Culture

DALLAS - Sept. 17, 2019 - In work suggesting new therapeutic targets to fight obesity, UT Southwestern researchers have identified a novel mechanism that regulates the creation of fat in mammals.

"Obesity is a global health problem that represents a major risk for several chronic diseases, including Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular disease, stroke, and cancer," said Dr. Joshua Mendell, Professor of Molecular Biology at UT Southwestern and an Investigator in the prestigious Howard Hughes Medical Institute. Dr. Mendell is corresponding author of the study appearing online in the journal Genes & Development.

Illustration of fat cells

Illustration of fat cells. Researchers found that loss of a family of microRNAs results in a dramatic increase in fat formation. In addition, the overexpression of the miR-26 family of miRNAs strongly protects against weight gain in mice.

The molecular mechanisms that regulate how and where fat tissue builds up in the body - or doesn't - are key to understanding the development of obesity. However, the genes and molecular pathways that influence the size and number of fat cells in the body are not completely understood.

"We found that loss of a family of microRNAs results in a dramatic increase in fat formation. In addition, we showed that overexpression of the miR-26 family of miRNAs strongly protects against weight gain in mice fed a high fat diet," said Dr. Asha Acharya, an Instructor of Molecular Biology and lead author of the study.

The researchers further found that the miR-26 family controls the levels of a protein called FBXL19 that is important for new fat cell production. "This protein had not been linked to fat formation or obesity in the past, so this result was unexpected," Dr. Mendell said.

In mammals, including mice and humans, a diet loaded with calories - such as the high fat diet used in this study - can cause existing fat cells to expand. It can also result in the creation of new fat cells from a population of stem-like progenitor cells, he explained.

"Fat storage in adult mammals is a highly regulated process that involves mobilizing progenitor cells that differentiate into fat cells," said Dr. Mendell, a member of the Harold C. Simmons Comprehensive Cancer Center and the Hamon Center for Regenerative Science and Medicine at UTSW, as well as a CPRIT Scholar in Cancer Research.

A feature of obesity is the uncontrolled expansion of white fat tissue, which does more than store energy in times of caloric surplus. It also plays an important role in metabolic regulation by secreting signaling proteins and lipids that influence pathways controlling appetite, blood sugar balance, and immune responses.

While earlier studies indicated important roles for the miR-26 family as suppressors of cancer and regulators of insulin sensitivity, the broader functions of these miRNAs had remained a mystery. In part, that was due to the difficulty of knocking out, or removing, all three genes that produce miR-26 family members in mammals in order to study their functions.

To overcome this technical challenge, the researchers used the gene-editing technique called CRISPR/Cas9 to remove all miR-26-encoding genes from the mouse genome. They found that although mice lacking these miRNAs developed normally in early life, they had a two- to threefold increase in white fat tissue beginning in early adulthood, even while consuming a normal diet.

To further test the role of these miRNAs in regulating fat formation, the scientists used a different genetically engineered mouse line that produces excess miR-26. After being fed a high fat diet, normal mice exhibited dramatic weight gain and an increase in fat content to 40 percent of their overall body mass. Mice with increased miR-26, however, were strongly resistant to weight gain and, despite consuming an identical diet, produced very little additional fat. Mice with increased miR-26 also showed lower blood sugar and lipid levels compared with controls.

"This study reveals a new mechanism of controlling fat production in the body," Dr. Mendell said. "A deeper understanding of this mechanism could lead to new therapies to treat obesity, for example by revealing strategies to increase miR-26 activity or to inhibit the downstream targets of this microRNA."

DURHAM, N.C.-- Biomedical engineers at Duke University have developed a new platform to create biologic drugs using specially engineered bacteria that burst and release useful proteins when they sense that their capsule is becoming too crowded.

The platform relies on two main components: the engineered bacteria, called "swarmbots," that are programmed to sense the density of their peers within their container, and the biomaterial that confines the swarmbots, a porous capsule that can shrink in response to changes in the bacterial population. When it shrinks, the capsule squeezes out targeted proteins created by the captive bacteria.

This self-contained platform could make it easier for researchers to create, analyze and purify diverse biologics for use in small-scale biomanufacturing.

The research appeared online Sept. 16 in the journal Nature Chemical Biology.

Bacteria are commonly used to produce biologics, which are products like vaccines, gene therapies and proteins that are created or synthesized from biological sources. Currently, this process involves a series of sophisticated steps including cell culturing, protein isolation and protein purification, each of which requires delicate infrastructure to ensure efficiency and quality. For industrial operations, these steps are carried out on a large scale. While this helps produce large quantities of certain molecules, this setup is not flexible or financially viable when researchers need to produce small amounts of diverse biologics or work in resource-limited settings.

The new technology was developed by Lingchong You, a Professor of Biomedical Engineering at Duke University, and a former Duke postdoctoral researcher, Zhuojun Dai, now an Associate Professor at Shenzhen Institute of Advanced Technologies. In the new study, they show how their new platform uses communication between swarmbots and their capsule to achieve versatile production, analysis and purification of diverse proteins and protein complexes.

In an earlier proof of concept, You and his team engineered a non-pathogenic strain of E. coli bacteria to produce an antidote to antibiotics when the bacteria reached a certain density. These swarmbots were then confined to a capsule, which was bathed in antibiotics. If a bacterium left the capsule it was destroyed, but if it remained inside the container where the population density was high, it survived.

"Our first study essentially showed one-way communication, where the cells could sense the environment within the capsule but the environment didn't react to the cells," said You. "Now, we have two-way communication -- the engineered swarmbots can still sense their density and their confinement, but we have introduced a material that can respond when the bacterial population inside it changes. It's like the two components are talking to each other, and collectively they give you very dynamic behavior."

Once the population inside the capsule reaches a certain density, the bacteria start to 'pop,' releasing all of their cellular contents, including the protein product of interest. At the same time, this bacterial growth changes the chemical environment within the capsule, causing it to shrink. As it shrinks, it squeezes out the protein released from the bursting cells while the bacteria and cell debris are kept within the capsule.

Once the proteins are collected, researchers can add a nutrient replenishment to the dish as a cue for the capsules to enlarge. This resets the interior environment and allows the bacteria to begin growing again, restarting the process. According to You, this cycle can be repeated for up to a week.

To make the approach useful for biomanufacturing, the team added the capsules to a microfluidic chip, which included a chamber for them to detect and quantify which proteins were released. This could be replaced with a purification chamber to prepare the proteins for use in biologics.

"It's a very compact process. You don't need electricity, and you don't need a centrifuge to produce and isolate these proteins," said You. "It makes this a good platform for biomanufacturing. You have the ability to produce a certain type of medicine in a very compact format at a low cost, and it's easy to deliver. On top of that, this platform offers an easy way to produce multiple proteins simultaneously."

According to You, this ease of use has enabled the team to produce, quantify and purify more than 50 different proteins in collaboration with the lab of Ashutoshi Chilkoti, Alan L. Kaganov Professor and Chair of the Department of Biomedical Engineering at Duke. They have also explored how their platform can simplify the creation of protein complexes, which are structures made from multiple proteins.

On a proof-of-concept experiment to produce a fatty acid synthesis pathway from multiple enzymes, "we were able to use seven versions of our microbial swarmbots, each of which was programmed to produce a different enzyme," said You. "Usually, to produce a metabolic pathway you'd need to balance the supply chain, which could involve upregulating the expression of one enzyme and downregulating the expression of another. With our platform you don't need to do that, you just need to set the correct ratio of swarmbots."

"This technology is incredibly versatile," he said. "That's a capability we want to take advantage of."

Two years after discovering a way to neutralize a rogue protein linked to Alzheimer's disease, University of Alberta Distinguished University Professor and neurologist Jack Jhamandas has found a new piece of the Alzheimer's puzzle, bringing him closer to a treatment for the disease.

In a study published in Scientific Reports, Jhamandas and his team found two short peptides, or strings of amino acids, that when injected into mice with Alzheimer's disease daily for five weeks, significantly improved the mice's memory. The treatment also reduced some of the harmful physical changes in the brain that are associated with the disease.

"In the mice that received the drugs, we found less amyloid plaque buildup and a reduction in brain inflammation," said Jhamandas, who is also a member of the Neuroscience and Mental Health Institute.

"So this was very interesting and exciting because it showed us that not only was memory being improved in the mice, but signs of brain pathology in Alzheimer's disease were also greatly improved. That was a bit of a surprise for us."

This discovery builds on previous findings of a compound called AC253 that can block the toxic effects of a protein called amyloid beta, which is believed to be a major contributor to Alzheimer's because it is often found in large quantities in the brains of patients with the disease. AC253 blocks amyloid beta from attaching to certain receptors in brain cells--a process Jhamandas likens to plugging a keyhole.

However, while AC253 was shown to prevent a buildup of amyloid beta, it isn't very effective at reaching the brain and is quickly metabolized in the bloodstream. As a result, treatment using AC253 requires large amounts of the compound to be effective, which is impractical and increases the chances of the body developing an immune reaction to treatment. Transforming AC253 from an injectable drug into a pill would address the metabolism issues and increase efficacy, but AC253 was too complex to be able to make an effective oral drug.

Jhamandas' solution was to chop AC253 into pieces to see whether he could create smaller peptide strings that blocked amyloid beta in the same way AC253 did. Through a series of tests using mice genetically modified to carry Alzheimer's disease, Jhamandas' team found two shorter pieces of AC253 that replicated the preventative and restorative abilities of the larger peptide.

With the short peptides identified, Jhamandas and his team, which includes renowned virologists Lorne Tyrell and Michael Houghton, used a process of computer modelling and artificial intelligence to discover a small-molecule drug--similar to medications used to treat high blood pressure or cholesterol--it's now developing.

The team is focused on manufacturing an optimized and oral version of the drug so human clinical trials can begin, said Jhamandas, who added small-molecule drugs are preferable for treatments, particularly for drug companies, because they are cheaper to make, can be taken orally and can more easily reach the brain through the blood, said Jhamandas.

While Jhamandas is optimistic about the potential of his new drug to change the way Alzheimer's is managed, he is quick to point out the years of research he and other researchers have done to get to this point.

"This has been 15, 20 years of painstaking and incremental work," he said. "And it's like building a house: you put one brick down, then you put another brick on top of that, and pretty soon you have a foundation and then you have a house.

"Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I'm very excited that we are really on to something here."

COLUMBIA, Mo. - Near an old mining town in Central Europe, known for its picturesque turquoise-blue quarry water, lay Rudapithecus. For 10 million years, the fossilized ape waited in Rudabánya, Hungary, to add its story to the origins of how humans evolved.

What Rudabánya yielded was a pelvis -- among the most informative bones of a skeleton, but one that is rarely preserved. An international research team led by Carol Ward at the University of Missouri analyzed this new pelvis and discovered that human bipedalism -- or the ability for people to move on two legs -- might possibly have deeper ancestral origins than previously thought.

The Rudapithecus pelvis was discovered by David Begun, a professor of anthropology at the University of Toronto who invited Ward to collaborate with him to study this fossil. Begun's work on limb bones, jaws and teeth has shown that Rudapithecus was a relative of modern African apes and humans, a surprise given its location in Europe. But information on its posture and locomotion has been limited, so the discovery of a pelvis is important.

"Rudapithecus was pretty ape-like and probably moved among branches like apes do now -- holding its body upright and climbing with its arms," said Ward, a Curators Distinguished Professor of Pathology and Anatomical Sciences in the MU School of Medicine and lead author on the study. "However, it would have differed from modern great apes by having a more flexible lower back, which would mean when Rudapithecus came down to the ground, it might have had the ability to stand upright more like humans do. This evidence supports the idea that rather than asking why human ancestors stood up from all fours, perhaps we should be asking why our ancestors never dropped down on all fours in the first place."

Modern African apes have a long pelvis and short lower back because they are such large animals, which is one reason why they typically walk on all fours when on the ground. Humans have longer, more flexible lower backs, which allow them to stand upright and walk efficiently on two legs, a hallmark characteristic of human evolution. Ward said if humans evolved from an African ape-like body build, substantial changes to lengthen the lower back and shorten the pelvis would have been required. If humans evolved from an ancestor more like Rudapithecus, this transition would have been much more straightforward.

"We were able to determine that Rudapithecus would have had a more flexible torso than today's African apes because it was much smaller -- only about the size of a medium dog," Ward said. "This is significant because our finding supports the idea suggested by other evidence that human ancestors might not have been built quite like modern African apes."

Ward teamed up with Begun to study the pelvis along with MU alumna Ashley Hammond, Assistant Curator of Biological Anthropology at the American Museum of Natural History, and J. Michael Plavcan, a professor of anthropology at University of Arkansas. Since the fossil was not 100% complete, the team used new 3D modeling techniques to digitally complete its shape, then compared their models with modern animals. Ward said their next step will be to conduct a 3D analysis of other fossilized body parts of Rudapithecus to gather a more complete picture of how it moved, giving more insight into the ancestors of African apes and humans.

By scraping tubeworms off the bottom of boats in the San Diego harbor to study them, San Diego State University researchers discovered that a beneficial bacterium that aids them in establishing colonies could also be a boon for human health, because the same process might already take place in the human gut.

By examining this bacterium that causes metamorphosis in the humble tubeworm, marine microbiologists at SDSU discovered that the nanoscale syringe-like structures produced by it - a structure nicknamed the Death Star for the effect it has - could be used in the future to deliver novel therapeutics or vaccines to targeted cells and tissues in humans.

Tubeworms (Hydroides elegans) are tiny marine creatures with hard shells that cause a lot of trouble and economic loss for boat and ship owners. They stick to the bottoms of boats and form inches-thick crusty layers, and also attract other invertebrates like barnacles that then form on top of them. This so called 'biofouling' leads to additional weight and higher fuel consumption. So, everyone from the U.S Navy to the shipping and boat building industry is interested in finding out how they do this and what can be done to prevent it from happening.

Marine research led to significant discovery

Nicholas Shikuma with SDSU has been studying tubeworms for several years with students in his lab, to understand exactly why they are drawn to certain places in the ocean where they establish colonies.

Previous research by others showed that like coral reefs, sea urchins and sea squirts, the tubeworms also needed a conducive environment to reproduce, so they typically gravitated to areas with healthy populations of bacteria like Pseudoalteromonas, a beneficial bacterium. Shikuma discovered that the bacterium has Metamorphosis Associated Contractile structures (MACs) - syringe-like structures that inject content into the larvae of tubeworms, helping transform it into juvenile worms.

What he and fellow scientists did not know was if the MACs were injecting a biochemical into the tubeworm to cause metamorphosis and to stick to boat hulls. Shikuma's lab used cryo-electron tomography imaging to study the structures and found arrays of death star shaped injection systems, which are released by the bacterium.

They discovered that the syringe structures contained a novel effector protein, Mif1, that regulates biological activity in the tubeworm host, and it's this protein that's responsible for causing metamorphosis.

"Lots of pathogens produce these syringe structures that typically cause disease," Shikuma said. "But this is the first time we discovered bacteria that use the syringe for a symbiotic purpose."

Stealing syringes from phages, but for good cause

The MACs resemble similar syringe structures found on bacteriophages - viruses that infect bacteria - and with evolution, the bacteria have 'stolen' this structure from the phages, and have put it to good use.

"Phage typically attack bacteria with these structures, but instead of using it to infect other bacteria, the Pseudoalteromonas now uses it to interact with other animals, such as tubeworms, insects, and mouse cells," Shikuma said.

"MACs are created when the bacteria undergo cell lysis - when the cells blow themselves up - and the bacteria that do this die afterwards, so it's almost like altruism because it benefits the rest of the bacterial population."

Not every bacterium in this strain produces the MACs, only about one out of 50 do so, but since we can produce trillions of these bacteria, supply will not be an issue and more of them can be engineered to produce MACs, he explained.

The findings will be published September 17th in eLife journal, and follow on the heels of a recent publication from Shikuma's lab that was published in Cell Reports in June this year which looked at how this bacterium interacts in vitro with insect and mouse cells. That paper showed how the microscopic syringe structures could be modified with payloads that could potentially carry therapeutics or vaccines.

Shikuma has obtained a provisional patent for the findings in both papers, on using the MACs to deliver modified proteins. As a next step, current research in his lab involves mining data from the Human Microbiome Project to see if we humans have this same bacterial syringe structure in our guts that can be harnessed for therapeutics.

Dark matter is only known by its effect on massive astronomical bodies, but has yet to be directly observed or even identified. A theory about what dark matter might be suggests that it could be a particle called an axion and that these could be detectable with laser-based experiments that already exist. These laser experiments are gravitational-wave observatories.

The hunt is on for dark matter. There are many theories as to what manner of thing it might turn out to be, but many physicists believe dark matter is a weakly interacting massive particle, or WIMP. What this means is that it does not interact easily with ordinary matter. We know this to be true because it hasn't been seen directly yet. But it must also have at least some mass as its presence can be inferred by its gravitational attraction.

There have been enormous efforts to detect WIMP dark matter, including with the Large Hadron Collider in Switzerland, but WIMPs haven't been observed yet. An alternative candidate particle gaining attention is the axion.

"We assume the axion is very light and barely interacts with our familiar kinds of matter. Therefore, it is considered as a good candidate for dark matter," said Assistant Professor Yuta Michimura from the Department of Physics at the University of Tokyo. "We don't know the mass of axions, but we usually think it has a mass less than that of electrons. Our universe is filled with dark matter and it's estimated there are 500 grams of dark matter within the Earth, about the mass of a squirrel."

Axions seem like a good candidate for dark matter, but since they may only interact very weakly with ordinary matter, they are extraordinarily difficult to detect. So physicists devise increasingly intricate ways to compensate for this lack of interaction in the hope of revealing the telltale signature of dark matter, which makes up over a quarter of the visible universe.

"Our models suggest axion dark matter modulates light polarization, which is the orientation of the oscillation of electromagnetic waves," explained Koji Nagano, a graduate student at the Institute for Cosmic Ray Research at the University of Tokyo. "This polarization modulation can be enhanced if the light is reflected back and forth many times in an optical cavity composed of two parallel mirrors apart from each other. The best-known examples of these kinds of cavities are the long tunnel arms of gravitational-wave observatories."

Dark matter research does not get as much attention or funding as other more applicable areas of scientific research, so great efforts are made to find ways to make the hunt cost-effective. This is relevant as other theoretical ways to observe axions involve extremely strong magnetic fields which incur great expense. Here, researchers suggest that existing gravitational-wave observatories such as the Laser Interferometer Gravitational-Wave Observatory (LIGO) in the USA, Virgo in Italy or KAGRA in Japan could be cheaply modified to hunt for axions without detriment to their existing functions.

"With our new scheme, we could search for axions by adding some polarization optics in front of photodiode sensors in gravitational-wave detectors," described Michimura. "The next step I would like to see is the implementation of optics to a gravitational-wave detector like KAGRA."

This idea has promise because the upgrades to the gravitational-wave facilities would not reduce the sensitivity they rely on for their primary function, which is to detect distant gravitational waves. Attempts have been made with experiments and observations to find the axion, but thus far no positive signal has been found. The researchers' proposed method would be far more precise.

"There is overwhelming astrophysical and cosmological evidence that dark matter exists, but the question 'What is dark matter?' is one of the biggest outstanding problems in modern physics," said Nagano. "If we can detect axions and say for sure they are dark matter, it would be a truly exciting event indeed. It's what physicists like us dream for."

OAK BROOK, Ill. - Selective mammography screening can provide potentially lifesaving early detection of breast cancer in men who are at high risk for the disease, according to a landmark study published in the journal Radiology.

Breast cancer in men is a rare but often deadly disease. The American Cancer Society projects that 2,670 new cases of invasive breast cancer will be diagnosed in men in 2019, and about 500 men will die from it.

There are no formal screening guidelines for men in high-risk groups such as those who have a personal history of the disease, breast-cancer-associated genetic mutations or family members who had breast cancer. As a result, men diagnosed with breast cancer tend to have worse outcomes than women.

"Mammographic screening has helped improve the prognosis for women with breast cancer," said study lead author Yiming Gao, M.D., from the Department of Radiology at New York University Langone Medical Center in New York City. "But men don't have any formalized screening guidelines, so they are more likely to be diagnosed at a more advanced stage and often don't do as well as women."

There is anecdotal evidence that selective screening with mammography in men with identifiable risk factors is beneficial, but little is known as to how and to what extent breast imaging is used in this population.

In the first study of its kind, Dr. Gao and colleagues evaluated breast imaging utilization patterns and screening outcomes in 1,869 men, median age 55, who underwent mammography over a 12-year period.

Mammography helped detect a total of 2,304 breast lesions, 149 of which were biopsied. Of those, 41 (27.5 percent) proved to be malignant. The cancer detection rate of 18 per 1,000 exams in men at high risk of breast cancer was significantly higher than the average detection rate of three to five per 1,000 exams in average risk women. In addition, the cancers in men detected were at an early stage, before they had spread to the lymph nodes, improving the prognosis for survival.

"These results show that it is possible to detect male breast cancer early, and it appears that mammography is effective in targeted screening of high-risk men," Dr. Gao said. "We've shown that male breast cancer doesn't have to be diagnosed only when symptomatic."

In men, mammographic screening sensitivity, or the ability to detect cancer, was 100 percent, while specificity, or the ability to distinguish breast cancer from other findings, was 95 percent. This excellent performance is related to men having a relative lack of breast fibroglandular tissue that in women often masks abnormal results, the researchers said.

Personal history of breast cancer was the most significant risk factor associated with breast cancer in men. Ashkenazi Jewish ancestry, genetic mutations, and first-degree family history of breast cancer were also significant factors.

Currently, the National Comprehensive Cancer Network (NCCN) does not support screening because of a lack of evidence, even in men with elevated risk. Earlier NCCN guidelines suggested consideration of baseline mammograms on an individual basis, an approach the new study results may support.

Moving forward, the researchers hope to see larger multi-institutional studies that have the statistical power to delineate more nuanced information based on different breast cancer risk factors in men.

"Rethinking our strategy toward male breast cancer diagnosis is necessary," Dr. Gao said. "We hope these results will provide a foundation for further investigations, and potentially help pave the way to standardizing screening for certain high-risk groups of men."

Crispr technology has greatly facilitated gene editing. Associate Professor Thorsten Müller from Ruhr-Universität Bochum and Dr. Hassan Bukhari from Harvard Medical School discuss its pros and cons in a review article in the journal Trends in Cell Biology from 12 September 2019. They believe Crispr technology has future potential primarily if it can be rendered usable in the field of stem cell research.

In order to analyse the effects of genes or gene products, they used to be artificially over-activated. "Thus, they would occur up to 1,000 times more frequently than in nature," says Thorsten Müller. "The cell was flooded with gene products, the proteins, which can falsify function analysis." The Crispr method eliminates this difficulty. It can be used to implant blueprints of fluorescent proteins in cells and to position them behind a specific gene. "This has enabled us to monitor for the first time a protein's function live under natural conditions - rather than after 1,000-fold overproduction," explains the biochemist.

The Crispr method, too, has been optimised. Initially, researchers had to create so-called vectors in a time-consuming process, in order to label genes in the genome. Vectors are DNA segments whose sequence has to be to some extent identical with the DNA of the target cell, to ensure that the implanted gene finds the right spot. Today, they take advantage of the cells' natural DNA repair function, which considerably simplifies the creation of vectors, and are consequently able to introduce fluorescent proteins quickly and easily.

How drugs work

In addition, fluorescent tagging makes it possible to observe where the labelled gene products are located in the cell live under the microscope. "This could be interesting in order to test the effects of drugs on certain gene products," explains Müller. To this end, researchers would have to stimulate the cell with the active substance and track if and how the position of the gene product changes.

Different genes could be labelled with fluorescent biosensors in different colours and analysed simultaneously. The stronger the reading of a tagged gene, the more strongly does the cell fluoresce in the respective colour.

Organoids could replace animal testing

The authors believe a combination of this method with so-called organoids offers considerable potential. Organoids are mini organs derived from induced pluripotent stem cells that can be extracted from an adult organism. They can be used to, for example, build mini brains that are the equivalent to the human brain as far as function is concerned.

Should the application of Crispr technology in stem cells become more widespread, researchers would be able to analyse the effects of gene modification in complex tissues, rather than just in isolated cells. "We could study human genes live in tissues resembling those of humans and wouldn't have to rely on animal models as much as we do now," concludes Müller.

Following these considerations, Müller and Bukhari have compiled a number of key research questions in the review article, which have to be answered in order to consolidate Crispr technology and organoid technology.

Researchers at the University of East Anglia have discovered how nitrogen-fixing bacteria sense iron - an essential but deadly micronutrient.

Some bacteria naturally fix nitrogen from the soil into a form that plants can use. In nature, most plants get nitrogen either from soil bacteria that do this work or from plants and microbes that die and recycle their nitrogen into the soil. In agriculture, soil is enriched with synthetic nitrogen fertilizers.

Virtually all life forms require iron to survive, yet too much of the metal can be catastrophic. In healthy cells, many systems regulate this delicate balance.

In many nitrogen-fixing bacteria, a protein called RirA plays a key role in regulating iron. It senses high levels of the metal and helps to shut down the production of proteins that bring in more iron.

RirA contains a cluster of four iron and four sulfur atoms, which acts as a sensor for iron availability. But until now, exactly how this cluster structure detects iron levels in a cell was unclear.

The UEA research team was led by Prof Nick Le Brun from the School of Chemistry in collaboration with researchers at the University of Essex.

They used a technique known as time-resolved mass spectrometry to examine the sensory response of the iron-sulfur cluster of RirA when different levels of iron were available.

The results revealed a 'loose' iron atom in the cluster. When iron levels drop, this atom is rapidly lost as it is scavenged for use in other essential cellular processes.

Without it, the cluster in RirA collapses and the protein becomes inactive, which prompts the cell to produce proteins that enable the cell to take up iron from its surroundings.

Once iron levels are sufficient again, RirA regains its cluster and becomes active again, stopping the production of proteins that bring in more iron.

Iron-sulfur clusters are common in many proteins, and this work offers new insight into their various roles. It also highlights the potential to use time-resolved mass spectrometry to examine biological processes in depth.

Prof Le Brun said 'This research provides unprecedented detail of how the iron-sensing cluster of RirA responds to low iron conditions, and establishes, for the first time, how an iron-sulfur cluster can be used to sense iron.

"This is an important piece in the bigger puzzle of how life deals with iron, a nutrient it cannot do without but one it must also avoid having in excess."

TAMPA, Fla. (September 17, 2019)- A therapeutic shoe engineered to improve stroke recovery is proving successful and expected to hit the market by the end of the year. Clinical trials have been completed on the U.S. patented and licensed iStride Device, formerly the Gait Enhancing Mobile Shoe (GEMS), with results just published in the Journal of NeuroEngineering and Rehabilitation.

Stroke sufferers experience muscle weakness or partial paralysis on one side of the body, which greatly impacts how they walk, known as gait. Gait asymmetry is associated with poor balance, a major cause of degenerative issues that make individuals more susceptible to falls and injuries.

The iStride device is strapped over the shoe of the good leg and generates a backwards motion, exaggerating the existing step, making it harder to walk while wearing the shoe. The awkward movement strengthens the stroke-impacted leg, allowing gait to become more symmetrical once the shoe is removed. The impaired foot wears a matching shoe that remains stationary.

"The backward motion of the shoe is generated passively by redirecting the wearer's downward force during stance phase. Since the motion is generated by the wearer's force, the person is in control, which allows easier adaptation to the motion," said developer Kyle Reed, PhD, associate professor of mechanical engineering at the University of South Florida. "Unlike many of the existing gait rehabilitation devices, this device is passive, portable, wearable and does not require any external energy."

The trial included six people between ages 57 and 74 who suffered a cerebral stroke at least one-year prior to the study. They all had asymmetry large enough to impact their walking ability. Each received twelve, 30-minute gait training sessions for four weeks. With guidance from a physical therapist, the patients' gait symmetry and functional walking were measured using the ProtoKinetics Zeno Walkway system.

All participants improved their gait's symmetry and speed. That includes how long it takes to stand up from a sitting position and walk, as well as how long it takes to walk to a specific location and distance traveled within six minutes. Four improved the percentage of time spent in a gait cycle with both feet simultaneously planted on the ground, known as double limb support. As far as the other two that didn't improve, one started the study with severe impairment, while the other was highly functional. It's also important to note that three participants joined the study limited to walking in their homes. Following the trial, two of them could successfully navigate public venues.

Reed compared his method to a previous study conducted on split-belt treadmill training (SBT), which is commonly used by physical therapists to help stroke patients improve their gait. The equipment allows the legs to move at different speeds, forcing the patient to compensate in order to remain on the treadmill. While the SBT improves certain aspects of gait, unlike the iStride, it doesn't strengthen double limb support.

That research concluded only about 60 percent of patients trained on the SBT corrected their gait when walking in a normal environment. Walking is context dependent where visual cues impact how quickly one tries to move, and in what direction. The iStride allows patients to adjust accordingly. Movement on a treadmill is predictable and provides individuals a static scene.

Since patients are often disappointed in their progress after being discharged from rehabilitation, the iStride's portability allows patients to relearn to walk in a typical setting more often and for a longer duration. Reed is now working on a home-based clinical trial with 21 participants and expects to publish results within the next year. He recently received a Fulbright scholarship to conduct research at Hong Kong Polytechnic University. He's working in the rehabilitation sciences and biomedical engineering departments throughout the 2019-2020 academic year.

A lot of people worry about microplastics and plastic pollution, but not as many of us are aware of the large number of chemicals we encounter in plastic products that we use every day.

Researchers know of more than 4,000 chemicals that are currently used in plastic food packaging. But with more than 5,000 different types of plastic on the market, the number of chemicals used to make plastics is likely even larger.

"The problem is that plastics are made of a complex chemical cocktail, so we often don't know exactly what substances are in the products we use. For most of the thousands of chemicals, we have no way to tell whether they are safe or not," says Martin Wagner, a biologist at the Norwegian University of Science and Technology (NTNU). "This is because, practically speaking, it's impossible to trace all of these compounds. And manufacturers may or may not know the ingredients of their products, but even if they know, they are not required to disclose this information."

Wagner specializes in the environmental and health impacts of plastics, and is the senior author of a new study on the toxicity and chemical composition in various plastic products.

The work is part of the PlastX research group led by ISOE - the Institute for Social-Ecological Research Frankfurt and was carried out in collaboration with the Goethe University in Frankfurt am Main, Germany. The article was recently published in Environmental Science and Technology.

"We studied eight types of plastics commonly used to make everyday products, such as yogurt cups and bath sponges, and examined their toxicity and chemical composition. Three out of four products contained toxic chemicals," Lisa Zimmermann, Wagner's colleague and first author of the study, says.

The researchers used cell cultures to investigate the effects of the mix of chemicals in each product. They found that many plastics contain chemicals that induced general toxicity (six out of ten products), oxidative stress (four out of ten) and endocrine-disrupting effects (three out of ten).

It is impossible to pinpoint specifically which chemicals were the culprits: the research group discovered more than 1,400 substances in plastics but identified only 260 of them. That means that most of the plastic chemicals remain unknown and cannot be assessed for their safety.

Given that, the authors were able to conclude that plastic chemicals in polyvinyl chloride (PVC) and polyurethane (PUR) were the most toxic. Compared to PVC and PUR, polyethylene terephthalate (PET) and high-density polyethylene (HDPE) were less toxic.

"Plastics contain chemicals that trigger negative effects in a culture dish. Even though we do not know whether this will affect our health, such chemicals simply shouldn't be in plastics in the first place," Wagner says.

Traditionally, plastics consist of polymers and as a rule, are made from petroleum products. Now "green" alternatives to regular plastic can be found as well.

Bioplastics are made from renewable biomass sources, such as plants, instead of from petroleum. But they are still plastic - the polymers that make up the plastic just come from another source.

"Regarding toxicity," Wagner says, "it's the same problem. We are in the dark as to which chemicals are used in the bioplastics as well."

The PlastX team also investigated products made of polylactic acid (PLA), a common type of bioplastic. They found toxicity in all of them.

Even plastic products that seem similar may contain different substances.

"We examined four different yogurt cups and found toxicity in two of them, but not in the other two," Zimmermann says.

In other words, it is almost impossible for consumers to know whether a product is safe or not. This sounds discouraging but there is something you can do.

The PlastX researchers suggest:

Refuse buying unnecessary plastics and reduce your plastics exposure and footprint, for example, by buying fresh and unpackaged products.

Avoid PVC products when possible, which are labelled #3 in the recycling code, and all "other types of plastic" labelled as #7 because it is not clear which material they are made from.

Consumers can and should demand safer plastics. One way is to ask retailers for transparency regarding what materials a product is made of and which chemicals are in the product.

Ultimately, Wagner says, it is the responsibility of manufacturers and retailers to improve the chemical safety of their products.

"We found that there was at least one product that was far less toxic than others made from the same material, Wagner says. "This is encouraging because it shows that safer plastics are already on the market."

That means manufacturers could conceivably make plastics that do not contain toxic chemicals. Wagner says that big retail chains and brand owners have the power to make that happen. However, at this stage, transparency regarding the chemical composition remains an issue that must be resolved.

Wagner calls on policymakers to consider the safety of plastics to which the public is exposed to regularly a priority. "We need to avoid demonizing plastics. But given that we live in the plastic age, we need to make sure they don't affect our health," he argues.

This requires taking action, from consumer choices in the supermarket to the international level.

New research presented at this year's Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain (16-20 Sept) suggests that a 16-week vegan diet can boost the gut microbes that are related to improvements in body weight, body composition and blood sugar control. The study is by Dr Hana Kahleova, Physicians Committee for Responsible Medicine (PCRM), Washington, DC, USA, and colleagues.

Gut microbiota play an important role in weight regulation, the development of metabolic syndrome, and type 2 diabetes. The aim of this study was to test the effect of a 16-week plant-based diet on gut microbiota composition, body weight, body composition, and insulin resistance in overweight adults with no history of diabetes.

The study included 147 participants (86% women and 14% men; mean age was 55.6±11.3 years), who were randomised to follow a low-fat vegan diet (n=73) or to make no changes to their diet (n=74) for 16 weeks. At baseline and 16 weeks, gut microbiota composition was assessed, using uBiome kits. Dual energy X-ray absorptiometry was used to measure body composition. A standard method called the PREDIM index was used to assess insulin sensitivity.

Following the 16-week study, body weight was reduced significantly in the vegan group (treatment effect average -5.8 kg), particularly due to a reduction in fat mass (average -3.9 kg) and in visceral fat. Insulin sensitivity also increased significantly in the vegan group.

The relative abundance of Faecalibacterium prausnitzii increased in the vegan group (treatment effect +4.8%). Relative changes in Faecalibacterium prausnitzii were associated with decreases in body weight, fat mass and visceral fat. The relative abundance of Bacteoides fragilis also increased in the vegan group (treatment effect +19.5%). Relative changes in Bacteroides fragilis were associated with decreases in body weight, fat mass and visceral fat, and increases in insulin sensitivity.

The authors conclude: "A 16-week low-fat vegan dietary intervention induced changes in gut microbiota that were related to changes in weight, body composition and insulin sensitivity in overweight adults."

However, the authors acknowledge that further work is needed to separate out the effects of the vegan diet itself from that of the reduced calories. They say: "A plant-based diet has been shown to be effective in weight management, and in diabetes prevention and treatment. This study has explored the link between changes in the gut microbiome, and changes in body weight, body composition, and insulin sensitivity. We have demonstrated that a plant-based diet elicited changes in gut microbiome that were associated with weight loss, reduction in fat mass and visceral fat volume, and increase in insulin sensitivity."

They add: "The main shift in the gut microbiome composition was due to an increased relative content of short-chain fatty acid producing bacteria that feed on fibre. Therefore, high dietary fibre content seems to be essential for the changes observed in our study. We plan to compare the effects of a vegan and a standard portion-controlled diet on gut microbiome in people with type 2 diabetes, in order to separate out the positive effects of the reduced calories in the diet from those caused by the vegan composition of the diet."

They continue: "This is a fascinating area of research and we have been collecting data from more study participants. We hope we will be able to present them at the next year's 2020 EASD meeting."

The authors say that fibre is the most important component of plant foods that promotes a healthy gut microbiome. Faecalibacterium prausnitzii is one of the short-chain fatty acids producing bacteria, which degrade plant complex sugars and starch to produce health-promoting butyrate and/or other short-chain fatty acids that have been found to have a beneficial effect on body weight, body composition, and insulin sensitivity. The authors say: "Eating more fibre is the number one dietary recommendation for a healthy gut microbiome."

A new study suggests employee safety could be improved through use of Virtual Reality (VR) in Health and Safety training, such as fire evacuation drills.

The Human Factors Research Group at the University of Nottingham, developed an immersive VR system to stimulate participants' perception of temperature, and senses of smell, sight and hearing to explore how they behaved during two health and safety training scenarios: an emergency evacuation in the event of a fire and a fuel leak.

In one scenario, participants had to evacuate from a virtual fire in an office, seeing and hearing using a VR headset but could also feel heat from three 2kW heaters, and could smell smoke from a scent diffuser, creating a multisensory virtual environment. This group was compared against another group who were observed in this scenario using only audio-visual elements of VR.

Observing real life behaviours

Previous research on human behaviour during real-world fire incidents has shown that a lack of understanding of the spread and movement of fire often means that occupants are unprepared and misjudge appropriate actions. Immersive health and safety training enables employers to train people about hazards and hazardous environments without putting anyone at risk.

The Nottingham research, funded by the Institution of Occupational Safety and Health (IOSH), found contrasts between the groups in the way participants reacted to the scenario. Those in the multi-sensory group had a greater sense of urgency, reflecting a real-life scenario, and were more likely to avoid the virtual fires. Evidence from the audio-visual participants suggested that they were treating the experience more like a game and behaviours were less consistent with those expected in a real world situation.

Dr Glyn Lawson, Associate Professor in the Faculty of Engineering, University of Nottingham, said: "Health and safety training can fail to motivate and engage employees and can lack relevance to real-life contexts. Our research, which has been funded by the Institution of Occupational Safety and Health, suggests that virtual environments can help address these issues, by increasing trainees' engagement and willingness to participate in further training. There are also business benefits associated with the use of virtual environment training, such as the ability to deliver training at or near the workplace and at a time that is convenient to the employee."

Virtual Reality vs. PowerPoint

A further test was done, as part of the study, to measure the effectiveness of VR training versus traditional PowerPoint training. Participants took questionnaires, testing their knowledge on either fire safety or safe vehicle disassembly procedure, before and after training as well as one week later.

While those trained via PowerPoint appeared to have gained more knowledge when tested directly after training, there was a significantly larger decrease in knowledge scores when participants were retested one week later. In comparison, the VR group's long term retention was better and reported higher levels of engagement; attitude to occupational safety and health; and willingness to undertake training in the future.

The research suggests that the increased cognitive engagement of learning in the virtual environment creates more established and comprehensive mental models which can improve recall, and implies that testing an employee's knowledge immediately following health and safety training may not be an effective means of gaging long-term knowledge of health and safety.

Applications to the work place

Mary Ogungbeje, Research Manager at IOSH, said: "The wheels are turning so that virtual and smart learning is increasingly engrained in the workplace and everyday life.

"Technology is continuously advancing and in many cases becoming more affordable, so this study gives us a taste of what's to come. By improving training strategies with the use of technology and stimulated sensory experiences, we are heading in a direction where the workforce will not just enjoy a more immersive and interesting training course but participate in an effective learning experience, so they are better prepared and equipped to stay safe, healthy and well at work."

The researchers conducted meetings, discussions, and visits with partners including Rolls-Royce, for expert advice around fire safety and safe handling of hazardous chemicals. The University of Nottingham's Health and Safety advisors also contributed to help the researchers better understand how the training may be implemented in industry.

The study aims to produce evidence-based guidance for the development and use of virtual environments in engaging and effective training using cost-effective and accessible solutions. The full study features in a report, titled 'Immersive virtual worlds: Multisensory virtual environments for health and safety training', to be released at the IOSH's annual conference on Tuesday 17 September.

The guardians of the human genome that work to prevent potentially disease-causing gene expression might not be as effective at their jobs as previously thought, according to new University of Arizona research.

Human chromosomes are made up of DNA, about half of which includes ancient remnants of a type of virus called transposons. Also known as "jumping genes," transposons have the potential to attack other parts of the genome and cause mutations and damage if they're ever free to be expressed.

"To keep transposons from disrupting how our genes function, cells create a structure called heterochromatin," said Keith Maggert, UA associate professor of cellular and molecular medicine and member of the UA Cancer Center.

Heterochromatin, the guardian that basically handcuffs the dangerous transposons in a compact tangle of DNA strand, prevents transposons from being copied or expressed. But researchers are still working to understand the fundamentals of heterochromatin, and much of what is thought is based on assumption, Maggert said.

One assumption was that once heterochromatin formed on a transposon, it was stable, locked up for good. But research done by Maggert and his team suggests that even early on, some cells fail to silence the transposons, and even the silenced ones aren't completely quiet.

"People thought heterochromatin was good at its job," said Maggert, lead author on the paper published today in the journal Proceedings of the National Academy of Sciences. "But heterochromatin makes mistakes, and so it slips from time to time, flickering on and off constantly. Each time it drops the ball, we're at risk, and certain environmental conditions can lead to increased instability."

It's Maggert's ongoing hypothesis that transposons can do their damage as heterochromatin flickers on and off and becomes unstable, allowing for errors in DNA transcription and, ultimately, the emergence of diseases such as cancer. More research is required to confirm this linkage, Maggert stressed.

Until now, studies were only able to assess how genes were expressed at the end of a fruit fly's life, but the team's novel methods allowed for the observation of heterochromatin activity throughout cell development.

"We designed a system to track the history of silencing (flickering) throughout an organism's life," Maggert said. "Imagine a game of pinball. Before, we could only see if the ball finally went in the hole, but we couldn't see all the interesting stuff - the ball bounce against the weird bumpers, what path it took, what it did before reaching that final state. The flickering on and off was a total mystery no one expected."

It took the team years to create the experiment, which consisted of a combination of biological observations of fruit flies, a novel mathematical model and genes borrowed from yeast, jellyfish and coral. It took four years to make, but just 24 hours to get the results, which have implications for how human heterochromatin functions.

"It was an exciting day, but it was also a very scary day to come in and look at the results," Maggert said.

Not only has his team learned that heterochromatin is surprisingly unstable, but "the very unusual thing about heterochromatin is it seems to 'remember' whether it's been strong or weak (handcuffed or not) even after a cell divides," Maggert said. "It's wiped away during cell division then restored afterward. This is called epigenetics - the term for silencing transposons."

No one yet understands how it happens.

"I've always been fascinated by the idea of epigenetics, and when I started working on it as a graduate student, I was totally on board. But as I've done more and more research - it's now been 20 years - I think it's all wrong," he said. "How did I lose the faith? Memory requires a mechanism, and a lot of smart people have been looking for one for 20 years and have come up empty handed. Lack of evidence is not the evidence of the lack, but at some point, you start to think, maybe we won't find it."

Next, Maggert, who is in year three of a five-year $2.5 million Transformative Research Award grant from the National Institutes of Health, hopes to complete a study where he explains how heterochromatin memory works without invoking epigenetics.

An international research group at UBC, Harvard University and Cardiff Metropolitan University has discovered how the human heart has adapted to support endurance physical activities.
This research examines how the human heart has evolved and how it adapts in response to different physical challenges, and will bring new ammunition to the international effort to reduce hypertensive heart disease--one of the most common causes of illness and death in the developed world.

The landmark study analyzed 160 humans, 43 chimpanzees and five gorillas to gain an understanding of how the heart responds to different types of physical activity. In collaboration with Harvard University's Daniel Lieberman and Aaron Baggish, UBC Professor Robert Shave and colleagues compared left ventricle structure and function in chimpanzees and a variety of people, including some who were sedentary but disease-free, highly active Native American subsistence farmers, resistance-trained football linemen and endurance-trained long-distance runners.

The wide variety of participants were specifically recruited in order to examine cardiac function in an evolutionary context. From the athletic stadium to wildlife sanctuaries in Africa, the team measured a diverse array of cardiac characteristics and responses to determine how habitual physical activity patterns, or a lack of activity influence cardiac structure and function, explains Shave.

"While apes showed adaptations to support the pressure challenge associated with activities such as climbing and fighting, humans showed more endurance related adaptations," says Shave, director of UBCO's School of Health and Exercise Sciences

Guiding their inquiry is the well-known idea that the heart remodels itself in response to different physiological challenges, he notes

"Moderate-intensity endurance activities such as walking and running stimulate the left ventricular chamber to become larger, longer and more elastic--making it able to handle high volumes of blood," he says. "But pressure challenges like chronic weight-lifting or high blood pressure, stimulate thickening and stiffening of the left ventricular walls."

Among humans, the research team showed there is a trade-off between these two types of adaptations. This trade-off means that people who have adapted to pressure cannot cope as well with volume and vice versa. Basically, the hearts of endurance runners aren't great at dealing with a pressure challenge, and the weight lifter's heart will not respond well to increases in volume.

This new research provides evidence that the human heart evolved for the purpose of moderate-intensity endurance activities, but adapts to different physical (in)activity patterns.

"As a result, today's epidemic of physical inactivity in conjunction with highly processed, high-sodium diets contributes to thicker, stiffer hearts that compromise the heart's ability to cope with endurance physical activity, and importantly this may start to occur prior to increases in resting blood pressure," explains Shave.

This is often followed by the onset of high blood pressure and can eventually lead to hypertensive heart disease.

"We hope our research will inform those at highest risk of developing hypertensive heart disease," says Shave. "And ensure that moderately intense endurance-type activities are widely encouraged in order to ultimately prevent premature deaths."