Culture

RESEARCH TRIANGLE PARK, N.C. -- A material from a rare earth element, tellurium, could produce the world's smallest transistor, thanks to an Army-funded project.

Computer chips use billions of tiny switches called transistors to process information. The more transistors on a chip, the faster the computer.

A project at Purdue University in collaboration with Michigan Technological University, Washington University in St. Louis, and the University of Texas at Dallas, found that the material, shaped like a one-dimensional DNA helix, encapsulated in a nanotube made of boron nitride, could build a field-effect transistor with a diameter of two nanometers. Transistors on the market are made of bulkier silicon and range between 10 and 20 nanometers in scale.

"This research reveals more about a promising material that could achieve faster computing with very low power consumption using these tiny transistors," said Joe Qiu, program manager for the Army Research Office, an element of the U.S. Army Combat Capabilities Development Command's Army Research Laboratory, which funded this work. "That technology would have important applications for the Army."

The Army-funded research is published in the journal Nature Electronics. The Army is focused on integration, speed and precision to ensure the Army's capability development process is adaptable and flexible enough to keep pace with the rate of technology change.

"This tellurium material is really unique. It builds a functional transistor with the potential to be the smallest in the world," said Dr. Peide Ye, Purdue's Richard J. and Mary Jo Schwartz Professor of Electrical and Computer Engineering.

One way to shrink field-effect transistors, the kind found in most electronic devices, is to build the gates that surround thinner nanowires. These nanowires are protected within nanotubes.

Ye and his team worked to make tellurium as small as a single atomic chain and then build transistors with these atomic chains or ultrathin nanowires.

They started off growing one-dimensional chains of tellurium atoms, and were surprised to find that the atoms in these one-dimensional chains wiggle. These wiggles were made visible through transmission electron microscopy imaging performed at the University of Texas at Dallas and at Purdue.

"Silicon atoms look straight, but these tellurium atoms are like a snake. This is a very original kind of structure," Ye said.

The wiggles were the atoms strongly bonding to each other in pairs to form DNA-like helical chains, then stacking through weak forces called van der Waals interactions to form a tellurium crystal.

These van der Waals interactions set apart tellurium as a more effective material for single atomic chains or one-dimensional nanowires compared with others because it's easier to fit into a nanotube, Ye said.

Because the opening of a nanotube cannot be any smaller than the size of an atom, tellurium helices of atoms could achieve smaller nanowires and, therefore, smaller transistors.

The researchers successfully built a transistor with a tellurium nanowire encapsulated in a boron nitride nanotube. A high-quality boron nitride nanotube effectively insulates tellurium, making it possible to build a transistor.

"Next, the researchers will optimize the device to further improve its performance, and demonstrate a highly efficient functional electronic circuit using these tiny transistors, potentially through collaboration with ARL researchers," Qiu said.

Hemp is technically legal in Texas, but proving that hemp is not marijuana can be a hurdle, requiring testing in a licensed laboratory. So, when a truck carrying thousands of pounds of hemp was recently detained by law enforcement near Amarillo, the driver spent weeks in jail awaiting confirmation that the cargo was legal.

Stories like that one inspired a team of Texas A&M AgriLife researchers to create a "hemp scanner" that could easily fit in a police cruiser and distinguish hemp and marijuana instantly, without damaging any of the product. The study was published in January in the scientific journal RSC Advances.

HEMP'S HEYDAY

In 2019, Texas lawmakers made a distinction between hemp and marijuana based on the level of THC, or tetrahydrocannabinol, in a plant. THC is the major psychoactive agent in marijuana. If a plant has less than 0.3% THC, it is designated hemp.

Both federal and state restrictions on hemp have loosened in recent years. As a result, the value of hemp has skyrocketed, said Dmitry Kurouski, Ph.D., assistant professor of biochemistry and biophysics at the Texas A&M University College of Agriculture and Life Sciences, who led the study. Hemp is rich in compounds that are prized for their medicinal properties and flavor. The most well-known is CBD, or cannabidiol, which is thought to help with pain, anxiety and depression.

But farmers wanting to grow valuable hemp plants need a way to know that the plants contain little to no THC. When hemp can be legally grown in Texas later this year, producers will want to know if their plants' THC levels are approaching 0.3%, which would classify the plants as marijuana and therefore illegal to have and grow. An easy test for THC would be a boon for farmers as well as for law enforcement.

COULD AN EXISTING SCANNER WORK?

Kurouski said that the catalyst for creating the hemp scanner was his colleague David Baltensperger, Ph.D., professor of soil and crop sciences at the Texas A&M University College of Agriculture and Life Sciences. Baltensperger had worked with both farmers and police officers and knew about the demand for a better test for THC, Kurouski said.

Kurouski's lab was experienced in using a technique called Raman spectroscopy to create quick and noninvasive tests for plant diseases and foods' nutritional content. The technique uses harmless laser light to illuminate structures within materials. Each material's scan is unique, akin to a fingerprint.

Kurouski had a hunch that Raman could be used to create a quick and accurate test for THC. A portable Raman scanner had been created for previous studies by lab members Lee Sanchez, a research assistant, and Charles Farber, a graduate student.

What was then needed was a way to scan many marijuana and hemp plants in order to search for patterns in how their Raman spectra differed.

FINGERPRINTING THC

Testing dozens of samples of marijuana and hemp fell to Sanchez. The testing needed to happen near Denver, where recreational marijuana is legal.

"Lee Sanchez was the hero who was traveling to Colorado three times, staying there in hotels and driving from one location to another. Most of those locations are old fire stations. They are not fancy greenhouses but old, shaky buildings with plants inside," Kurouski said.

Back in Texas, Sanchez and Kurouski analyzed the collected spectra. A statistical analysis method found seven regions in the spectra that differed slightly among marijuana and hemp varieties, a high-tech version of the "spot the difference" brain teaser. Taken together, the readout in these seven regions distinguishes hemp and marijuana with 100% accuracy.

"We know plants from A to Z in terms of their spectroscopic signature," Kurouski said. "But when we saw such a crystal-clear picture of THC that appeared in one second of spectral acquisition, that was mind-blowing."

WHAT'S NEXT?

Now that Kurouski's team has demonstrated its quick, noninvasive test for THC, they are looking to collaborate with industry to mass-produce their hemp scanner. Mass production could feasibly begin in two or three years, Kurouski said.

The team also aims to create a similar test for CBD. Farmers looking to grow hemp may want to know the amount of CBD in their plants to better estimate their value.

The study also uncovered the scanner's ability to distinguish among different varieties of hemp and marijuana. In the changing legal landscape, there are thousands of varieties of cannabis, many of questionable quality.

"Our colleagues, the farmers, were positively surprised that we could identify the variety with 98% accuracy," Kurouski said. "That blew them away."

It's no coincidence that some of the worst viral disease outbreaks in recent years -- SARS, MERS, Ebola, Marburg and likely the newly arrived 2019-nCoV virus -- originated in bats.

A new University of California, Berkeley, study finds that bats' fierce immune response to viruses could drive viruses to replicate faster, so that when they jump to mammals with average immune systems, such as humans, the viruses wreak deadly havoc.

Some bats -- including those known to be the original source of human infections -- have been shown to host immune systems that are perpetually primed to mount defenses against viruses. Viral infection in these bats leads to a swift response that walls the virus out of cells. While this may protect the bats from getting infected with high viral loads, it encourages these viruses to reproduce more quickly within a host before a defense can be mounted.

This makes bats a unique reservoir of rapidly reproducing and highly transmissible viruses. While the bats can tolerate viruses like these, when these bat viruses then move into animals that lack a fast-response immune system, the viruses quickly overwhelm their new hosts, leading to high fatality rates.

"Some bats are able to mount this robust antiviral response, but also balance it with an anti-inflammation response," said Cara Brook, a postdoctoral Miller Fellow at UC Berkeley and the first author of the study. "Our immune system would generate widespread inflammation if attempting this same antiviral strategy. But bats appear uniquely suited to avoiding the threat of immunopathology."

The researchers note that disrupting bat habitat appears to stress the animals and makes them shed even more virus in their saliva, urine and feces that can infect other animals.

"Heightened environmental threats to bats may add to the threat of zoonosis," said Brook, who works with a bat monitoring program funded by DARPA (the U.S. Defense Advanced Research Projects Agency) that is currently underway in Madagascar, Bangladesh, Ghana and Australia. The project, Bat One Health, explores the link between loss of bat habitat and the spillover of bat viruses into other animals and humans.

"The bottom line is that bats are potentially special when it comes to hosting viruses," said Mike Boots, a disease ecologist and UC Berkeley professor of integrative biology. "It is not random that a lot of these viruses are coming from bats. Bats are not even that closely related to us, so we would not expect them to host many human viruses. But this work demonstrates how bat immune systems could drive the virulence that overcomes this."

The new study by Brook, Boots and their colleagues was published this month in the journal eLife.

Boots and UC Berkeley colleague Wayne Getz are among 23 Chinese and American co-authors of a paper published last week in the journal EcoHealth that argues for better collaboration between U.S. and Chinese scientists who are focused on disease ecology and emerging infections.

Vigorous flight leads to longer lifespan - and perhaps viral tolerance

As the only flying mammal, bats elevate their metabolic rates in flight to a level that doubles that achieved by similarly sized rodents when running.

Generally, vigorous physical activity and high metabolic rates lead to higher tissue damage due to an accumulation of reactive molecules, primarily free radicals. But to enable flight, bats seem to have developed physiological mechanisms to efficiently mop up these destructive molecules.

This has the side benefit of efficiently mopping up damaging molecules produced by inflammation of any cause, which may explain bats' uniquely long lifespans. Smaller animals with faster heart rates and metabolism typically have shorter lifespans than larger animals with slower heartbeats and slower metabolism, presumably because high metabolism leads to more destructive free radicals. But bats are unique in having far longer lifespans than other mammals of the same size: Some bats can live 40 years, whereas a rodent of the same size may live two years.

This rapid tamping down of inflammation may also have another perk: tamping down inflammation related to antiviral immune response. One key trick of many bats' immune systems is the hair-trigger release of a signaling molecule called interferon-alpha, which tells other cells to "man the battle stations" before a virus invades.

Brook was curious how bats' rapid immune response affects the evolution of the viruses they host, so she conducted experiments on cultured cells from two bats and, as a control, one monkey. One bat, the Egyptian fruit bat (Rousettus aegyptiacus), a natural host of Marburg virus, requires a direct viral attack before transcribing its interferon-alpha gene to flood the body with interferon. This technique is slightly slower than that of the Australian black flying fox (Pteropus alecto), a reservoir of Hendra virus, which is primed to fight virus infections with interferon-alpha RNA that is transcribed and ready to turn into protein. The African green monkey (Vero) cell line does not produce interferon at all.

When challenged by viruses mimicking Ebola and Marburg, the different responses of these cell lines were striking. While the green monkey cell line was rapidly overwhelmed and killed by the viruses, a subset of the rousette bat cells successfully walled themselves off from viral infection, thanks to interferon early warning.

In the Australian black flying fox cells, the immune response was even more successful, with the viral infection slowed substantially over that in the rousette cell line. In addition, these bat interferon responses seemed to allow the infections to last longer.

"Think of viruses on a cell monolayer like a fire burning through a forest. Some of the communities -- cells -- have emergency blankets, and the fire washes through without harming them, but at the end of the day you still have smoldering coals in the system -- there are still some viral cells," Brook said. The surviving communities of cells can reproduce, providing new targets for the the virus and setting up a smoldering infection that persists across the bat's lifespan.

Brook and Boots created a simple model of the bats' immune systems to recreate their experiments in a computer.

"This suggests that having a really robust interferon system would help these viruses persist within the host," Brook said. "When you have a higher immune response, you get these cells that are protected from infection, so the virus can actually ramp up its replication rate without causing damage to its host. But when it spills over into something like a human, we don't have those same sorts of antiviral mechanism, and we could experience a lot of pathology."

The researchers noted that many of the bat viruses jump to humans through an animal intermediary. SARS got to humans through the Asian palm civet; MERS via camels; Ebola via gorillas and chimpanzees; Nipah via pigs; Hendra via horses and Marburg through African green monkeys. Nonetheless, these viruses still remain extremely virulent and deadly upon making the final jump into humans.

Brook and Boots are designing a more formal model of disease evolution within bats in order to better understand virus spillover into other animals and humans.

"It is really important to understand the trajectory of an infection in order to be able to predict emergence and spread and transmission," Brook said.

Your good deed for the day--whether lending a hand to a stranger or giving up your seat on the subway--may prompt others to see you as a good and trustworthy person, but not always. In certain circumstances, it may do just the opposite.

New research published in Psychological Science, the flagship journal of the Association for Psychological Science, suggests that someone who helps a total stranger is generally viewed as morally better and more trustworthy than someone who helps a family member. But this is true only if the helper did not have to choose between those options.

Through a series of five online experiments, a team of psychology researchers from Boston College and Harvard University recruited more than 1,300 volunteers and asked them to evaluate several "Good Samaritan" scenarios. The goal was to determine if familial obligations factor into people's everyday judgments of moral character, and if so, in what way.

In each of these scenarios, the researchers manipulated one specific element: whether the person being helped was a stranger or, alternatively, was distantly related to the person lending a hand. The good deeds presented in the tests were basic courtesies, like helping someone move into a new apartment. They did not require extreme physical or financial sacrifice.

In one series of tests, participants read scenarios in which only one person--either a stranger or kin--could be helped. People who helped a stranger were judged as more morally good and more trustworthy than people who helped an equally deserving family member.

"In these cases, we found that perceptions of a helper's moral character clearly changed based on whether their help was directed at a family member," said Ryan McManus, a second-year PhD student at Boston College and lead author on the paper. Additional members of the research team included Liane Young, an associate professor of psychology at Boston College, and Max Kleiman-Weiner, a postdoctoral researcher at Harvard University.

"All things being equal, people who helped a stranger were judged to be more moral and more trustworthy than people who helped a family member," said McManus.

In a second series of tests, participants were faced with similar scenarios, except for one difference: The helper had to choose between helping either a stranger or a family member. Helping one meant forgoing help to the other.

The addition of this either/or choice reversed the outcome. Participants judged that people who chose to help a stranger over a family member were less morally good and less trustworthy than people who opted to help a family member.

"What struck us was how clearly participants' judgments changed when they viewed these acts of kindness through the lens of choice between kin and strangers," said McManus.

The researchers think these seemingly contradictory character judgments are actually connected by a single principle: familial obligation.

This same concept carried over into a third series of tests in which people simply chose to offer no help at all, (e.g., preferring to play videogames rather than help a neighbor move into a new apartment). In these cases, people who ignored the needs of a stranger were judged less critically than people who withheld help from a family member.

"The take-home message from this work is that, from a third-party perspective, the way that we think about others' moral character depends on who their helpful, or unhelpful, behavior is directed at," concluded McManus.

The team plans to continue their investigations by examining the role of obligations in judgment when comparing closely related family members to more distant relations.

Having genetically higher testosterone levels increases the risk of metabolic diseases such as type 2 diabetes in women, while reducing the risk in men. Higher testosterone levels also increase the risks of breast and endometrial cancers in women, and prostate cancer in men.

The findings come from the largest study to date on the genetic regulation of sex hormone levels, published today in Nature Medicine and led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and the University of Exeter. Despite finding a strong genetic component to circulating testosterone levels in men and women, the authors found that the genetic factors involved were very different between the sexes.

The team used genome wide association studies (GWAS) in 425,097 UK Biobank participants to identify 2,571 genetic variations associated with differences in the levels of the sex hormone testosterone and its binding protein sex-hormone binding globulin (SHGB).

The researchers verified their genetic analyses in additional studies, including the EPIC-Norfolk study and Twins UK, and found a high level of agreement with their results in UK Biobank.

The team next used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to understand whether known associations between testosterone levels and disease are causal rather than correlative. They found that in women, genetically higher testosterone increases the risks of type 2 diabetes by 37 per cent, and polycystic ovary syndrome (PCOS) by 51 per cent. However, they also found that having higher testosterone levels reduces T2D risk in men by 14 per cent. Additionally, they found that genetically higher testosterone levels increased the risks of breast and endometrial cancers in women, and prostate cancer in men.

Dr John Perry from the MRC Epidemiology Unit at the University of Cambridge, and joint senior author on the paper, says:

"Our findings that genetically higher testosterone levels increase the risk of PCOS in women is important in understanding the role of testosterone in the origin of this common disorder, rather than simply being a consequence of this condition."

"Likewise, in men testosterone-reducing therapies are widely used to treat prostate cancer, but until now it was uncertain whether lower testosterone levels are also protective against developing prostate cancer. Our findings show how genetic techniques such as Mendelian randomisation are useful in understanding of the risks and benefits of hormone therapies."

Dr Katherine Ruth, of the University of Exeter, one of the lead authors of the paper, added:

"Our findings provide unique insights into the disease impacts of testosterone. In particular they emphasise the importance of considering men and women separately in studies, as we saw opposite effects for testosterone on diabetes. Caution is needed in using our results to justify use of testosterone supplements, until we can do similar studies of testosterone with other diseases, especially cardiovascular disease."

Most memories fade in a matter of days or weeks, while some persist for months, years, or even for life. What allows certain experiences to leave such a long-lasting imprint in our neural circuits? This is an age-old question in neurobiology that has never been resolved, but new evidence is pointing to a surprising new answer.

In a study published February 10, 2020 in Nature Neuroscience, UC San Francisco scientists have discovered that mice quickly learn a fearful response to a situation perceived as threatening, but for such a conditioned response to become long-lasting requires brain cells to increase amounts of an insulating material called myelin, which may serve to reinforce and stabilize newly formed neural connections.

According to the UCSF researchers, continued research on this role of myelin in learning might one day lead to new treatments for afflictions such as post-traumatic stress disorder (PTSD), in which unwanted, intrusive memories are continually retrieved because they are so strongly encoded in the brain.

"We find that a single, brief fear-learning experience can cause long-term changes in myelination and associated neurophysiological changes within the brain that can be detected even a month later," said study author Mazen Kheirbek, PhD, an assistant professor in the Department of Psychiatry and a member of the UCSF Weill Institute for Neurosciences.

"Investigating the role of new myelin formation in adaptive and maladaptive learning is an important opportunity both for understanding basic mechanisms of learning and memory, as well as for identifying new targets for the treatment of mood and anxiety disorders," he said.

Kheirbek, whose research at UCSF focuses on the neural circuits that generate mood and anxiety-related behaviors, jointly supervised the study with Jonah Chan, PhD, a Weill Institute member and the Debbie and Andy Rachleff Distinguished Professor in the Department of Neurology, whose research focus is on how the brain creates myelin and why it decays in multiple sclerosis (MS).

Growing Evidence That Myelin Plays Role in Learning

Myelin is formed during early development by brain cells called oligodendrocytes, which wrap themselves hundreds of times around the branching axons emanating from certain key neurons. This forms a thick sheath of protein and fat that acts like an insulator around an electrical cable, strengthening and speeding electrical signaling in the nerve pathways that connect one neuron to the next.

This insulation is particularly important for the brain's busiest information superhighways, like the high-speed nerve fibers that can extend three feet or more, giving your brain nearly instant command over your body's muscles. Damage to this myelin and an associated loss of muscle control are hallmarks of MS, but comparatively little attention has been given to the possibility that myelin could also undergo dynamic changes in the healthy adult brain.

However, in the past few years scientists have discovered new myelination forming within the brain during long-term learning, specifically in motor learning (mice learning to run on complex wheels, for example) and in spatial learning (mice learning to find their way back to a particular location within a maze).

Scientists have known for decades that learning depends initially on the brain's ability to rewire itself by forming new connections between neurons. These new studies represent growing evidence that myelin's ability to reinforce and maintain these new connections may determine what makes certain memories stick.

Robust Myelin May Stabilize Persistent Memories

The new study takes these findings a step further, showing that changes in myelin play a critical role not only in animals' physical movements, but also in laying down long-lasting emotional memories.

When mice receive a mild electrical foot shock in a conditioning chamber with various contextual cues, they quickly learn to associate the shock with this specific context: when they are later returned to the same chamber, they freeze, even in the absence of the shock. This is interpreted as a behavioral expression of remembered fear.

In their new study, the UCSF researchers determined that acquiring a memory of a foot shock in this way was accompanied by increased myelin formation in the medial prefrontal cortex, a brain region important for the formation of long-term memories.

To test whether this new myelin was required for the animals to learn, the researchers repeated the experiment with mice genetically engineered to be unable to form new myelin. These mice initially froze in the conditioning chamber, but unlike normal mice their fear appeared to fade away after about a month. The researchers concluded that new myelin formation is not needed for initial learning, but plays a specific role in the consolidation and maintenance of long-lasting fear memories.

Because myelin acts to increase the speed and efficiency of signals passing along axons, changes in myelination may influence important electrical signaling patterns within neural networks. In their new study the researchers discovered that losing the ability to form new myelin produced long-term changes in the activity of neurons in the mouse prefrontal cortex.

Simon Pan, a graduate student in UCSF's MD/PhD program and first author of the new Nature Neuroscience study, conceptualized and initiated the interdisciplinary project between the Chan and Kheirbek labs.

"This study is a significant advance in our understanding of how the brain remodels itself in response to a learning experience," Pan said. "A cardinal property of myelin is its stability, which uniquely positions it to support enduring, even life-long, memories in humans, mice, and other animals."

Understanding Myelin Plasticity Could Aid PTSD Treatment

In one experiment, the UCSF researchers discovered that mice first treated with the antihistamine clemastine fumarate, a potential MS therapy identified by Chan in 2014 that works by increasing myelin production, showed unusually robust long-term recall of the conditioned fear memory.

The study co-authors noted that magnetic resonance imaging (MRI) of combat veterans with PTSD suggests that they have increased myelin content in the brain's hippocampus, a region associated with consolidating experiences, transferring them from short- to long-term memory.

"This raises the possibility that aberrant myelination might be implicated in the pathophysiology of PTSD," Kheirbek said. "The intense fear responses observed in PTSD patients may be comparable to the increased fear responses exhibited by clemastine-treated mice with increased myelination. Myelin plasticity could be beneficial for skilled learning such as playing a piano or remembering locations, but also detrimental if it leads to persistent, overgeneralized fear responses to everyday situations."

Chan added, "We are now seeing that the process of oligodendrocyte generation and myelination can be quite dynamic in the normal adult brain. It's a form of plasticity that responds to experience and that causes long-lasting changes. This is a very recent concept that we are in the early days of exploring."

Scientists at the University of Groningen turned a non-enzymatic protein into a new, artificial enzyme by adding two abiological catalytic components: an unnatural amino acid and a catalytic copper complex. This is the first time that an enzyme has been created using two non-biological components to create an active site. The study demonstrates that such a synergistic combination is a powerful approach to achieving catalysis that is normally outside the realm of artificial enzymes. The study was published in Nature Catalysis on 10 February.

Enzymes are natural catalysts that operate under mild conditions. This makes them an attractive alternative for industrial chemical catalysis, which may require high temperature and pressure and toxic solvents or metals. However, not all chemical reactions can be catalysed by natural enzymes. Modifying existing enzymes is one option but University of Groningen Professor of Biomolecular Chemistry Gerard Roelfes believes that creating new enzymes could be another valuable option.

Catalytic group

'Natural enzymes evolved to catalyse specific reactions. Adapting requires a kind of devolving of the enzyme. That is why we pioneered the creation of new, unnatural enzymes,' he says. In 2018, he created a non-enzymatic protein, the bacterial transcription factor LmrR, which could form non-biological hydrazone structures after the insertion of the unnatural amino acid p aminophenylalanine. This was the first enzyme created using an unnatural amino acid as a catalytic group.

This time, Roelfes and his postdoc Zhi Zhou used the same LmrR protein and added two abiological catalytic components to it: one was the same unnatural amino acid p aminophenylalanine and the other a copper-containing complex. Both can activate the reaction partners for the classic Michael addition reaction, which is widely used in organic chemistry to create carbon-carbon bonds. 'But they both have to be in the right position to efficiently and selectively catalyse this reaction,' says Roelfes. Just adding both components to a test tube would not work: 'In fact, they cancel each other out when they come too close.'

Sidechain

The copper-containing complex attaches itself to the doughnut-shaped LmrR protein through supramolecular bonds. 'Its position is determined by the interaction with the protein,' explains Roelfes. 'From this position, we determined where the p-aminophenylalanine should be inserted into the protein to create an active site.' The catalytic part of this amino acid is an aniline side chain. 'From my experience in organic chemistry, I knew the potential utility of this aniline side chain for catalysis and envisioned that it would be possible to combine it with copper catalysis.' When the novel enzyme was constructed, it turned out that Roelfes' ideas were spot on: the adapted protein turned out to be a very selective catalyst for the Michael addition.

'This was a proof of principle study,' says Roelfes. 'The enzyme is not yet fast enough for practical use but, with standard techniques such as directed evolution, this could be improved.' The experiment does show that it is possible to create a new enzyme using two abiological catalysts. Other types of new catalytic enzymes could be created in a similar way. 'The method we used required that the molecular biological technique for insertion of the unnatural amino acids could be used by chemists like us,' says Roelfes. This is now the case and the scientists in his group are trying to create more artificial enzymes.

So far, adding unnatural amino acids to enzymes has been used mostly to study catalytic mechanisms and to probe the structure-function relationship of enzymes. Recently, Roelfes published a Perspective article in Nature Catalysis(1) together with his former PhD student Ivana Drienovská (now at the Graz University of Technology), describing the use of genetically encoded non-canonical amino acids in enzymes. 'To me, the generation of new-to-nature enzymes is the most exciting option.'

Simple Science Summary

University of Groningen scientists created a new enzyme that can catalyse (speed up) an important reaction in organic chemistry. They added a copper complex to a protein that had no enzymatic properties. Next, they inserted an unnatural amino acid into the protein. Together with the copper, a side chain of the amino acid was able to catalyse the required reaction. The method to add unnatural groups to a protein could be used to design many other new enzymes. These could replace standard chemical catalysis and thereby contribute to making chemistry cleaner and more energy-efficient.

Researchers at the Center for Nanoparticle Research, within the Institute for Basic Science (IBS, South Korea) in collaboration with collaborators at Zhejiang University, China, have reported a highly sensitive and specific nanosensor that can monitor dynamic changes of potassium ion in mice undergoing epileptic seizures, indicating their intensity and origin in the brain.

Epilepsy is a central nervous system disorder accompanied by abnormal brain activity, causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness. If epileptic seizures last for 30 minutes or longer, they can cause permanent brain damage or even death. The need of technologies to evaluate the degree of abnormal electrical activity associated with epilepsy is well known.

One of the main investigation targets is potassium (K+) ion. This ion affects the difference in electric potential between the interior and exterior membrane of the neurons, and impacts the neuronal intrinsic excitability and synaptic transmission. Despite the significant efforts to improve the selectivity of K+ sensors, they are still far from satisfactory because currently available optical reporters are not capable of detecting small changes in potassium ion, in particular, in freely moving animals. Furthermore, they are susceptible to interference from sodium ions because Na+ influx is shortly followed by K+ efflux when impulses pass along the membrane of nerve cell. In this study published in Nature Nanotechnology, the researchers report a highly sensitive and selective K+ nanosensor that can monitor the changes of K+ in the different parts of the brains of freely moving mice.

The new nanosensor is created with porous silica nanoparticles shielded by an ultrathin potassium-permeable membrane that is very similar to the potassium channel in brain cells. The size of the pores allows only K+ to diffuse in and out, reaching a detection limit as low as 1.3 micromolar. This allows the specific readout of sub-millimolar variations of extracellular K+ and the spatial mapping of this ion in the brain.

This study successfully demonstrated that K+-permeable membrane filter on the nanosensor is effective at filtering out other cations and capturing K+ ions exclusively. Such a nanosensor construction strategy would contribute not only to scientific discoveries and breakthroughs in neuroscience research, but also to the development of other selective ion sensors.

Using these nanosensors in the hippocampal CA3 region, the team was able to report the degree of epileptic seizures in living mice and compare it with the recordings of neural activity done with electroencephalography (EEG).

To further check whether the nanosensors are capable of measuring K+ in multiple sub-regions of the brain in freely moving mice, the researchers injected the nanosensors into three different locations of the mouse brains: hippocampus, amygdala, and cortex. After the electrical stimulation at the hippocampus, the EEG and optical responses of the nanosensors at the injected locations were simultaneously recorded. Interestingly, the external K+ concentration increases from hippocampus to amygdala and cortex over time in focal seizures, while it increases almost simultaneously in the three brain regions in generalized seizures. These results are in good agreement with the widely accepted view that electrical stimulation in the hippocampus first involves the adjacent brain area and then propagates throughout the entire brain.

HYEON Taeghwan, director of the IBS Center for Nanoparticle Research (Distinguished Professor at Seoul National University) and leading author of the study notes, "Further development of these nanosensors could facilitate diagnosis and therapy, decreasing the need for surgery. Ideally, these nanosensors could also carry antiepileptic drugs to be released in the right points of the brain where seizures originated."

BUFFALO, N.Y. -- Like breathing or blinking, behaviors regulated by our circadian rhythms, such as digestion and sleep-wake cycles, go unnoticed by most people. But when circadian rhythms malfunction, the result can be any one of a broad range of serious, chronic disorders, from insomnia and depression to obesity, diabetes and bipolar disorder.

A key piece to the puzzle of circadian rhythms and the disorders they're involved in is the hormone melatonin, which the brain produces in the evening, to facilitate falling asleep and fine-tune circadian adjustments.

Now, a team of researchers from UC San Francisco (UCSF), the University of North Carolina at Chapel Hill (UNC) and the University at Buffalo (UB) has discovered through a vast and novel computational library the first molecules that can modulate circadian rhythms by binding with high selectivity to the MT1 melatonin receptor in the biological clock, located in the hypothalamus at the base of the brain.

The research, published Feb. 10 online before print in Nature, will greatly facilitate the development of targeted therapies that can either mimic or counteract the actions of melatonin, which is implicated in numerous circadian disorders ranging from depression, blindness, seasonal affective disorder and sleep disorders to difficulties experienced as a result of jet lag and shift work.

Rhythms in sync

"This discovery allows us to now focus on the development of unique new molecules to generate a response that will help bring sleep patterns and other biological rhythms in line with environmental light and dark cycles, providing the sense of well-being that is only experienced when such rhythms are in sync," said Margarita L. Dubocovich, PhD, SUNY Distinguished Professor in the Department of Pharmacology and Toxicology in the Jacobs School of Medicine and Biomedical Sciences at UB.

Dubocovich is one of three corresponding authors, with Brian K. Shoichet, PhD, professor in the Department of Pharmaceutical Chemistry at UCSF, and Bryan L. Roth, MD, PhD, Michael Hooker Distinguished Professor in the UNC School of Medicine.

They note that the new research represents a remarkable confluence of major, complementary achievements and expertise at three institutions. They are all three members of the Clinical and Translational Science Awards Program of the National Center for Advancing Translational Sciences of the National Institutes of Health.

These achievements are:

The discovery of ligands unrelated to any known melatonin receptor ligands through the computational docking (simulating three-dimensional binding) of more than 150 million diverse, "make-on-demand" molecules (UCSF).

The discovery that these molecules (UCSF 7447 and UCSF 3384) that never existed before, attach with high strength and selectivity to human or mouse MT1 melatonin receptors. They generate cellular responses opposite to that of melatonin, which provided the rationale for the mouse circadian behavior. (UNC)

The discovery that the cellular responses seen in vitro translated directly to in vivo function, slowing down adjustment to a new environmental light/dark period in the mouse model of jet lag, with one unexpected finding demonstrating that they mimic melatonin to modulate rhythms in the absence of light cues (UB).

This work was further facilitated by the publication last spring of the first crystal structure of the MT1 receptor, providing the team with the "template" to fit new melatonin molecules into the receptor pocket.

"For us, it was at first exciting to see the novelty of the new ligands that emerged from fitting members of an ultra-large chemical library into the receptor structure," said Shoichet. "That's what one always hopes for in a structure-based program--finding new chemistries not imaginable from knowing the endogenous ligand (here, melatonin). What made this doubly exciting was to see the new chemistries lead to new signaling, in the Roth lab experiments, and to unexpected animal pharmacology in the Dubocovich lab."

Roth added: "My UNC lab spent more than a year characterizing the pharmacology and drug-like properties of the molecules before we could hand them off for animal testing in the Dubocovich lab at UB. We were all excited to see that the new compounds Brian and I had discovered had interesting properties in mice."

Fifteen-year search

The new research caps what Dubocovich says has been her 15-year search to discover MT1 ligands.

"Ever since we demonstrated that melatonin's effect of resetting biological clocks in vivo circadian models occurs through actions at the MT1 receptors, we have focused through various collaborations on searching for ligands that would better fit the human melatonin receptor," she said. "Our hope has always been to find selective MT1 -type molecules, either one that works to modulate circadian rhythms responses as with melatonin or its opposite as with the molecules discovered in this study."

The ultimate goal, she said, was always to develop drugs that could address all the disorders that disrupted circadian rhythms can cause. "So," she noted, "when Brian Schoichet called to ask about our interest in testing in our circadian mouse models the novel molecules they had identified from his ultra-large library of over 150 million compounds, we were eager to collaborate!"

The availability of the UCSF vast virtual library was a critical aspect of the research. Dubocovich described it as a "gold mine" of millions of molecules with distinct shapes, many of which have never been synthesized or seen in nature, and all of them available for mining and "docking" (fitting) into the pocket of the targeted receptor. The team advanced the research directly from discovery of these molecules to the assessment of their ability to mimic or oppose the effect of melatonin, to in vivo demonstrations of how these molecules impact the animals' circadian function.

The team found it especially interesting that the two molecules discovered in this study generate two distinct and opposite mouse circadian responses that are dependent on clock time and the environmental light conditions that the animals experience.

In the experiments where the onset of dark is advanced (known as reentrainment or the jet lag model) the molecules slow this reentrainment or adjustment, an effect opposite to that of melatonin. However, when mice were exposed to constant dark, the two molecules demonstrate an effect identical to that of melatonin.

"This could be potentially useful to entrain rhythms to the 24-hour day in populations removed from natural light/dark exposure, including the blind as well as some shift workers, submarine workers or those working in extreme environments, such as polar explorers," she said.

Jet lag and chronopharmocology

"When the body is exposed to an abrupt change in the light/dark cycle, like what we experience when we travel across continents, there isn't sufficient time for the biological clock to adjust upon reaching the destination," Dubocovich explained.

"Giving these new molecules at the appropriate clock time under a light/dark cycle would allow us to decelerate our ability to adjust to the new environment, potentially providing a treatment for certain types of jet lag and, more importantly, addressing other conditions affected by circadian rhythm disruptions, such as shift work, sleep disorders and depression," she said.

This finding reinforces the increased interest in chronopharmacology, the premise of which is that pharmaceuticals given at the time when a patient's biological clock is ready to receive them - given conditions of a precise time of day and environmental lighting - will produce a more effective outcome.

Dubocovich said the next step will be to identify the molecular and signaling pathways that translate the response exerted by these molecules from the time they interact with the receptors in the biological clock to the ultimate circadian behavior expressed in a mouse or human.

Rapid climate change is putting increasing pressure on marine organisms. Warming, acidification and oxygen deprivation of seawater are already causing massive changes in marine ecosystems and are likely to lead to massive species extinction by the end of the century. So which groups of animals are particularly at risk? To assess this, biology and paleontology go different ways. Biologists extrapolate from experimental studies and especially predict a gloomy future for those species that are particularly sensitive to warming or oxygen deprivation in the laboratory. Paleontologists, on the other hand, interpolate from fossil data which groups of animals were particularly badly affected in earlier, "natural" warming phases. They argue that these groups should continue to be more sensitive in the future.

The study, published in the renowned journal Nature Climate Change by a German research team headed by Dr. Carl Reddin, Museum für Naturkunde Berlin, and Prof. Dr. Wolfgang Kießling, Chair of Palaeontology at FAU, presents extensive data that combines both approaches for the first time. On the one hand, the scientists collected previously published data from experiments in which marine animals were exposed to warming, lack of oxygen, acidification or a combination of these factors. At the same time, they evaluated millions of fossil finds and searched for laws of extinction sensitivity within animal groups and functional (e.g. dietary) groups.

In view of the gigantic differences in the space-time scales considered, the results agree surprisingly well. Bony fish stand out as particularly sensitive in both approaches, while snails and oysters are less threatened. The study thus lays an important basis for future collaboration. Using fossil data, biologists can make more precise predictions of the fate of species for which there are no experimental studies. Meanwhile, paleontologists can use modern experiments to assess the most relevant factors in species extinction. For example, experiments show that the combination of heating and oxygen deprivation is particularly lethal.

The study is a result of the research group TERSANE, which is based at the FAU (FOR 2332). In this interdisciplinary project, eight working groups are investigating the conditions under which natural greenhouse gas emissions can reach catastrophic proportions and how they are related to biodiversity crises.

Women's educational attainment has increased tremendously and even exceeded men's all over the world in the late 20th century. China's One-Child Policy had a beneficial effect on women's education and explains about half of the increase in educational attainment for women born between 1960-1980, according to a review published in Contemporary Economic Policy.

In China, the One-Child Policy was the biggest social movement that fundamentally changed the lives and family structure of the entire generation born in the 1960s. Analyses in the review indicate that reductions in fertility expectations in China increased women's educational attainment and helped to close the gender education gap.

"Women anticipated having fewer children, which may have delayed their entry into parenthood and even delayed the decision to get married, which allowed them to get more education," said author Xuan Jiang, PhD, of The Ohio State University.

Cancer research using experimental models--everything from cancer cells in a dish to patient tumors transplanted in mice--has been extremely useful for learning more about the disease and how we might treat it. For some cancers, however, these models have failed to provide sufficient insight for medical progress. Diffuse glioma, the most common malignant brain tumor, is a prominent example, and it continues to have near-universal rates of recurrence and poor patient prognoses.

A significant problem with the experimental systems is that while they may model the cancer cells quite well, they don't fully capture their environment within the body, including nearby healthy tissues, immune cells and signaling, and more. So how can researchers learn how to better treat cancers within the context of a patient's body instead of isolated from it? In a paper published in Cancer Cell, "Comparative molecular life history of spontaneous canine and human gliomas," a team led by Jackson Laboratory (JAX) Professor Roel Verhaak, Ph.D., presents a possible answer: working to cure our beloved pet dogs.

Molecular similarity:

Companion dogs spontaneously develop gliomas about as often as humans do. They arise in adult dogs, but at the age of human children in calendar years. And, as in humans, they're sadly very difficult to treat. Caring for pet dogs with glioma can be quite challenging for their owners. Therein lies an opportunity: they may benefit from experimental approaches, which at the same time may provide clues on how to better treat glioma in humans. But it's not known how well they resemble human tumors. To investigate how similar canine tumors are to human tumors--or not--Verhaak and his team obtained posthumous tumor samples from 83 dogs for thorough molecular examination. By comparing the results in detail to those from human glioma patients, both from children and adults, they identified the commonalities driving the disease. The molecular "life history" obtained provides a better understanding of glioma across both species.

What they found was that there are indeed important similarities between gliomas across dogs, children and adults. Shared molecular traits included mutations in particular genes and pathways such as the DNA repair system known to be altered in human glioma. These findings extended to changes in the number of chromosomes, known as aneuploidy. A remarkable outcome of the comparison was the observation that canine glioma resembled pediatric glioma much more than glioma in adult patients.

The team also assessed how well canine gliomas model human immune response and the immune microenvironment. They found that the immunological features of dogs with spontaneously arising gliomas closely resemble those in human patients. The advent of immunotherapies in human medicine has seen encouraging successes but also low patient response rates. Using them for canine gliomas may provide an effective venue to assess efficacy and to improve response in both dogs and people.

Convergent evolution:

Overall, the convergence of glioma traits across species indicates the tumors are adapting to similar selective pressures exerted by their environments in both human and dog brains. An interesting note is that the average age of the canine cohort was about nine years. Their glioma samples had a lower number of mutations than human adult gliomas but resembled pediatric gliomas, whose patients have also aged relatively few calendar years, in the rates of genetic changes found. This aspect of canine gliomas can be important for studying the functional role of such variation and how it can be targeted for therapy.

The paper's findings provide important insight into canine gliomas and indicate that the results are likely relevant to human gliomas and potential therapies, particularly in children. While the veterinarian's office is somewhat different from both human medical and basic research settings, dogs represent a potentially effective model for humans. Striving to cure them, and learning what works best--and, importantly, why it works--can inform our own therapy regimens, providing an important opportunity to improve prognoses for glioma patients.

Boulder, Colo., USA: In Australia, the onset of human occupation (about 65,000 years?) and dispersion across the continent are the subjects of intense debate and are critical to understanding global human migration routes. A lack of ceramic artifacts and permanent structures has resulted in a scarcity of dateable archaeological sites older than about 10,000 years.

Existing age constraints are derived largely from radiocarbon dating of charcoal and/or optically stimulated luminescence (OSL) dating of quartz grains in rock shelter sediments, and there is a need for independent age constraints to test more controversial ages. In southeastern Australia, only six sites (located in Tasmania, New South Wales, and South Australia) older than 30,000 years are considered definitively dated by 14C and/or OSL methods, with ages spanning 37,000-50,000 years.

The strong oral traditions of Australian Aboriginal peoples have enabled perpetuation of ecological knowledge across many generations and can likely provide additional archeological insights. Some surviving traditions allude to different geological events, such as volcanic eruptions, earthquakes, and meteorite impacts. It has been proposed that some of these traditions may have been transmitted for thousands of years.

The Newer Volcanic Province of southeastern Australia contains over 400 basaltic eruption centers, a number of which are thought to have erupted within the last 100,000 years, although precise ages remain elusive for most. Technological improvements over the last decade have firmly established applicability of the 40Ar/39Ar dating technique (which relies on the natural radioactive decay of 40K in minerals) to archeological timescales, enabling many of these younger volcanoes to be dated by this method.

Rare reported occurrences of archaeological evidence beneath volcanic ash deposits and lava flows, and the longevity of Aboriginal oral histories, presents an opportunity for novel investigation into the timing of human occupation of this region. In particular, oral traditions surrounding the Budj Bim Volcanic Complex (previously Mount Eccles) in western Victoria have been interpreted to reference volcanic activity.

This new study published in Geology presents a new 40Ar/39Ar eruption age of 36,900 ± 3,100 thousand years for the Budj Bim Volcanic Complex and an age of 36,800 ± 3,800 thousand years for the nearby Tower Hill Volcanic Complex; the latter is of archaeological significance due to the historical discovery of a stone axe from a sequence of volcanic ash deposits.

These ages fall within the range of 14C and OSL ages reported for the six earliest known occupation sites in southeastern Australia. The age of Tower Hill directly represents the minimum age for human presence in Victoria. If oral traditions surrounding Budj Bim do indeed reference volcanic activity, this could mean that these are some of the longest-lived oral traditions in the world.

Diabetes is more common in First Nations people, especially women, and occurs at younger ages than in other people in Ontario, found a new study in CMAJ (Canadian Medical Association Journal).

The study, a partnership between Chiefs of Ontario and academic researchers, analyzed health services and population data on 158 241 First Nations people and more than 13.2 million other Ontarians between 1995 and 2014.

The prevalence of diabetes in First Nations people continues to rise, although the gap has narrowed from three times to twice as high in First Nations people as in the general population. This narrowing is likely due a decline over time in new cases of diabetes in all groups, but especially in First Nations people.

"While these findings represent promising progress, and may indicate real declines in the risk of diabetes, the declines in incidence do not track with declining prevalence of diabetes risk factors and may be an artifact of changing diagnostic criteria or screening practices," writes Dr. Jennifer Walker, School of Rural and Northern Health, Laurentian University, Sudbury, Ontario and Scientist, ICES (formerly the Institute for Clinical Evaluative Sciences), Toronto, with coauthors.

First Nations women aged 20-34 years had double the prevalence rate of diabetes compared with other women (4.2% compared with 1.6%), and in women aged 35-49 years, the rate was almost three times as high (17.6% compared with 6%).

"It is particularly important to address diabetes in women of reproductive age because of the potential generational impacts on metabolic health," write the authors. "Efforts to prevent and manage diabetes in First Nations people requires a grounded understanding of the determinants of health that affect First Nations in Canada, including the ongoing, intergenerational impacts of colonial policy associated with social, political, economic and cultural inequities."

The researchers say their findings, published Feb. 3 in Injury Epidemiology, suggest that adopting safety measures for rifles or shotguns may prevent suicides, particularly among young people and rural-area residents.

"Our goal as clinicians at Johns Hopkins Medicine is to save lives, and it's concerning to see that it's not just handguns, but long guns that are used commonly in youth suicide," says Paul Nestadt, M.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "Many of the safety protections that we have in place around the country typically don't apply to long guns, and the data suggest that our strategy needs to be modified."

In many states, there is no minimum age for owning long guns, and federal background checks are only required if buying from a licensed gun dealer. Requirements for permits and safety courses for rifles vary from state to state.

The public has long thought that handguns are more responsible for human deaths, including suicides, than long guns such as rifles and shotguns, which have been believed to be more commonly used for hunting or protection from wild animals. But now, in an analysis of data from 16 years of gun suicides in Maryland, Johns Hopkins Medicine researchers found that long guns were used more often in suicides by kids and teens than by adults, and were more commonly used in suicide by people in rural counties.

The data analysis reviewed 3,931 gun suicides in Maryland from 2003 to 2018. About 45% of children and teens used long guns to die by suicide, compared to 20% of adults over age 65 who used long guns. The researchers found that 52% of rural firearm suicides were by long gun, compared to 17% in urban counties. Using rifles for suicide increased by 60% during hunting season, when researchers say rifles may be out and more available.

"In the midst of a suicidal impulse, a person will use what they have. Firearms are particularly lethal. If one is easily available, that will be the method of choice," says Nestadt. "Holidays and hunting season are times when many young people receive hunting rifles as gifts, and I would advise family members to also provide gun locks or gun storage cabinets with their present. Just adding an extra protective step could be enough of a barrier to protect their family member from making an impulsive decision."