

In preclinical tests using mouse models with peripheral nerve injuries, Butlers lab showed that this molecular process can be manipulated to make nerves grow faster. Specifically, they found that mice that were genetically engineered so that the Limk1 gene was removed exhibited a 15% increase in the speed of nerve regrowth following injury.

This is a modest improvement for a mouse but one that could translate into a major improvement for a human because our nerves have so much farther to grow, said Butler, who noted that nerves regrow at the same rate in both mice and humans.

This increased rate of nerve regrowth resulted in faster recovery of both motor and sensory functions as measured by how fast the injured mice regained the ability to walk and the sensation in their paws. This is significant because sensory function can take longer than motor function to recover after a traumatic injury, yet sensory function is critical to quality of life.

As a next step, Butler and her lab are using human stem cell-derived motor neurons to screen for drug candidates that could modify this molecular process and speed nerve regeneration in humans. They are also expanding the scope of their study by examining if adding more cofilin rather than inhibiting Limk1 could be even more effective in speeding up recovery from peripheral nerve injuries.

The experimental treatment model described above was used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans.

Reference

Frendo, M.E. et al. (2019) The cofilin/Limk1 pathway controls the growth rate of both developing and regenerating motor axons. The Journal of Neuroscience. DOI: https://doi.org/10.1523/JNEUROSCI.0648-19.2019

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Giving a Speed Boost to Nerve Regrowth - Technology Networks

A group of researchers at Baylor College of Medicine, the Texas Heart Institute and the University of Texas Health Science Center at Houston reveals today in the journal Genes & Development new insights into the recently discovered healing capacity of the heart involving the Hippo cellular pathway. The group previously reported that inactivating the Hippo pathway in the adult murine heart promoted cardiac muscle regeneration after injury, opening the possibility of developing promising heart failure therapies.

In this study, the researchers discovered that inactivating the Hippo pathway in cardiac fibroblasts, non-muscle heart cells intertwined with cardiac muscle cells, promoted cardiac fibrosis and adversely effected cardiac function. These results highlight the need for targeting the Hippo pathway specifically in cardiac muscle cells, and not in cardiac fibroblasts, for safe and effective heart failure therapy.

Heart failure remains the leading cause of mortality in the U.S., and one of the interests of my lab is to develop ways to heal heart muscle by studying cellular pathways involved in heart development and regeneration, said corresponding author Dr. James F. Martin, professor and Vivian L. Smith Chair in Regenerative Medicine atBaylor and director of theCardiomyocyte Renewal Lab at the Texas Heart Institute.

During a heart attack, blood stops flowing into the heart; without oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with a scar, made from cells called fibroblasts. If there is too much scarring, the heart progressively weakens; a large proportion of people who had a severe heart attack will develop heat failure and scarring in the heart.

In previous studies, Martin and his colleagues discovered that inactivating the Hippo signaling pathway in adult murine hearts triggered cardiac muscle cell regeneration after heart attack. These findings raised hope for the development of promising heart failure therapies involving the Hippo pathway.

In the current study, Martin and his colleagues further investigated the Hippo pathway in the adult murine heart, this time focusing on its role in cardiac fibroblasts, non-muscle cells that are closely associated with cardiac muscle cells. The researchers conducted a number of basic studies, including single cell sequencing experiments that provided a high level of resolution to their analyses.

We inactivated the Hippo pathway in resting adult hearts that did not have any injury and observed that the fibroblasts became activated; they proliferated and developed into myofibroblasts, a major cell type that appears in heart tissues after an injury, Martin said.

Mouse hearts with a deficient Hippo pathway in cardiac fibroblasts spontaneously developed cardiac fibrosis, even without injury, which resulted in severe heart dysfunction, said co-first author Dr. Yang Xiao, who was a postdoctoral fellow in the Martin lab during this project. This and other evidence indicated that the Hippo pathway is required to restrain cardiac fibrosis; Hippo is important for maintaining the fibroblasts in their resting state.

In addition, the researchers found that inactivating the Hippo pathway also triggered a molecular cascade resulting in an inflammatory response that was mediated by Yap, a molecule that regulates a number of molecular pathways.

We know that Hippo and Yap work together. Hippo acts like a brake for Yap, so when we took away Hippo, Yap remained active and regulated the expression of important signaling molecules that talk to macrophages and other immune cells luring them into the heart, Martin said.

The researchers believe they have identified important insights into heart function. Their findings inform about the genetic pathways that are important for maintaining the fibroblasts in their resting state.

Other contributors to this work include co-first author Matthew C. Hill, Lele Li, Vaibhav Deshmukh, Thomas J. Martin and Jun Wang. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Texas Heart Institute and the University of Texas Health Science Center at Houston.

This study was supported by grants from the National Institutes of Health (DE023177, HL127717, HL130804, HL118761; F31HL136065; K01DE026561); American Heart Association (14SDG19840000), Vivian L. Smith Foundation, State of Texas funding, Fondation LeDucq Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01) Defining the genomic topology of atrial fibrillation. Further support was provided by Intellectual and Developmental Disabilities Research Center grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the Mouse Phenotyping Core at Baylor College of Medicine (U54 HG006348).

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New insights into heart's healing capacity - Baylor College of Medicine News

Leading p53 researcher Hua Lu, PhD, of Tulane University School of Medicine, was chosen to edit a special edition of a medical journal dedicated to the history of p53 research.

Its the most important suppressor of growth in cancer tumors and the most intensively studied molecule in biomedical research, yet scientists are still unraveling the mysteries of p53 almost 40 years after its discovery.

Leading p53 researcher Hua Lu, PhD, of Tulane University School of Medicine, was chosen to edit a special edition of theJournal of Molecular Cell Biologydedicated to the history of p53 research. The issue includes articles and perspectives from some of the worlds top research scientists in the field from Princetons Institute of Advanced Study, Massachusetts Institute of Technology, Johns Hopkins, Columbia, Northwestern, the Weizmann Institute of Science, the Francis Crick Institute, and other universities along with St Jude Childrens Research Hospital.

Its a tremendous honor to have one of our Tulane researchers chosen to edit this journal, says Dr. Lee Hamm, senior vice president and dean of Tulane School of Medicine. This reflects the breakthroughs Dr. Lu has made in this important field of research.

Scientists have long known that the p53 protein protects against cancer by triggering cells with DNA damage to self-destruct before they become malignant. The protein also triggers DNA repair processes and cell cycle arrest. P53 is kept in check by two genes, MDM2 and MDMX, which regulate its production and degradation in a negative feedback loop. While overproduction of either the p53 protein or its two suppressors is harmful, with one possible result being the formation of cancer, the balance between both p53 and its suppressors allows for normal cell function, in particular the maintenance of genome integrity.

Lu, professor and Reynolds and Ryan Families Chair in Translational Cancer Research, was honored to lead the effort to commemorate advances of p53 research.

The more we study p53, the less we know about it, Lu said. This special issue of JMCB celebrates the 40th anniversary of p53s discovery and highlight researchers in the field of cancer, all of whom are pioneering, world-class scientists.

Lu and his team have recently been looking at how different proteins work to suppress normal p53 function within the cell. One of the proteins, PHLDB3, was thought to be a potential tumor suppressor, but actually allows cancer cells to thrive in the context of pancreatic, prostate, colon, breast, lung, and other cancers. Tulane researchers discovered that PHLDB3 works with MDM2 to inhibit p53, promoting tumor growth. The protein could also cause therapeutic resistance for some late-stage cancers by helping to thwart treatments that work by causing DNA damage to the cancer cell. The other protein of interest is SPIN1, which can promote tumor growth by inactivating p53. The team also discovered how a novel molecular signaling pathway can lead to oncogenic activity of a specific p53 hotspot mutant in the context of liver cancer.

Read more:
Tulane researcher is editor of journal issue honoring 40th anniversary of key cancer discovery - News from Tulane

One of the most remarkable characteristics of germ cell tumors is that they are developmental cancers, meaning that they closely resemble phenomena that occur during embryonic and germ cell development. It is only natural, then, that comprehensive knowledge about developmental biology drives the process of uncovering relevant disease biomarkers with a high likelihood of actual clinical use. This was the case for the classical serum markers AFP and HCG (secreted during embryogenesis), pluripotency factors (such as OCT3/4 and SOX2/17) and embryonic microRNAs (miR-371a-3p), which proved to be true biomarkers of germ cell neoplasms.

Pursuing this strategy, the evolutionary well-known event of X-chromosome inactivation in mammalian cells also resulted in another putative biomarker: XIST. This long non-coding RNA inactivates extra X-chromosome material in female cells, a process that is retained in testicular germ cell tumors as they have a super numerical X-chromosome constitution (because of the initial polyploidization step). Hence, in this work we explored and validated a demethylated XIST fragment (i.e., related to expression of the gene) as a biomarker of these tumors. Two different quantitative methodologies were applied, both with high sensitivity, including high-resolution melting analyses. Importantly, this biomarker was particularly useful in Seminomas, for which informative serum markers commonly used in the clinic are often detected in the normal range. Therefore, the demethylated XIST fragment in serum/plasma could be a promising biomarker for the clinical management of these patients.

Besides applications in the germ cell tumor field, we also demonstrated a valuable use of the demethylated XIST fragment for assessing spermatogenesis extent in testicular parenchyma samples. XIST has been shown to be only and specifically expressed in males during spermatogenesis when the germ cells enter meiosis. This is in line with the higher amount of demethylated XIST promoter identified by us in this study, being of relevance because infertility is a frequent side effect from cancer treatments, with a severe impact on cancer survivors quality of life. This novel finding may help to overcome the limitations of the time consuming and often inaccurate Johnsens score as evaluated by Pathologists to estimate spermatogenesis efficiency in clinical practice. Accordingly, we are pursuing an evaluation of our findings in seminal plasma samples.

Written by:Joo Lobo, MD, Resident in Pathology, PhD student, Cancer Biology & Epigenetics Group, Research Center,Portuguese Oncology Institute of Porto (IPO-Porto) & PhD student in Molecular Pathology and Genetics, Lecturer in Pathology, Master Degree in Medicine,Biomedical Sciences Institute Abel Salazar, University of Porto (ICBAS-UP) & PhD student, Looijenga Group,Princess Mxima Center (PMC) for Pediatric Oncology, Utrecht.

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XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality - Beyond the Abstract - UroToday