Sunbathers may want to avoid midnight snacks before catching some rays.

A study in mice from the O’Donnell Brain Institute and UC Irvine shows that eating at abnormal times disrupts the biological clock of the skin, including the daytime potency of an enzyme that protects against the sun’s harmful ultraviolet radiation.

Although further research is needed, the finding indicates that people who eat late at night may be more vulnerable to sunburn and longer term effects such as skin aging and skin cancer, said Dr. Joseph S. Takahashi, Chairman of Neuroscience at UT Southwestern Medical Center’s Peter O’Donnell Jr. Brain Institute.

“This finding is surprising. I did not think the skin was paying attention to when we are eating,” said Dr. Takahashi, also an Investigator with the Howard Hughes Medical Institute.

The study showed that mice given food only during the day an abnormal eating time for the otherwise nocturnal animals sustained more skin damage when exposed to ultraviolet B (UVB) light during the day than during the night. This outcome occurred, at least in part, because an enzyme that repairs UV-damaged skin xeroderma pigmentosum group A (XPA) shifted its daily cycle to be less active in the day.

Mice that fed only during their usual evening times did not show altered XPA cycles and were less susceptible to daytime UV rays.

“It is likely that if you have a normal eating schedule, then you will be better protected from UV during the daytime,” said Dr. Takahashi, holder of the Loyd B. Sands Distinguished Chair in Neuroscience. “If you have an abnormal eating schedule, that could cause a harmful shift in your skin clock, like it did in the mouse.”

Previous studies have demonstrated strong roles for the body’s circadian rhythms in skin biology. However, little had been understood about what controls the skin’s daily clock.

The latest research published in Cell Reports documents the vital role of feeding times, a factor that scientists focused on because it had already been known to affect the daily cycles of metabolic organs such as the liver.

The study found that besides disrupting XPA cycles, changing eating schedules could affect the expression of about 10 percent of the skin’s genes.

However, more research is needed to better understand the links between eating patterns and UV damage in people, particularly how XPA cycles are affected, said Dr. Bogi Andersen of University of California, Irvine, who led the collaborative study with Dr. Takahashi.

“It’s hard to translate these findings to humans at this point,” said Dr. Andersen, Professor of Biological Chemistry. “But it’s fascinating to me that the skin would be sensitive to the timing of food intake.”

Dr. Takahashi, noted for his landmark discovery of the Clock gene regulating circadian rhythms, is researching other ways in which eating schedules affect the biological clock. A study earlier this year reinforced the idea that the time of day food is eaten is more critical to weight loss than the amount of calories ingested. He is now conducting long-term research measuring how feeding affects aging and longevity.

Reference: 1Hong Wang, Elyse van Spyk, Qiang Liu, Mikhail Geyfman, Michael L. Salmans, Vivek Kumar, Alexander Ihler, Ning Li, Joseph S. Takahashi, Bogi Andersen. Time-Restricted Feeding Shifts the Skin Circadian Clock and Alters UVB-Induced DNA Damage. Cell Reports, 2017; 20 (5): 1061 DOI: 10.1016/j.celrep.2017.07.022

Researchers at The Ohio State University Wexner Medical Center and Ohio State’s College of Engineering have developed a new technology, Tissue Nanotransfection (TNT), that can generate any cell type of interest for treatment within the patient’s own body. This technology may be used to repair injured tissue or restore function of aging tissue, including organs, blood vessels and nerve cells. Results of the regenerative medicine study were published in the journal Nature Nanotechnology.

“By using our novel nanochip technology, injured or compromised organs can be replaced. We have shown that skin is a fertile land where we can grow the elements of any organ that is declining,” said Dr. Chandan Sen, director of Ohio State’s Center for Regenerative Medicine & Cell Based Therapies, who co-led the study with L. James Lee, professor of chemical and biomolecular engineering with Ohio State’s College of Engineering in collaboration with Ohio State’s Nanoscale Science and Engineering Center.

Researchers studied mice and pigs in these experiments. In the study, researchers were able to reprogram skin cells to become vascular cells in badly injured legs that lacked blood flow. Within one week, active blood vessels appeared in the injured leg, and by the second week, the leg was saved. In lab tests, this technology was also shown to reprogram skin cells in the live body into nerve cells that were injected into brain-injured mice to help them recover from stroke.

“This is difficult to imagine, but it is achievable, successfully working about 98 percent of the time. With this technology, we can convert skin cells into elements of any organ with just one touch. This process only takes less than a second and is non-invasive, and then you’re off. The chip does not stay with you, and the reprogramming of the cell starts. Our technology keeps the cells in the body under immune surveillance, so immune suppression is not necessary,” said Sen, who also is executive director of Ohio State’s Comprehensive Wound Center.

TNT technology has two major components: First is a nanotechnology-based chip designed to deliver cargo to adult cells in the live body. Second is the design of specific biological cargo for cell conversion. This cargo, when delivered using the chip, converts an adult cell from one type to another, said first author Daniel Gallego-Perez, an assistant professor of biomedical engineering and general surgery who also was a postdoctoral researcher in both Sen’s and Lee’s laboratories.

TNT doesn’t require any laboratory-based procedures and may be implemented at the point of care. The procedure is also non-invasive. The cargo is delivered by zapping the device with a small electrical charge that’s barely felt by the patient.

“The concept is very simple,” Lee said. “As a matter of fact, we were even surprised how it worked so well. In my lab, we have ongoing research trying to understand the mechanism and do even better. So, this is the beginning, more to come.”

Researchers plan to start clinical trials next year to test this technology in humans, Sen said.

Reference: Daniel Gallego-Perez, Durba Pal, Subhadip Ghatak, Veysi Malkoc, Natalia Higuita-Castro, Surya Gnyawali, Lingqian Chang, Wei-Ching Liao, Junfeng Shi, Mithun Sinha, Kanhaiya Singh, Erin Steen, Alec Sunyecz, Richard Stewart, Jordan Moore, Thomas Ziebro, Robert G. Northcutt, Michael Homsy, Paul Bertani, Wu Lu, Sashwati Roy, Savita Khanna, Cameron Rink, Vishnu Baba Sundaresan, Jose J. Otero, L. James Lee, Chandan K. Sen. Topical tissue nano-transfection mediates non-viral stroma reprogramming and rescue. Nature Nanotechnology, 2017; DOI: 10.1038/nnano.2017.134

Like much of the rest of the body, the brain loses flexibility with age, impacting the ability to learn, remember, and adapt. Now, scientists at University of Utah Health report they can rejuvenate the plasticity of the mouse brain, specifically in the visual cortex, increasing its ability to change in response to experience. Manipulating a single gene triggers the shift, revealing it as a potential target for new treatments that could recover the brain’s youthful potential. The research was published online in the Proceedings of the National Academy of Sciences (PNAS) on August 8.

“It’s exciting because it suggests that by just manipulating one gene in adult brains, we can boost brain plasticity,” says lead investigator Jason Shepherd, Ph.D., Associate Professor of Neurobiology and Anatomy at University of Utah Health.

“This has implications for potentially reducing normal cognitive decline with aging, or boosting recovery from brain injury after stroke or traumatic brain injury,” he says. Additional research will need to be done to determine whether plasticity in humans and mice is regulated in the same way.

The dramatic way in which the brain changes over time has long captured the imagination of scientists. A “critical window” of brain plasticity explains why certain eye conditions such as lazy eye can be corrected during early childhood but not later in life. The phenomenon has raised the questions: What ordinarily keeps the window open? And, once it’s shut, can plasticity be restored?

Earlier work that Shepherd carried out in collaboration with Mark Bear, Ph.D., a professor at the Massachusetts Institute of Technology and co-author of the current study, showed that the critical window never opens in mice lacking a gene called Arc. Temporarily closing a single eye of a young mouse for a few days deprives the visual cortex of normal input, and the neurons’ electrophysiological response to visual experience changes. By contrast, young mice without Arc cannot adapt to the new experience in the same way.

“Given our previous studies, we wondered whether Arc is essential for controlling the critical period of plasticity during normal brain development,” says Shepherd.

If there is no visual plasticity without Arc, the thinking goes, then perhaps the gene plays a role in keeping the “critical window” open.

In support of the idea, the new investigation finds that in the mouse visual cortex, Arc rises and falls in parallel with visual plasticity. The two peak in teen mice and fall sharply by middle-age, suggesting they are linked.

The researchers probed the connection further in two more ways. First, in collaboration with co-author Harohiko Bito, Ph.D., a professor at the University of Tokyo, they tested mice that have a strong supply of Arc throughout life. At middle-age, these mice responded to visual deprivation as robustly as their juvenile counterparts. By prolonging Arc’s availability, the window of plasticity remained open for longer.

Manipulating Arc is not the first treatment to prolong plasticity. Chronically treating mice with an antidepressant, fluoxetine, and raising rodents in a stimulating environment with toys and plenty of social interaction, are among other paradigms that do the same.

But the second set of experiments raised the bar higher. Viruses were used to deliver Arc to middle age mice, after the critical window had closed. Following the intervention, these older mice responded to visual deprivation as a youngster woulds. In this case even though the window had already shut, Arc enabled it to open once again.

“It was incredible to see that in adult mice, who have gone through normal development and aging, simply overexpressing Arc with a virus restored plasticity,” says co-first author Kyle Jenks, a graduate student in Shepherd’s lab.

The prevailing notion of how plasticity declines is that as the brain develops, inhibitory neurons mature and become stronger. Shepherd explains that he believes their findings add a new dimension for how critical periods of learning are regulated.

“Increased inhibition in the brain makes it harder to express activity-dependent genes, like Arc, in response to experience or learning,” he says. “And that leads to decreased brain plasticity.”

Normally, Arc is rapidly activated in response to stimuli and is involved in shuttling neurotransmitter receptors out of synapses that neurons use to communicate with one another. Additional research will need to be done to understand precisely how manipulating Arc boosts plasticity.

Whether Arc is involved in regulating the plasticity of other neurological functions mediated by other brain structures, like learning, memory, or repair, remains to be tested but will be examined in the future, says Shepherd.

Reference: Kyle R. Jenks, Taekeun Kim, Elissa D. Pastuzyn, Hiroyuki Okuno, Andrew V. Taibi, Haruhiko Bito, Mark F. Bear, and Jason D. Shepherd. Arc restores juvenile plasticity in adult mouse visual cortex. Proceedings of the National Academy of Sciences, August 2017 DOI: 10.1073/pnas.1700866114

A study published online in The FASEB Journal, involving mice, suggests that EGCG (epigallocatechin-3-gallate), the most abundant catechin and biologically active component in green tea, could help insulin resistance and improve cognition. Previous research pointed to the potential of EGCG to help a variety of human conditions, yet until now, EGCG’s impact on insulin resistance and cognition triggered in the brain remained unclear.

“Green tea is the second most consumed beverage in the world after water, and is grown in at least 30 countries,” said Xuebo Liu, Ph.D., a researcher at the College of Food Science and Engineering, Northwest A&F University, in Yangling, China. The ancient habit of drinking green tea may be beneficial when it comes to combatting obesity, insulin resistance, and improving memory.

Liu and colleagues divided 3-month-old male C57BL/6J mice into three groups based on diet: 1) a control group fed with a standard diet, 2) a group fed with an HFFD diet (high-fat and high-fructose diet), and 3) a group fed with an HFFD diet and 2 grams of EGCG per liter of drinking water. For 16 weeks, researchers monitored the mice and found that those fed with HFFD had a higher final body weight than the control mice, and a significantly higher final body weight than the HFFD+EGCG mice. In performing a Morris water maze test, researchers found that mice in the HFFD group took longer to find the platform compared to mice in the control group. The HFFD+EGCG group had a significantly lower escape latency and escape distance than the HFFD group on each test day. When the hidden platform was removed to perform a probe trial, HFFD-treated mice spent less time in the target quadrant when compared with control mice, with fewer platform crossings. The HFFD+EGCG group exhibited a significant increase in the average time spent in the target quadrant and had greater numbers of platform crossings, showing that EGCG could improve HFFD-induced memory impairment.

“Many reports, anecdotal and to some extent research-based, are now greatly strengthened by this more penetrating study,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal.

Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries. Now new techniques developed at the Morgridge Institute for Research and the University of Wisconsin in Madison have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for modeling and clinical application.

Reporting in the July 10 issue of the journal Proceedings of the National Academy of Sciences, scientists in the lab of stem cell pioneer James Thomson describe methods for generating and characterizing arterial endothelial cells which are the cells that initiate artery development and exhibit many of the specific functions required by the body.

Further, these cells contributed both to new artery formation. ?No one has been able to make those kinds of cells efficiently before,? says Jue Zhang, a Morgridge assistant scientist and lead author. ?The key finding here is a way to make arterial endothelial cells more functional and clinically useful.?

The Thomson lab has made arterial engineering one of its top research priorities. New techniques have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for modeling and clinical application.

The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, Zhang says.

The research team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signaling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR-Cas9 gene editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.

?With this technology, you can test the function of these candidate genes and measure what percentage of cells are generating into our target arterial cells,? says Zhang.

The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.

?Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery,? says Thomson, director of regenerative biology at Morgridge and a UW?Madison professor of cell and regenerative biology. ?This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.?

Thomson?s team, along with many UW?Madison collaborators, is in the first year of a seven-year project supported by the National Institutes of Health on the feasibility of developing artery banks suitable for use in human transplantation.

?Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line,? says Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

Reference: Zhang, J., Chu, L., Hou, Z., Schwartz, M. P., Hacker, T., Vickerman, V., Thomson, J. A. (2017). Functional characterization of human pluripotent stem cell-derived arterial endothelial cells. Proceedings of the National Academy of Sciences, 201702295. doi:10.1073/pnas.1702295114

Whether using embryonic or adult stem cells, coercing these master cells to convert to the desired target cell and reproduce flawlessly is difficult. Now an international team of researchers has a two-part system that can convert the cells to the targets and then remove the remnants of that conversion, leaving only the desired DNA behind to duplicate.

“One difficulty with human pluripotent stem cells is that you can’t use them directly,” said Xiaojun Lian, assistant professor of biomechanical engineering, biology and a member of the Huck Institutes of the Life Sciences, Penn State. They need to be the right type of differentiated cells for each tissue in the body.

Normally, pluripotent stem cells induced from both adult and embryonic cells receive a chemical signal to change from a stem cell to a functional cell. Pluripotent stem cells can change to any cell in the human body. However, this natural cell change is part of a complex series of triggers controlled by DNA. Researchers have in the past inserted DNA into the pluripotent cells to convert them, but remnants of the inserted DNA remain.

In this current work, published in a recent issue of Scientific Reports, the researchers are not incorporating a piece of DNA that will tell the cells to convert, but DNA that will make the cell glow green when illuminated by a blue light. This marker allows the researchers to see that the DNA plasmid is incorporated into the cell, and that it is completely gone upon removal. A plasmid is a circular piece of DNA that contains functional DNA fragments that control gene expression in cells.

“We wanted to explore the limits for turning the conversion on and off and to have the ability to control the level of expression and removal of DNA after conversion,” said Lauren N. Randolph, doctoral student in bioengineering, Penn State.

Previous approaches incorporated the appropriate DNA to switch on the conversions, but did not completely remove all the DNA inserted.

The researchers are using a Tet-On 3G inducible PiggyBac system that is a plasmid they named XLone to achieve insertion, activation and removal. The PiggyBac portion of the system includes the DNA to insert that DNA into the cell’s DNA. The Tet-On 3G portion contains the necessary signaling information. This system also makes the cells more sensitive to doxycycline, which is the drug used to initiate the conversion.

“We are using abundant multiple copies of the plasmid to increase the likelihood that it gets in and does what it is supposed to do and actually follows through reproduction of the cells,” said Lian.

If only one or a few plasmids are inserted into the cell, the new DNA could just be silenced. Insertion of multiple plasmids assures that at least one will function.

“The first advantage with our system is that it does not have any leakage expression,” said Randolph. “If we don’t induce the system with doxycycline, we get nothing.”

The second advantage is that once the cells are reproducing as heart cells or nerve cells, the plasmid can be removed and the cells continue to reproduce without any remnant of the plasmid system.

While the researchers are currently aiming to understand and study gene function and directed cell differentiation in human stem cells, eventually they would like to be able to create cell-based therapies.

Reference: Lauren N. Randolph, Xiaoping Bao, Chikai Zhou, Xiaojun Lian. An all-in-one, Tet-On 3G inducible PiggyBac system for human pluripotent stem cells and derivatives. Scientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-01684-6