Selenium protects a specific type of interneurons in the brain

Selenium protects a specific type of interneurons in the brain.

Exactly 200 years ago, the Swedish scientist Jöns Jacob Berzelius discovered the trace element selenium, which he named after the goddess of the moon, Selene. Besides its industrial applications (chemical industry, production of semiconductors and toners), selenium is an essential trace element and indispensable for humans, many animals and some bacteria. A team led by Dr. Marcus Conrad, research group leader at the Institute of Developmental Genetics (IDG) at Helmholtz Zentrum München, showed for the first time why selenium is a limiting factor for mammals.

Scientific 'by-catch' solves decades-old mystery

The scientists have been investigating for years the processes of a novel type of cell death, known as ferroptosis. In this context, the enzyme GPX4, which normally contains selenium in the form of the amino acid selenocysteine, plays an important role.

In order to better understand the role of GPX4 in this death process, we established and studied mouse models in which the enzyme was modified," said study leader Conrad. "In one of these models, we observed that mice with a replacement of selenium to sulfur in GPX4 did not survive for longer than three weeks due to neurological complications."

In their search for the underlying reasons, the researchers identified a distinct subpopulation of specialized neurons in the brain, which were absent when selenium-containing GPX4 was lacking. "In further studies, we were able to show that these neurons were lost during postnatal development, when sulfur- instead of selenium-containing GPX4 was present," stated first author of the study, Irina Ingold.

Furthermore, the scientists were able to show that ferroptosis is triggered by oxidative stress, which is known to occur for instance during high metabolic activity of cells and high neuronal activity. "Our study demonstrates for the first time that selenium is an essential factor for the postnatal development of a specific type of interneurons," said Dr. José Pedro Friedmann Angeli, a scientist at the IDG, describing the results. "Selenium-containing GPX4 protects these specialized neurons from oxidative stress and from ferroptotic cell death."

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Berry gives boost to cervical cancer therapy

This is Yujiang Fang, M.D., Ph.D., a visiting professor at the MU School of Medicine.

According to the Centers for Disease Control and Prevention, approximately 12,000 women in the United States are diagnosed with cervical cancer each year. One of the most common treatments for cervical cancer is radiation. While radiation therapy destroys cancer cells, it also destroys nearby healthy cells. University of Missouri School of Medicine researchers studied in vitro human cancer cells to show that combining blueberry extract with radiation can increase the treatment's effectiveness.

"Radiation therapy uses high-energy X-rays and other particles such as gamma rays to destroy cancer cells," said Yujiang Fang, M.D., Ph.D., a visiting professor at the MU School of Medicine and lead author of the study. "For some cancers, such as late-stage cervical cancer, radiation is a good treatment option. However, collateral damage to healthy cells always occurs. Based on previous research, we studied blueberry extract to verify it could be used as a radiosensitizer."

Radiosensitizers are non-toxic chemicals that make cancer cells more responsive to radiation therapy. In a previous study, Fang and his research team showed that resveratrol, a compound in red grapes, could be used as a radiosensitizer for treating prostate cancer. Blueberries also contain resveratrol.

"In addition to resveratrol, blueberries also contain flavonoids," said Fang, who also has appointments as an academic pathologist and assistant professor of microbiology and immunology at Des Moines University in Iowa. "Flavonoids are chemicals that may have antioxidant, anti-inflammatory and antibacterial properties."

The researchers used human cervical cancer cell lines to mimic clinical treatment. The cell lines were divided into four groups that included a control group, a group that received only radiation, a group that received only blueberry extract, and a group that received both radiation and the extract.

"Our team used three different measures to confirm results of the study," Fang said. "Radiation decreased cancer cells by approximately 20 percent. Interestingly, the cell group that received only blueberry extract had a 25 percent decrease in cancer. However, the biggest decline in cancer cells occurred in the radiation and extract group, with a decrease of about 70 percent."

Fang explained that the mechanism that makes blueberry extract a radiosensitizer also reduces the abnormal explosion of cell growth ? which is what cancer is.

"Cancer cells avoid death by remodeling themselves," Fang said. "Along with reducing cell proliferation, the extract also 'tricks' cancer cells into dying. So it inhibits the birth and promotes the death of cancer cells."

Fang said an animal study is the next step to confirm that his team can achieve the same results.

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Ebola virus inhibited

A single enzyme. That is all the researchers behind a new study need to manipulate to prevent the feared Ebola virus from spreading. Because with the enzyme they also take away the virus' ability to copy itself and thus produce more virus particles and more infection.

The study has been published in the scientific journal Molecular Cell and was conducted by researchers from the University of Copenhagen and Phillips Universität Marburg in Germany.

'When the Ebola virus enters the human cell, its only purpose is to copy itself, fast. First it must copy all its proteins, then its genetic material. But by inhibiting a specific enzyme we rob the Ebola virus of its ability to copy itself. And that may potentially prevent an Ebola infection from spreading', says Professor Jakob Nilsson from the Novo Nordisk Foundation Center for Protein Research.

A few years ago the Ebola virus ravaged West Africa, where thousands of people died from the extremely infectious Ebola infection. Once you are infected, all you can do is hope that your own immune system is able to kill the infection. Because there is currently no available treatment.

However, the researchers behind the new study have found what is called a new host factor for Ebola virus. It can be described as a small part of the host's -- for example the human body's -- own cells, which the Ebola virus uses to copy itself and produce more infection.

The virus uses the host factor enzyme PP2A-B56 to start producing proteins. So if the researchers switch off PP2A-B56, the virus' ability to copy itself and produce more infection is never 'switched on'.

'When we inhibit the PP2A-B56 enzyme, we remove the first link in a long process, which ends with Ebola spreading. And we can tell that it works. The Ebola infection in cell cultures where we have inhibited the PP2A-B56 enzyme is 10 times smaller after 24 hours compared to infections where we have not inhibited this enzyme', says Jakob Nilsson.

But because the researchers have so far focussed on cell cultures, there is still work to be done before their results can be used to treat people infected with Ebola. Initially the researchers hope to be able to test it on animals and, in the long term, develop a drug that inhibits the relevant enzyme.

The potential of the new discovery may turn out to work on other viruses too, because the structure of Ebola virus is very similar to the other so-called filoviruses, Lloviu virus and Marburg virus. But whether the same mechanisms apply to them too still needs to be uncovered.

From Science Daily

Jaguar conservation depends on neighbors' attitudes

Jaguar.

According to a new survey of residents living near two major national parks in Panama, jaguars deserve increased protection. Nature and wildlife are considered national treasures. But because most residents still support road-building in the parks, the survey team -- including Ricardo Moreno, a Smithsonian Tropical Research Institute research associate -- recommends further education to emphasize the connection between healthy ecosystems and jaguar survival.

"Attitudes of stakeholder groups are especially important to consider, as they can significantly affect policy, thus making the foundations of carnivore management as social and political as they are scientific," the study concludes.

Cerro Hoya National Park is an isolated tropical forest remnant (325 square kilometers, 125 square miles) on Panama's Pacific coast, whereas Darién National Park is Panama's most extensive park (5,790 square kilometers, 2235 square miles) in the area between Panama and Colombia, the only gap in the Pan-American highway from Alaska to Chile.

"According to our study, there is more human -- jaguar conflict in Darién National Park, probably because communities are near larger tracts of unbroken forest, which is much better jaguar habitat," Moreno said. "Ironically, the respondents' ideas about roads into the parks are likely to increase this conflict and make effective park management significantly more challenging."

Moreno's jaguar camera-trapping work is featured in the new Smithsonian Channel production, Panama's Animal Highway. He was recently chosen as one of National Geographic's 2017 Emerging Explorers.

The survey team, including Jessica Fort, Clayton Neilsen and Andrew Carver from Southern Illinois University with Moreno and Ninon Meyer from Fundación Yaguará Panama and the Sociedad Panameña de Biología, surveyed 85 residents of 23 rural communities around Cerro Hoya National Park and 54 residents of five communities around Darién National Park. They interviewed one adult over 18 years of age per household, focusing on residents such as landowners and cattle ranchers, who were most likely to be affected by jaguars.

Retaliation for livestock predation is the primary cause of jaguar deaths: 96 percent of the estimated 230 jaguar killings between 1989 and 2014 were attributed to this cause.

Road building is another well-known cause of environmental degradation. Earlier this year, STRI research associate William Laurance published a paper in Science, stressing the importance of considering wildlife conservation during transportation infrastructure planning, because it is well known in the conservation community that roads "can unleash a Pandora's box of environmental ills, such as land encroachment, wildlife poaching, forest fragmentation, exotic species invasions and illegal mining."

At the beginning of the survey, respondents were asked to identify jaguars, pumas and ocelots from photographs. Only respondents who could distinguish between these species were included in the analysis. In both study areas, the majority of respondents were male. Researchers asked 32 questions to assess their socioeconomic status, personal experience with jaguars, perceptions and attitudes about jaguars and perceptions of the park and its management.

A higher number of respondents in Darién had personally seen a jaguar in their lifetime. Communities in Darién report more livestock losses: Six respondents in Darién reported 33 predation events involving cattle, whereas only one reported a predation event in Cerro Hoya. Nearly a third of respondents at Cerro Hoya admitted to hunting within park boundaries during the previous year, their preferred prey being the collared peccary, Pecari tajacu. No respondents in the Darién National Park group said they had hunted in the park in the previous year, but those who had in the past preferred the spotted paca, Cuniculus paca. Women in the survey were more likely to agree than men that they would be happier without jaguars.

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New patch aims to turn energy-storing fats into energy-burning fats

Prof Chen Peng (left) holding the new microneedle fat burning patch with Asst Prof Xu Chenjie.

A new approach to reducing bulging tummy fats has shown promise in laboratory trials.

It combines a new way to deliver drugs, via a micro-needle patch, with drugs that are known to turn energy-storing white fat into energy-burning brown fat. This innovative approach developed by scientists from Nanyang Technological University, Singapore (NTU Singapore) reduced weight gain in mice on a high fat diet and their fat mass by more than 30 per cent over four weeks.

The new type of skin patch contains hundreds of micro-needles, each thinner than a human hair, which are loaded with the drug Beta-3 adrenergic receptor agonist or another drug called thyroid hormone T3 triiodothyronine.

When the patch is pressed into the skin for about two minutes, these micro-needles become embedded in the skin and detach from the patch, which can then be removed.

As the needles degrade, the drug molecules then slowly diffuse to the energy-storing white fat underneath the skin layer, turning them into energy-burning brown fats.

Brown fats are found in babies and they help to keep the baby warm by burning energy. As humans grow older, the amount of brown fats lessens and is replaced with visceral white fats.

Published in the journal Small Methods recently by NTU Professor Chen Peng and Assistant Professor Xu Chenjie, this approach could help to address the worldwide obesity problem without resorting to surgical operations or oral medication which could require large dosages and could have serious side effects.

"With the embedded microneedles in the skin of the mice, the surrounding fats started browning in five days, which helped to increase the energy expenditure of the mice, leading to a reduction in body fat gain," said Asst Prof Xu, who focuses on research in drug delivery systems.

"The amount of drugs we used in the patch is much less than those used in oral medication or an injected dose. This lowers the drug ingredient costs while our slow-release design minimises its side effects," said Asst Prof Xu.

Obesity which results from an excessive accumulation of fat is a major health risk factor for various diseases, including heart disease, stroke and type-2 diabetes. The World Health Organisation estimates that 1.9 billion adults in the world are overweight in 2016 with 650 million of them being obese.

"What we aim to develop is a painless patch that everyone could use easily, is unobtrusive and yet affordable," said Prof Chen, a biotechnology expert who researches on obesity. "Most importantly, our solution aims to use a person's own body fats to burn more energy, which is a natural process in babies."

Under the two scientists' guidance at NTU's School of Chemical and Biomedical Engineering, research fellow Dr Aung Than conducted experiments which showed that the patch could suppress weight gain in mice that were fed a high fat diet and reduce their fat mass by over 30 per cent, over a period of four weeks.

The treated mice also had significantly lower blood cholesterol and fatty acids levels compared to the untreated mice.

Being able to deliver the drug directly to the site of action is a major reason why it is less likely to have side effects than orally delivered medication.

The team estimates that their prototype patch had a material cost of about S$5 (US$3.50) to make, which contains beta-3 adrenergic receptor agonist combined with Hyaluronic acid, a substance naturally found in the human body and commonly used in products like skin moisturisers.

Beta-3 adrenergic receptor agonist is a drug approved by the Federal Drug Administration of the United States and is used to treat overactive bladders, while T3 triiodothyronine is a thyroid hormone commonly used for medication for an underactive thyroid gland.

Both have been shown in other research studies to be able to turn white fats brown, but their use in reducing weight gain is hampered by potentially serious side-effects and drug accumulation in non-targeted tissues if conventional drug delivery routes were used, such as through oral intake.

NTU's Lee Kong Chian School of Medicine Associate Professor Melvin Leow, who was not affiliated with this study, said it is exciting to be able to tackle obesity via the browning of white fat, and the results were promising.

"These data should encourage Phase I Clinical studies in humans to translate these basic science findings to the bedside, with the hope that these microneedle patches may be developed into an established cost-effective modality for the prevention or treatment of obesity in the near future," added Assoc Prof Leow, an endocrinologist.

Read more at Science Daily

These Countries Have the Most Unique Music in the World

Gnawa music is a mixture of sub-Saharan African, Berber, and Arabic religious songs and rhythms. A new study found music traditions in several sub-Saharan African nations are distinctly different from those found elsewhere in the world.

“There's only one song,” Keith Richards, legendary songwriter, guitarist, and bon vivant of the Rolling Stones, once quipped. “Adam and Eve wrote it; the rest is a variation on a theme.”

Richards, who co-wrote tunes like “(I Can’t Get No) Satisfaction” and “Wild Horses” with frontman Mick Jagger, knew a thing or two about how to pen a hit. And while he may have been downplaying the importance of originality, he was referencing the age-old notion that any piece of music, no matter how groundbreaking, owes a huge debt of gratitude to the songwriting that came before.

But not all types of music, from all countries, show the same amount of “variation” on that “theme.” Some kinds of music are simply more unique in a global context than others. And now, science can prove it — at least, when it comes to the world’s many different types of traditional folk music.

A new computational analysis of 8,200 field recordings from 137 countries found that some places simply boast more unique and unusual folk music than others when judged against the rest of the world’s output. The conclusion was based on the musical components of rhythm, melody, timbre, and harmony.

“We found countries that do seem to have really distinct music recordings,” Maria Panteli of Queen Mary's School of Electronic Engineering and Computer Science told Seeker. “This is the first study to investigate outliers in world music with such a large scale.”

Panteli was the lead author of a new paper describing the research, which was published in the journal PLOS ONE.

Judging from the results, one region of the world in particular appears to stand out for its originality: sub-Saharan Africa.

Botswana, a land of mouthbows and syncopated dance numbers in which a group sings and claps together, turns out to be the country with the most unique folk music in the world, the study found.

In Botswana, a striking majority — 61 percent — of recordings analyzed by the researchers were found to be global “outliers” — that is, recordings that the computer said were distinctly and objectively different from what can generally heard elsewhere in the world.

Several countries in southern and western Africa also displayed more unique “outlier” recordings than other places, the study found.

Heavy hitters also included Ivory Coast (60 percent outliers), where singers are joined by woodwinds and guitars, and Chad (55 percent), where wind instruments are backed up by percussion.

An earlier 2015 analysis of hundreds of world music recordings led by Patrick Savage, a musicologist at the Tokyo University of the Arts, concluded that there are no “absolute universals” in music — that is, no properties that can be found in all music without exception. Rather, while there are exceptions to seemingly every musical rule, some characteristics are found in most types of music around the world.>

And to be sure, not all the world’s original folk music comes from Africa. Other countries displayed exceptionally distinctive musical traditions as well, like the unusual harmonies heard in music from Pakistan and Indonesia, Panteli said.

Benin, with its solo Yoruba drumming, was found to have music with the most original rhythm and harmony. French Guiana, with its flute and vocal music, displayed most unique timbre (a term that refers to the quality of the sounds themselves, as opposed to their pitch or intensity). Zimbabwe, with its mbira, or thumb piano, had the most original melodies.

The audio analyzed in the study was made up of field recordings drawn from two large archives of world folk music: the Smithsonian Folkways Recordings and the world and traditional music collection from the British Library.

Read more at Seeker

A classic Darwinian ecological hypothesis holds up -- with a twist

New University of Colorado Boulder-led research shows that a long-held hypothesis about the factors that govern species ranges largely holds true, but may be the result of a previously underappreciated ecological mechanism.

The prediction, first iterated by Charles Darwin in 1859, holds that climate factors will limit species expansion in more stressful environments (such as cold or dry regions), but that interactions with other species, like competition and pollination, will limit a species range in less stressful environments, where the climate is more temperate.

The new CU Boulder study, published today in the journal Proceedings of the National Academy of Sciences, finds that while the broad outline of Darwin's hypothesis holds true -- the effects of species interactions on a specific plant population increased in conjunction with decreasing environmental stress -- there is a nuance to the commonly held model.

"Darwin and others have said that what drives this pattern is gradients in density or diversity of interacting species, but instead it seems to be effects of stress on growth, survival, reproduction and germination of the plant species," said Allison Louthan, who led the research while completing her PhD dissertation in CU Boulder's Environmental Studies Program.

At three field sites in central Kenya that varied in overall aridity, the researchers studied the population dynamics of Hibiscus meyeri, a common flowering plant, over a period of four years. The ubiquity of this particular flowering species, Louthan said, makes it a useful model system for studying differences in population dynamics across an ecological gradient.

As expected, pollination, herbivory and competition with other herbs and shrubs played a strong role in setting the edges of the plant's range in the wetter sites. Those same interactions, however, did not seem to have a strong hand in H. meyeri's expansion to drier sites.

"This research provides a guide about where and when species interactions are important and where they are less important," said Louthan, now a post-doctoral researcher at Duke University. "Understanding the different forces that set limits to a species range and allow populations to expand or contract is crucial for understanding both ecological and evolutionary dynamics."

Next, the researchers plan to expand their experimental method to other systems, in order to continue studying how a species reacts to various factors across a broad geographic area.

"Even before climate change, a major question was why species have the range limits that they do, and what the importance was of climate versus interactions with other species in setting these limits," said Dan Doak, a professor in CU Boulder's Environmental Studies Program and a coauthor on the study. "Now, with ongoing climate change, these questions are much more pressing. This work shows that multiple forces matter in shaping where a species lives and also that the mechanisms driving these effects are not what biologists have usually assumed."

From Science Daily

Prehistoric bling? Aesthetics crucial factor in development of earliest copper alloys

Above are 64 metal samples of using variable copper-tin-arsenic compositions created to use in the study.

While studies of ancient gold metallurgy and the colour characteristics of gold alloys are well supported by modern research, the colour properties of prehistoric copper alloys, such as tin bronzes or arsenical copper, the most abundant type of metal artefacts in prehistory, have largely been understudied. Until now.

In a study published today in the Journal of Archaeological Science an international team of Serbian and UK researchers have developed a Cu-As-Sn (Copper-Arsenic-Tin) colour ternary diagram to uncover the original colours of archaeological artefacts now patinated through age and exposure.

The study was prompted by the discovery of the world's earliest tin bronze artefacts four years ago in Serbia and the ongoing debate into what significance colour played in the advancement of metal-making technologies.

Dr Miljana Radivojevic, lead author and researcher at the McDonald Institute for Archaeological Research, University of Cambridge, said "Given the acknowledged importance of aesthetics in ancient metallurgy, we decided to experimentally replicate the most common prehistoric alloys, made of binary and ternary combinations of copper, arsenic and tin and produce a colour chart that comes the closest to showing the true 'bling' of such artefacts in the past. We were inspired by modern jewellery making where similar colour charts are used to explore properties of gold-copper-silver alloys."

Professor Zeljko Kamberovic, leader of the Serbian team from the University of Belgrade Faculty of Technology and Metallurgy said, "Our laboratory is one of the few in Europe to hold a license to experiment with arsenic, which is why we were approached to develop the study and produce 64 metal samples of variable copper-tin-arsenic compositions."

"The copper-tin-arsenic ternary colour charts enabled us to re-evaluate the claim that early tin bronzes in the Balkans had a distinctive golden hue," said Radivojevic. She added that it is "now highly likely that the production of this new alloy in the Balkans at the same time as gold could have been dictated by the demand for the 'exotic' golden hue, or its closest imitation."

"This research, although driven by the case study in the Balkans, yielded a valuable representation of colour of the most commonly produced prehistoric alloys worldwide. We now have the means to bring the original shine to the items that have lost their original aesthetic appeal during several millennia of deposition below ground," stated Professor Martinón-Torres from the UCL Institute of Archaeology, where chemical and colorimetric analyses for this study were conducted.

Read more at Science Daily

Adolescent brain makes learning easier

The brains of adolescents react more responsively to receiving rewards. This can lead to risky behaviour, but, according to Leiden University research, it also has a positive function: it makes learning easier. This work has been published in Nature Communications.

Alcohol abuse, reckless behaviour and poor choice in friends: all these are inextricably linked to puberty and adolescence. In the late teens, young people test their limits, and in many cases, push beyond their limits. This is due in part to increased activity in the corpus striatum, a small area deeply hidden away inside the brain. According to previous research, that part of the brain in young people is more responsive to receiving rewards.

Sensitive

Leiden University scientists are now able to show that this increased activity in the corpus striatum does not have only negative consequences. 'The adolescent brain is very sensitive to feedback,' says Sabine Peters, assistant professor of developmental and educational psychology and lead author of the article. 'That makes adolescence the ideal time to acquire and retain new information.'

Peters used a large data set for her research with MRI scans. Over a period of five years, no fewer than 736 brain scans were made of a total of 300 subjects between the ages of 8 and 29. According to Peters, the data set is about ten times larger than that of most comparable studies. In the MRI scanner, participants had to solve a memory game. During that game, the researchers gave feedback on the participants' performance.

Instructional feedback

'It showed that adolescents responded keenly to educational feedback', says Peters. 'If the adolescent received useful feedback, then you saw the corpus striatum being activated. This was not the case with less pertinent feedback, for example, if the test person already knew the answer. The stronger your brain recognises that difference, the better the performance in the learning task. Brain activation could even predict learning performance two years into the future.'

It has been known for some time that adolescent brains become more 'successful' when they receive the same reward as small children or adults. For example, it has already been proven that the use of drugs and/or alcohol in the teenage years is linked to powerful activation in the brain's reward system. Peters: 'It explains why adolescents and young adults go on a voyage of discovery, with all the positive and negative consequences that entails. You see the same behaviour in many animal species, including rats and mice.'

From Science Daily

Cancer overrides the circadian clock to survive

Hollings Cancer Center researchers Dr. Yiwen Bu and Dr. J. Alan Diehl explore how cancer overrides the circadian clock to survive.

Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) find. A key part of the circadian clock opposes this process, according to a paper published online Dec. 11 in Nature Cell Biology.

For tumors to grow and spread, cancer cells must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves. Yet in both normal and cancer cells that increase their synthesis of protein, a small percent of those proteins do not fold properly. When that happens, the cell activates its unfolded protein response (UPR), which slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the buildup of misfolded proteins becomes toxic and leads to cell death. However, cancer cells have learned to use the UPR to slow protein synthesis when needed, in order to handle the backlog of misfolded proteins. This helps them survive in conditions that would kill normal cells.

This pattern of adaptation is often seen in tumor cells, according to J. Alan Diehl, Ph.D., the SmartState Endowed Chair in Lipidomics, Pathobiology and Therapy at the MUSC Hollings Cancer Center and senior researcher on the project. "What a tumor cell is doing is taking a pathway that's already in the cell and using it to its advantage," said Diehl.

Yet it was not clear exactly how cancer cells were able to use UPR activity to influence circadian rhythm. Diehl's group found that the UPR and circadian rhythm are linked together to lead the clockwork of the cell and also that cancer cells use the UPR to manipulate the circadian clock in ways that allow them to survive conditions that are toxic to normal cells.

To start, Diehl and his fellow researchers formulated a new idea based on what was known about protein synthesis in the cell. First, as they knew, the UPR is altered in tumors, and second, cells establish a circadian rhythm to regulate metabolism by producing levels of certain proteins that rise and fall in coordination with natural cycles of light and dark. Third, other scientists had observed that circadian rhythm is altered in tumor cells. Since protein production is tied to circadian rhythm, Diehl's group asked if misfolded proteins might change circadian rhythm in cancer cells.

In their first set of experiments, Diehl's research team used chemicals to activate the UPR in osteosarcoma cells. They found that, when activated, the UPR changes levels of an important protein called Bmal1, which is a transcription factor that rises and falls with cycles of light and dark. As it does, it regulates the expression of major circadian rhythm genes. When cells were exposed to cycles of light and dark, Bmal1 levels peaked during dark hours. But when the UPR was chemically activated, Bmal1 stayed low during both light and dark phases, which caused a phase shift in the expression of circadian genes. When one of the main parts of the UPR machinery was absent in cells, the phase shift did not happen.

Next, the group found that the UPR functions much like a "middleman" between light-dark cycles and the ability of cells to establish a circadian rhythm from those cycles. Levels of the circadian protein Bmal1 continued to decrease, as the UPR was increasingly activated. In rodents that had their light-dark cycles suddenly reversed, Bmal1 stopped rising and falling -- a clear sign that their circadian rhythms were disrupted. Shifts in light exposure activated the UPR in those rodents' cells.

But what does that mean for the development of cancer? The team found that patients with breast, gastric or lung cancers survived longer when they had higher levels of Bmal1 protein. In myc-driven cancers, the UPR was causing the loss of Bmal1 protein, which caused the tumors to grow. Myc-driven tumors lost circadian rhythm, whereas normal cells maintained it. Conversely, high levels of Bmal1 overtook the UPR, thereby allowing protein synthesis to continue, which was toxic to tumor cells. In this way, Bmal1 directly encourages protein synthesis.

This is the first study showing that human cancer suppresses circadian rhythm by controlling protein synthesis through Bmal1. Cancer cells survived longer by using the UPR to suppress Bmal1 and short-circuit their circadian rhythms. These results are important for human biology, according to Yiwen Bu, Ph.D., a postdoctoral scholar in Diehl's laboratory and first author on the paper. "Every single normal cell in our body has circadian oscillation," said Bu. "We showed that resetting the circadian rhythms in cancer cells slows down their proliferation."

Still, do changes in light-dark cycles contribute to the development of cancer in humans? It is not yet clear in patients if circadian shifts contribute to changes in the UPR and if that, in turn, contributes to the development of cancer. But these results could help clinicians boost the effectiveness of current cancer treatments, Diehl said.

Read more at Science Daily

Engineers hack cell biology to create 3-D shapes from living tissue

This image shows the shapes made of living tissue made by the researchers. By patterning mechanically active mouse or human cells to thin layers of extracellular fibers, the researchers could create bowls, coils, and ripple shapes.

Many of the complex folded shapes that form mammalian tissues can be recreated with very simple instructions, UC San Francisco bioengineers report December 28 in the journal Developmental Cell. By patterning mechanically active mouse or human cells to thin layers of extracellular matrix fibers, the researchers could create bowls, coils, and ripples out of living tissue. The cells collaborated mechanically through a web of these fibers to fold themselves up in predictable ways, mimicking natural developmental processes.

"Development is starting to become a canvas for engineering, and by breaking the complexity of development down into simpler engineering principles, scientists are beginning to better understand, and ultimately control, the fundamental biology," says senior author Zev Gartner, part of the Center for Cellular Construction at the University of California, San Francisco. "In this case, the intrinsic ability of mechanically active cells to promote changes in tissue shape is a fantastic chassis for building complex and functional synthetic tissues."

Labs already use 3D printing or micro-molding to create 3D shapes for tissue engineering, but the final product often misses key structural features of tissues that grow according developmental programs. The Gartner lab's approach uses a precision 3D cell-patterning technology called DNA-programmed assembly of cells (DPAC) to set up an initial spatial template of a tissue that then folds itself into complex shapes in ways that replicate how tissues assemble themselves hierarchically during development.

"We're beginning to see that it's possible to break down natural developmental processes into engineering principles that we can then repurpose to build and understand tissues," says first author Alex Hughes, a postdoctoral fellow at UCSF. "It's a totally new angle in tissue engineering."

"It was astonishing to me about how well this idea worked and how simply the cells behave," Gartner says. "This idea showed us that when we reveal robust developmental design principles, what we can do with them from an engineering perspective is only limited by our imagination. Alex was able to make living constructs that shape-shifted in ways that were very close to what our simple models predicted."

Read more at Science Daily

Pain-free skin patch responds to sugar levels for management of type 2 diabetes

Concept illustration of microneedle device for type 2 diabetes treatment.

For millions of people with type 2 diabetes, ongoing vigilance over the amount of sugar, or glucose, in their blood is the key to health. A finger prick before mealtimes and maybe an insulin injection is an uncomfortable but necessary routine.

Researchers with NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB) have devised an innovative biochemical formula of mineralized compounds that interacts in the bloodstream to regulate blood sugar for days at a time. In a proof-of-concept study performed with mice, the researchers showed that the biochemically formulated patch of dissolvable microneedles can respond to blood chemistry to manage glucose automatically.

"This experimental approach could be a way to take advantage of the fact that persons with type 2 diabetes can still produce some insulin," said Richard Leapman, Ph.D., NIBIB scientific director. "A weekly microneedle patch application would also be less complicated and painful than routines that require frequent blood testing."

Insulin is a hormone made in the pancreas and secreted into the bloodstream to regulate glucose in response to food intake. It is needed to move glucose from the bloodstream into cells where the sugar can be converted to energy or stored. In type 1 diabetes, usually diagnosed in children and young adults, the body does not make insulin at all. Type 2 diabetes, which can be diagnosed at any age but more commonly as an adult, progressively lessens the body's ability to make or use insulin. Untreated, diabetes can result in both vascular and nerve damage throughout the body, with debilitating impacts on the eyes, feet, kidneys, and heart.

Global incidence of all types of diabetes is about 285 million people, of which 90 percent have type 2 diabetes. Many require insulin therapy that is usually given by injection just under the skin in amounts that are calculated according to the deficit in naturally generated insulin in the blood. Insulin therapy is not managed well in half of all cases.

NIBIB researchers led by Xiaoyuan (Shawn) Chen, senior investigator in the Laboratory of Molecular Imaging and Nanomedicine, are working on an alternate therapy approach to regulate blood sugar levels in type 2 diabetes using a painless skin patch. In a Nov. 24, 2017, study published online in Nature Communications, the team applied the treatment to mice to demonstrate its potential effectiveness.

The base of the experimental patch is material called alginate, a gum-like natural substance extracted from brown algae. It is mixed with therapeutic agents and poured into a microneedle form to make the patch. "Alginate is a pliable material -- it is soft, but not too soft," Chen said. "It has to be able to poke the dermis, and while not a commonly used material for needles, it seems to work pretty well in this case."

Chen's team infused the alginate with a formula of biochemical particles that stimulates the body's own insulin production when needed and curtails that stimulation when normal blood sugar concentration is reached. The responsive delivery system of the patch can meet the body's need for days instead of being used up all at once.

"Diabetes is a very serious disease and affects a lot of people," Chen said, explaining that his group is part of a crowded field of drug research and developers with competing ideas. "Everybody is looking for a long-acting formula."

Pain-free skin patch responds to sugar levels for management of type 2 diabetes | National Institute of Biomedical Imaging and Bioengineering

Chen's formula puts two drug compounds -- exendin-4 and glucose oxidase -- into one patch. The two compounds react with the blood chemistry to trigger insulin secretion. Each is matched with a phosphate mineral particle, which stabilizes the compound until it is needed. Acidity that occurs when sugar concentrations rise weakens the bond with the drug being held by one, but not the other mineral.

Exendin-4 is similar in genetic makeup to a molecule the body produces and secretes in the intestine in response to food intake. Though it is somewhat weaker than the naturally occurring molecule, the team chose exendin-4 for its application because exendin-4 does not degrade in the bloodstream for an hour or more, so can have long-lasting effect after being released. However, it can induce nausea when too much is absorbed. To control how quickly it is absorbed, the researchers combined exendin-4 with mineral particles of calcium phosphate, which stabilize it until another chemical reaction occurs. That chemical reaction is caused by the second drug compound in the patch -- glucose oxidase -- that is held in its mineral buffer of copper phosphate.

Chen explained that when blood sugar is elevated beyond a precise point, it triggers a reaction with copper phosphate and glucose oxidase to produce slight acidity, which causes calcium phosphate to release some exendin-4. Rising glucose levels trigger the release of exendin-4; but exendin-4 then gets insulin flowing to reduce the glucose level, which slows down and stops release of exendin-4. "That's why we call it responsive, or smart, release," said Chen. "Most current approaches involve constant release. Our approach creates a wave of fast release when needed and then slows or even stops the release when the glucose level is stable."

The researchers demonstrated that a patch about half an inch square contained sufficient drug to control blood sugar levels in mice for a week. For the approach to advance as an application that people with type-2 diabetes can use, the team will need to perform tests to treat larger animals with a patch that contains proportionately more therapeutic compound. In addition to its size, the patch would need to be altered for application on human skin, likely requiring longer needles.

"We would need to scale up the size of the patch and optimize the length, shape, and morphology of the needles," Chen said. "Also, the patch needs to be compatible with daily life, for instance allowing for showering or sweating."

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'Cosmic lantern' could help us further understand the fate of the universe

The image shows nearby emission line galaxies NCG 4038 - 4039. The pink parts in this image are showing the light from the gas heated by newly formed stars.

New research has provided a deeper insight into emission line galaxies, used in several ongoing and upcoming surveys, to help us further understand the composition and fate of the Universe.

The quest to determine the nature of both dark matter and dark energy has led scientists to adopt new tracers of the large-scale structure of the Universe, such as emission line galaxies. These galaxies present strong emission lines from the gas heated up by newly formed stars.

Lead author of the study, Dr Violeta Gonzalez-Perez from the University of Portsmouth's Institute of Cosmology and Gravitation, said: "Galaxies are cosmic lanterns that show small patches of cosmic history, informing us of the changes in the space-time fabric of the Universe. The strong formation of new stars in galaxies leave a characteristic imprint in their spectra that allows for a precise determination of their distance.

"Moreover, as young stars are very bright, galaxies with a strong star formation can be visible further back in cosmic time. These are the two characteristics that make emission line galaxies excellent cosmological tracers for a long time span."

However, current emission line galaxy samples are small and their characteristics are not well understood. Computational modelling is the only way to attempt to understand all the processes involved in the formation and evolution of these galaxies.

Astronomers from the University of Portsmouth's world-leading Institute of Cosmology and Gravitation (ICG) explored the characteristics of emission line galaxies through experiments on DiRAC's (Distributed Research utilising Advanced Computing) national supercomputing facility at Durham University.

The computational experiments were concentrated around the time when the Universe went from being matter dominated to becoming dark energy dominated as it is now. They found that most emission line galaxies live at the centres of gravitational potential wells, with masses equivalent to eleven billion of our suns. Current numerical models of formation and evolution of galaxies also show that emission line galaxies trace the underlying gravitational potentials in a different way to galaxies selected by their stellar mass.

They then compared their results with the expectations from the SDSS-IV/eBOSS surveys and Dark Energy Spectroscopic Instrument (DESI). Both surveys aim to measure the effect of dark energy on the expansion of the Universe.

Dr Gonzalez-Perez said: "This comparison will improve our understanding of galaxy formation and evolution and allow scientists to benefit from a more realistic model for the mechanisms that produce emission line galaxies."

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Bacteria acquire resistance from competitors

The T6SS (green, magenta) mediated killing and lysis of competing bacteria can lead to DNA release (cyan) and subsequent gene transfer.

Bacteria not only develop resistance to antibiotics, they also can pick it up from their rivals. In a recent publication in Cell Reports, Researchers from the Biozentrum of the University of Basel have demonstrated that some bacteria inject a toxic cocktail into their competitors causing cell lysis and death. Then, by integrating the released genetic material, which may also carry drug resistance genes, the predator cell can acquire antibiotic resistance.

The frequent and sometimes careless use of antibiotics leads to an increasingly rapid spread of resistance. Hospitals are a particular hot spot for this. Patients not only introduce a wide variety of pathogens, which may already be resistant but also, due to the use of antibiotics to combat infections, hospitals may be a place where anti-microbial resistance can develop and be transferred from pathogen to pathogen. One of these typical hospital germs is the bacterium Acinetobacter baumannii. It is also known as the "Iraq bug" because multidrug-resistant bacteria of this species caused severe wound infections in American soldiers during the Iraq war.

Multidrug-resistant bacteria due to gene exchange

The emergence and spread of multidrug resistance could be attributed, among other things, to the special skills of certain bacteria: Firstly, they combat their competitors by injecting them with a cocktail of toxic proteins, so-called effectors, using the type VI secretion system (T6SS), a poison syringe. And secondly, they are able to uptake and reuse the released genetic material. In the model organism Acinetobacter baylyi, a close relative of the Iraq bug, Prof. Marek Basler's team at the Biozentrum of the University of Basel, has now identified five differently acting effectors. "Some of these toxic proteins kill the bacterial competition very effectively, but do not destroy the cells," explains Basler. "Others severely damage the cell envelope, which leads to lysis of the attacked bacterium and hence the release of its genetic material."

The predator bacteria take up the released DNA fragments. If these fragments carry certain drug resistance genes, the specific resistance can be conferred upon the new owner. As a result, the antibiotic is no longer effective and the bacterium can reproduce largely undisturbed.

Pathogens with such abilities are a major problem in hospitals, as through contact with other resistant bacteria they may accumulate resistance to many antibiotics -- the bacteria become multidrug-resistant. In the worst case, antibiotic treatments are no longer effective, thus nosocomial infections with multidrug-resistant pathogens become a deadly threat to patients.

Toxic proteins and antitoxins

"The T6SS, as well as a set of different effectors, can also be found in other pathogens such as those which cause pneumonia or cholera," says Basler. Interestingly, not all effectors are sufficient to kill the target cell, as many bacteria have developed or acquired antitoxins -- so-called immunity proteins. "We have also been able to identify the corresponding immunity proteins of the five toxic effectors in the predator cells. For the bacteria it makes absolute sense to produce not only a single toxin, but a cocktail of various toxins with different effects," says Basler. "This increases the likelihood that the rivals can be successfully eliminated and in some cases also lysed to release their DNA."

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Growing organs a few ink drops at a time

This is a photograph of a 3-D hydrogel construct obtained through drop-on-drop multi-material bioprintinig.

Printed replacement human body parts might seem like science fiction, but this technology is rapidly becoming a reality with the potential to greatly contribute to regenerative medicine. Before any real applications, "bioprinting" still faces many technical challenges. Processing the bio-ink and making it stick to itself and hold the desired printed gel structure have been proving particularly difficult especially in inkjet printing. Few methods currently exist for gluing bio-ink droplets together and these do not work for every kind of cell, motivating new alternative approaches.

Building on their previous work, researchers at Osaka University have now refined an enzyme-driven approach to sticking biological ink droplets together, enabling complex biological structures to be printed. They recently published their findings in Macromolecular Rapid Communications.

Lead author, Shinji Sakai says, "Printing any kind of tissue structure is a complex process. The bio-ink must have low enough viscosity to flow through the inkjet printer, but also needs to rapidly form a highly viscose gel-like structure when printed. Our new approach meets these requirements while avoiding sodium alginate. In fact, the polymer we used offers excellent potential for tailoring the scaffold material for specific purposes."

Currently, sodium alginate is the main gelling agent used for inkjet bioprinting, but has some compatibility problems with certain cell types. The researchers' new approach is based on hydrogelation mediated by an enzyme, horseradish peroxidase, which can create cross-links between phenyl groups of an added polymer in the presence of the oxidant hydrogen peroxide.

Although hydrogen peroxide itself can also damage cells, the researchers carefully tuned the delivery of cells and hydrogen peroxide in separate droplets to limit their contact and keep the cells alive. More than 90% of the cells were viable in biological test gels prepared in this way. A number of complex test structures could also be grown from different types of cells.

"Advances in induced pluripotent stem cell technologies have made it possible for us to induce stem cells to differentiate in many different ways," co-author Makoto Nakamura says. "Now we need new scaffolds so we can print and support these cells to move closer to achieving full 3D printing of functional tissues. Our new approach is highly versatile and should help all groups working to this goal."

From Science Daily

Scientists describe how solar system could have formed in bubble around giant star

This simulation shows how bubbles form over the course of 4.7 million years from the intense stellar winds off a massive star. UChicago scientists postulated how our own solar system could have formed in the dense shell of such a bubble.

Despite the many impressive discoveries humans have made about the universe, scientists are still unsure about the birth story of our solar system.

Scientists with the University of Chicago have laid out a comprehensive theory for how our solar system could have formed in the wind-blown bubbles around a giant, long-dead star. Published Dec. 22 in the Astrophysical Journal, the study addresses a nagging cosmic mystery about the abundance of two elements in our solar system compared to the rest of the galaxy.

The general prevailing theory is that our solar system formed billions of years ago near a supernova. But the new scenario instead begins with a giant type of star called a Wolf-Rayet star, which is more than 40 to 50 times the size of our own sun. They burn the hottest of all stars, producing tons of elements which are flung off the surface in an intense stellar wind. As the Wolf-Rayet star sheds its mass, the stellar wind plows through the material that was around it, forming a bubble structure with a dense shell.

"The shell of such a bubble is a good place to produce stars," because dust and gas become trapped inside where they can condense into stars, said coauthor Nicolas Dauphas, professor in the Department of Geophysical Sciences. The authors estimate that 1 percent to 16 percent of all sun-like stars could be formed in such stellar nurseries.

This setup differs from the supernova hypothesis in order to make sense of two isotopes that occur in strange proportions in the early solar system, compared to the rest of the galaxy. Meteorites left over from the early solar system tell us there was a lot of aluminium-26. In addition, studies, including a 2015 one by Dauphas and a former student, increasingly suggest we had less of the isotope iron-60.

This brings scientists up short, because supernovae produce both isotopes. "It begs the question of why one was injected into the solar system and the other was not," said coauthor Vikram Dwarkadas, a research associate professor in Astronomy and Astrophysics.

This brought them to Wolf-Rayet stars, which release lots of aluminium-26, but no iron-60.

"The idea is that aluminum-26 flung from the Wolf-Rayet star is carried outwards on grains of dust formed around the star. These grains have enough momentum to punch through one side of the shell, where they are mostly destroyed -- trapping the aluminum inside the shell," Dwarkadas said. Eventually, part of the shell collapses inward due to gravity, forming our solar system.

As for the fate of the giant Wolf-Rayet star that sheltered us: Its life ended long ago, likely in a supernova explosion or a direct collapse to a black hole. A direct collapse to a black hole would produce little iron-60; if it was a supernova, the iron-60 created in the explosion may not have penetrated the bubble walls, or was distributed unequally.

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