Chemists could point way to new antibiotics — ScienceDaily

In a discovery that points to potential new antibiotic medicines, scientists from Rice University and the University of Michigan have deciphered the workings of a common but little-understood bacterial switch that cuts off protein production before it begins.

Many gram-positive bacteria use T-box riboswitches to regulate production of proteins that utilize amino acids, the basic building blocks of all proteins. A study in Nature Communications describes how one of these switches, a glycine regulator in Bacillus subtilis, flips and locks into the “on” position via a snap-lock mechanism. Engaging the lock increases production of proteins that utilize glycine, the simplest amino acid. Researchers also detailed the switch’s “off” position: A single glycine at the tip of the locking arm blocks protein production.

“T-box riboswitches are intriguing because they are regulated — turned on or off — by molecules central to protein production,” said study co-author Edward Nikonowicz, professor of biosciences at Rice. “While they were discovered a quarter century ago, it’s not been entirely clear how they operate. By highlighting their structural and kinetic details, we hope to spur interest in these switches as potential targets for new antibiotics.”

New antibiotics could help avert a looming health crisis, Nikonowicz said. The Centers for Disease Control and Prevention expects antibiotic-resistant bacteria to kill at least 23,000 people in the U.S. this year, and if current trends go unchecked, the World Health Organization estimates that by 2050, drug-resistant pathogens will kill 10 million people per year worldwide.

T-box riboswitches like the one highlighted in the new study are vital to many gram-positive bacteria, a broad class that includes pathogens that cause tuberculosis, gangrene, botulism, anthrax, inflammation of the inner heart lining and other diseases.

T-box riboswitches are located on strands of messenger RNA (mRNA), blueprints for proteins that are copied directly from a cell’s DNA. In complex organisms such as animals and plants, the writing, or “transcription,” of mRNA takes place in a vault-like DNA storage facility called the nucleus. Only after mRNA leaves the vault can its message be used, or “translated,” into a new protein. Because bacteria have no nucleus, “transcription” of mRNA and “translation,” decoding of mRNA by ribosomes to make new proteins, happen in close proximity.

“Riboswitches are common in many bacteria, but not in humans, making them such attractive targets for new drugs,” said study co-author Nils Walter, the Francis S. Collins Collegiate Professor of Chemistry, Biophysics and Biological Chemistry at the University of Michigan. “T-box riboswitches regulate transcription, the writing of the messenger RNA itself, but use a locking arm borrowed from the translation machinery, making it a unique jack-of-all-trades.”

The mRNA blueprints are used to build proteins, the workhorses of biology. Cells employ millions of proteins at a given time, but each of these is made from the same 20 building blocks, the amino acids that T-box riboswitches help regulate in gram-positive bacteria. To make a protein, cells string amino acids end to end, like beads on a necklace, based on the order specified in mRNA instructions.

The locking arm trigger in the glycine T-box riboswitch is part of another molecule called transfer RNA (tRNA). There are many types of tRNA in cells, but each acts like a kind of car, shuttling payloads to the ribosome, where proteins are strung together. Each type of tRNA can only carry one type of amino acid.

In the new study, Walter and Nikonowicz designed an experiment in which glycine-specific tRNA molecules, some loaded with glycine and others unloaded, would pass by and randomly attach to a T-box riboswitch.

“Ed’s team was able to attach a fluorescent marker to the tRNA in a such a way that it wouldn’t interfere with their binding,” Walter said. “My lab employed a technique called ‘single molecule fluorescence microscopy’ to probe the dynamic associations of single T-box riboswitches with the tRNA, either when the glycine cargo was attached or not.”

Each time a tRNA with a fluorescent tag attached took up a position on the T-box riboswitch, a bright signal appeared in the microscope. By measuring exactly how long the signal lasted, and thus how long the molecules stayed in position, the team was able to reconstruct the binding speed and ultimately the locking mechanism for the switch.

Nikonowicz said he and Walter began the glycine T-box riboswitch project about 2 1/2 years ago.

“Glycine was the simplest case, in part because there’s an additional domain in the T-box sensing other amino acids,” he said. “There are questions about what this domain does and how it operates. Given what we’ve already learned about the glycine T-box riboswitch, I’d like to extend this work to see what we can learn from other types of T-boxes.”

Walter added the findings could also pay off in the emerging field of RNA nanotechnology, in which scientists are attempting to use RNA templates for precision engineering of complex structures.

“In the active, locked position, the T-box-tRNA complex has a very stable three-dimensional shape,” he said. “It’s possible these could be exploited for ultra-stable ring-like complexes in novel biomimetic architectures.”

Replacement neurons, blood vessels fill in stroke cavity; gel provides scaffolding — ScienceDaily

In a first-of-its-kind finding, a new stroke-healing gel helped regrow neurons and blood vessels in mice with stroke-damaged brains, UCLA researchers report in the May 21 issue of Nature Materials.

“We tested this in laboratory mice to determine if it would repair the brain in a model of stroke, and lead to recovery,” said Dr. S. Thomas Carmichael, Professor and Chair of neurology at UCLA. “This study indicated that new brain tissue can be regenerated in what was previously just an inactive brain scar after stroke.”

The results suggest that such an approach may someday be a new therapy for stroke in people, said Dr. Tatiana Segura, a former Professor of Chemical and Biomolecular Engineering at UCLA who is now a professor at Duke University. Carmichael and Segura collaborated on the study.

The brain has a limited capacity for recovery after stroke and other diseases. Unlike some other organs in the body, such as the liver or skin, the brain does not regenerate new connections, blood vessels or new tissue structures. Tissue that dies in the brain from stroke is absorbed, leaving a cavity, devoid of blood vessels, neurons or axons, the thin nerve fibers that project from neurons.

To see if healthy tissue surrounding the cavity could be coaxed into healing the stroke injury, Segura engineered a gel to inject into the stroke cavity that thickens to mimic the properties of brain tissue, creating a scaffolding for new growth.

The gel is infused with molecules that stimulate blood vessel growth and suppress inflammation, since inflammation results in scars and impedes regrowth of functional tissue.

After 16 weeks, stroke cavities in mice contained regenerated brain tissue, including new neural networks — a result that had not been seen before. The mice with new neurons showed improved motor behavior, though the exact mechanism wasn’t clear.

“The new axons could actually be working,” said Segura. “Or the new tissue could be improving the performance of the surrounding, unharmed brain tissue.”

The gel was eventually absorbed by the body, leaving behind only new tissue.

This research was designed to explore recovery in acute stroke, or the period immediately following stroke — in mice, that is five days; in humans, that is two months. Next, Carmichael and Segura are determining if brain tissue can be regenerated in mice long after the stroke injury. More than 6 million Americans are living with the long-term outcomes of stroke, known as chronic stroke.

Story Source:

Materials provided by University of California – Los Angeles. Note: Content may be edited for style and length.

Are humans causing cancer in wild animals? Humans may influence cancer in many other species on the planet — ScienceDaily

As humans, we know that some of our activities can cause cancer to develop in our bodies. Smoking, poor diets, pollution, chemicals used as additives in food and personal hygiene products, and even too much sun are some of the things that contribute to an increased risk of cancer.

But, are human activities also causing cancer in wild animals? Are we oncogenic — a species that causes cancer in other species?

Researchers from Arizona State University’s School of Life Sciences think so and are urgently calling for research into this topic. In a paper published online today in “Nature Ecology & Evolution,” Mathieu Giraudeau and Tuul Sepp, both postdoctoral researchers in the lab of ASU life sciences professor Kevin McGraw, say that humans are changing the environment in a way that causes cancer in wild animal populations.

“We know that some viruses can cause cancer in humans by changing the environment that they live in — in their case, human cells — to make it more suitable for themselves,” said Sepp. “Basically, we are doing the same thing. We are changing the environment to be more suitable for ourselves, while these changes are having a negative impact on many species on many different levels, including the probability of developing cancer.”

In the paper, Giraudeau and Sepp and a team of international researchers, point out many pathways and previous scientific studies that show where human activities are already taking a toll on animals. These include chemical and physical pollution in our oceans and waterways, accidental release of radiation into the atmosphere from nuclear plants, and the accumulation of microplastics in both land- and water-based environments. In addition, exposure to pesticides and herbicides on farmlands, artificial light pollution, loss of genetic diversity and animals eating human food are known to cause health problems.

“Cancer in wild populations is a completely ignored topic and we wanted to stimulate research on this question,” shared Giraudeau. “We recently published several theoretical papers on this topic, but this time, we wanted to highlight the fact that our species can strongly influence the prevalence of cancer in many other species of our planet.

“Cancer has been found in all species where scientists have looked for it and human activities are known to strongly influence cancer rate in humans. So, this human impact on wild environments might strongly influence the prevalence of cancer in wild populations with additional consequences on ecosystem functioning,” he said.

Even something such as artificial light and light pollution, as well as food meant for humans, are negatively affecting wild animals.

Sepp said: “It is already known in human studies that obesity and nutrient deficiency can cause cancer, but these issues have been mostly overlooked in wild animals. At the same time, more and more wild species are in contact with anthropogenic food sources. In humans, it’s also known that light at night can cause hormonal changes and lead to cancer. Wild animals living close to cities and roads face the same problem — there is no darkness anymore. For example, in birds, their hormones — the same that are linked to cancer in humans — are affected by light at night. So, the next step would be to study if it also affects their probability of developing tumors.”

While these scientists are urgently calling for studies on cancer and its causes in wild animal populations, they realize that this is no easy subject to study.

“The next step is definitely to go into the field and measure cancer rate in wild populations,” said Giraudeau. “We are now trying to develop some biomarkers to be able to study this. I think it would be interesting to measure cancer prevalence in wild animals in human-impacted environments and also in more preserved areas for the same species.”

If humans are the cause of cancer in wild animals, then many species may be more threatened than people realize. Yet Tuul said, there is reason to hold out hope.

“To me, the saddest thing is that we already know what to do. We should not destroy the habitats of wild animals, pollute the environment, and feed wild animals human food,” shared Sepp. “The fact that everybody already knows what to do, but we are not doing it, makes it seem even more hopeless.

“But I see hope in education. Our kids are learning a lot more about conservation issues than our parents did. So, there is hope that the decision-makers of the future will be more mindful of the anthropogenic effects on the environment.”

Novel drug protects memory function in mice exposed to simulated cosmic radiation — ScienceDaily

Planning a trip to Mars? You’ll want to remember your anti-radiation pills.

NASA and private space companies like SpaceX plan to send humans to the red planet within the next 15 years — but among the major challenges facing future crewed space missions is how to protect astronauts from the dangerous cosmic radiation of deep space.

Now the lab of UCSF neuroscientist Susanna Rosi, PhD, has identified the first potential treatment for the brain damage caused by exposure to cosmic rays — a drug that prevents memory impairment in mice exposed to simulated space radiation. The study was published May 18, 2018 in Scientific Reports.

Humans venturing beyond the Earth’s protective magnetic fields will be exposed to levels of cosmic radiation estimated to be 1000 times higher than what we experience on Earth or even in the International Space Station’s low-earth orbit. Protecting astronauts from this harmful radiation will be key to making deep space exploration — and perhaps one day colonization — possible.

Rosi, who is Director of Neurocognitive Research in the UCSF Brain and Spinal Injury Center and a professor in the departments of Physical Therapy and Rehabilitation Science and of Neurological Surgery, has conducted NASA-funded research for the past four years to understand how deep space radiation may affect astronauts’ brains.

Rosi’s team has previously found that exposing mice to simulated space radiation causes problems with memory, social interactions, and anxiety, and has linked these symptoms of radiation exposure to activation of cells called microglia — part of the brain’s immune system. Activated microglia drive brain inflammation similar to what is seen in neurodegenerative disorders such as Alzheimer’s disease, and also seek out and consume synapses, the information-bearing connections between brain cells.

“We are starting to have evidence that exposure to deep space radiation might affect brain function over the long term, but as far as I know, no one had explored any possible countermeasures that might protect astronauts’ brains against this level of radiation exposure,” said Rosi, who is a member of the Weill Institute for Neuroscience, the Kavli Institute of Fundamental Neuroscience, and the UCSF Helen Diller Family Comprehensive Cancer Center.

In the new study, the researchers collaborated with co-authors at Loma Linda University in Southern California to expose mice for a day to a dose of radiation comparable to what they might experience in deep space. The experiments were conducted at the NASA Space Radiation Laboratory at Brookhaven National Laboratory in New York, the only facility in the country where such experiments are possible. A week later, after being shipped back to UCSF, some of the mice were treated for 15 days with PLX5622, a drug produced by Berkeley-based pharmaceutical company Plexxikon, Inc, and which the Rosi lab had previously shown to prevent cognitive deficits in a mouse model of cancer radiation therapy when administered prior to irradiation of the brain.

In the present study, the irradiated animals initially displayed no cognitive deficits, but after three months they began showing signs of memory impairment. Normally, when researchers place mice in a room with a familiar and an unfamiliar object, the animals spend more time exploring the new object. But mice that had been exposed to space radiation three months earlier explored the two objects equally — presumably because they didn’t remember having seen one of the objects just the day before.

Remarkably, animals that had been treated with PLX5622 soon after being exposed to radiation performed just like healthy mice on the memory task. The researchers examined the animals’ brains and showed that while the brains of untreated mice were full of activated microglia and had lost significant numbers of synapses, the brains of treated mice looked just like normal. The authors hypothesize that by forcing the brain to replace irritable, radiation-exposed microglia with new, healthy microglia, the drug had allowed the animals avoid the cognitive consequences of radiation.

“This is really neat evidence, first that rebooting the brain’s microglia can protect cognitive function following radiation exposure, and second that we don’t necessarily need to treat immediately following the radiation exposure for the drug to be effective,” Rosi said.

Similar compounds to PLX5622 produced by Plexxikon (inhibitors of a cellular receptor molecule called CSF1R) are already in clinical trials for multiple forms of human cancer, which suggests that the new findings could soon be translated to human use, the researchers say. Beyond spaceflight, these compounds could potentially be used to prevent cognitive impairments following cancer radiation therapy, or in age-related cognitive impairment — which has also been linked to microglia-driven brain inflammation.

“NASA is very interested in finding ways of ensuring both astronaut safety and mission success during deep space travel,” said study co-lead author Karen Krukowski, PhD, a postdoctoral researcher in Rosi’s lab. “But astronauts are a small population — it’s exciting that these findings could potentially help prevent many other forms of cognitive impairment.”

Nanoparticles could offer a new way to help eradicate the disease worldwide — ScienceDaily

A new nanoparticle vaccine developed by MIT researchers could assist efforts to eradicate polio worldwide. The vaccine, which delivers multiple doses in just one injection, could make it easier to immunize children in remote regions of Pakistan and other countries where the disease is still found.

While the number of reported cases of polio dropped by 99 percent worldwide between 1988 and 2013, according to the Centers for Disease Control, the disease has not been completely eradicated, in part because of the difficulty in reaching children in remote areas to give them the two to four polio vaccine injections required to build up immunity.

“Having a one-shot vaccine that can elicit full protection could be very valuable in being able to achieve eradication,” says Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the paper.

Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences the week of May 21. Stephany Tzeng, a former MIT postdoc who is now a research associate at Johns Hopkins University School of Medicine, is the paper’s lead author.

“We are very excited about the approaches and results in this paper, which I hope will someday lead to better vaccines for patients around the world,” Langer says.

Global eradication

There are no drugs against poliovirus, and in about 1 percent of cases, it enters the nervous system, where it can cause paralysis. The first polio vaccine, also called the Salk vaccine, was developed in the 1950s. This vaccine consists of an inactivated version of the virus, which is usually given as a series of two to four injections, beginning at 2 months of age. In 1961, an oral vaccine was developed, which offers some protection with only one dose but is more effective with two to three doses.

The oral vaccine, which consists of a virus that has reduced virulence but is still viable, has been phased out in most countries because in very rare cases, it can mutate to a virulent form and cause infection. It is still used in some developing countries, however, because it is easier to administer the drops than to reach children for multiple injections of the Salk vaccine.

For polio eradication efforts to succeed, the oral vaccine must be completely phased out, to eliminate the chance of the virus reactivating in an immunized person. Several years ago, Langer’s lab received funding from the Bill and Melinda Gates Foundation to try to develop an injectable vaccine that could be given just once but carry multiple doses.

“The goal is to ensure that everyone globally is immunized,” Jaklenec says. “Children in some of these hard-to-reach developing world locations tend to not get the full series of shots necessary for protection.”

To create a single-injection vaccine, the MIT team encapsulated the inactivated polio vaccine in a biodegradable polymer known as PLGA. This polymer can be designed to degrade after a certain period of time, allowing the researchers to control when the vaccine is released.

“There’s always a little bit of vaccine that’s left on the surface or very close to the surface of the particle, and as soon as we put it in the body, whatever is at the surface can just diffuse away. That’s the initial burst,” Tzeng says. “Then the particles sit at the injection site and over time, as the polymer degrades, they release the vaccine in bursts at defined time points, based on the degradation rate of the polymer.”

The researchers had to overcome one major obstacle that has stymied previous efforts to use PLGA for polio vaccine delivery: The polymer breaks down into byproducts called glycolic acid and lactic acid, and these acids can harm the virus so that it no longer provokes the right kind of antibody response.

To prevent this from happening, the MIT team added positively charged polymers to their particles. These polymers act as “proton sponges,” sopping up extra protons and making the environment less acidic, allowing the virus to remain stable in the body.

Successful immunization

In the PNAS study, the researchers designed particles that would deliver an initial burst at the time of injection, followed by a second release about 25 days later. They injected the particles into rats, then sent blood samples from the immunized rats to the Centers for Disease Control for testing. Those studies revealed that the blood samples from rats immunized with the single-injection particle vaccine had an antibody response against poliovirus just as strong as, or stronger than, antibodies from rats that received two injections of Salk polio vaccine.

To deliver more than two doses, the researchers say they could design particles that release vaccine at injection and one month later, and mix them with particles that release at injection and two months later, resulting in three overall doses, each a month apart. The polymers that the researchers used in the vaccines are already FDA-approved for use in humans, so they hope to soon be able to test the vaccines in clinical trials.

The researchers are also working on applying this approach to create stable, single-injection vaccines for other viruses such as Ebola and HIV.

The research was funded by the Bill and Melinda Gates Foundation.

Having an egg a day could reduce risk of stroke by 26 percent — ScienceDaily

People who consume an egg a day could significantly reduce their risk of cardiovascular diseases compared with eating no eggs, suggests a study carried out in China, published in the journal Heart.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, including China, mostly due to ischaemic heart disease and stroke (including both haemorrhagic and ischaemic stroke).

Unlike ischaemic heart disease, which is the leading cause of premature death in most Western countries, stroke is the most responsible cause in China, followed by heart disease.

Although ischaemic stroke accounted for the majority of strokes, the proportion of haemorrhagic stroke in China is still higher than that in high income countries.

Eggs are a prominent source of dietary cholesterol, but they also contain high-quality protein, many vitamins and bioactive components such as phospholipids and carotenoids.

Previous studies looking at associations between eating eggs and impact on health have been inconsistent, and most of them found insignificant associations between egg consumption and coronary heart disease or stroke.

Therefore, a team of researchers from China and the UK led by Professor Liming Li and Dr Canqing Yu from the School of Public Health, Peking University Health Science Center, set out to examine the associations between egg consumption and cardiovascular disease, ischaemic heart disease, major coronary events, haemorrhagic stroke and ischaemic stroke.

They used data from the China Kadoorie Biobank (CKB) study, an ongoing prospective study of around half a million (512,891) adults aged 30 to 79 from 10 different geographical areas in China.

The participants were recruited between 2004-2008 and were asked about the frequency of their egg consumption. They were followed up to determine their morbidity and mortality.

For the new study, the researchers focused on 416,213 participants who were free of prior cancer, cardiovascular disease (CVD) and diabetes.

From that group at a median follow-up of 8.9 years, a total of 83,977 cases of CVD and 9,985 CVD deaths were documented, as well as 5,103 major coronary events.

At the start of the study period, 13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day) of eggs.

Analysis of the results showed that compared with people not consuming eggs, daily egg consumption was associated with a lower risk of CVD overall.

In particular, daily egg consumers (up to one egg/day) had a 26% lower risk of haemorrhagic stroke — the type of stroke with a higher prevalence rate in China than in high-income countries — a 28% lower risk of haemorrhagic stroke death and an 18% lower risk of CVD death.

In addition, there was a 12% reduction in risk of ischaemic heart disease observed for people consuming eggs daily (estimated amount 5.32 eggs/week), when compared with the ‘never/rarely’ consumption category (2.03 eggs/week).

This was an observational study, so no firm conclusions can be drawn about cause and effect, but the authors said their study had a large sample size and took into account established and potential risk factors for CVD.

The authors concluded: “The present study finds that there is an association between moderate level of egg consumption (up to 1 egg/day) and a lower cardiac event rate.

“Our findings contribute scientific evidence to the dietary guidelines with regard to egg consumption for the healthy Chinese adult.”

Story Source:

Materials provided by BMJ. Note: Content may be edited for style and length.

Mice brain structure linked with sex-based differences in anxiety behavior — ScienceDaily

Using male individuals has long been a tradition in scientific mice studies. But new research enforces the importance of using a balanced population of male and female mice.

In a paper published May 22 in the journal Cell Reports, scientists studying the locus coeruleus brain structure in mice unexpectedly found substantial differences in the molecular structures of this part of the brain between male and female mice. They found that female mice had a three-fold higher abundance of the prostaglandin receptor EP3 (PTGER3), as well as elevated levels of Slc6a15 and Lin28b, both genes in regions associated with major depressive disorder (MDD).

“This is particularly interesting because many of the same diseases that are targeted by drugs that work on this structure, such as ADHD or depression, also really have differences in prevalence between men and women in the general population,” says senior author Joseph Dougherty of the Department of Genetics at Washington University School of Medicine in St. Louis.

Women are usually two to four times more likely to suffer from depression or anxiety, and ADHD is more commonly found in males. “We thought it really striking that there was this structure in the brain that is the target of these drugs that also has this very profound molecular-level difference between males and females,” he says.

The researchers initially set out to study gene expression in the mouse locus coeruleus, a small nucleus of neurons in the brain that is the primary source for the neurotransmitter norepinephrine. Norepinephrine is a major target of many drugs to treat disorders like ADHD and depression.

“We are the first to take a genome-wide view of all of the genes utilized in this small structure,” adds Dougherty. In this study, he and his team studied mouse noradrenergic neurons found in the locus coeruleus in vivo and identified over 3,000 transcripts it expressed.

Because Dougherty follows current practices mandated by the National Institutes of Health since 2016, his experiments included a balanced population of both male and female mice in the experiment. When they studied the gene expression of the mice, they unexpectedly found these differences in the transcriptome between the male and female mice in this part of the brain structure.

This finding prodded the researchers to test whether this molecular difference had any functional consequences. They next delivered sulprostone, a drug targeting PTGER3, to see if they could influence its activity. When both male and female mice received sulprostone directly to the locus coeruleus via cannula after a simulated stress event, only the females responded. “We could turn off a stress-induced anxiety like behavior, specifically in the female mice, but not in the males,” says Dougherty, who believes that this sex-based difference may help inform how to conduct experimentation around mood disorders and development of therapeutics.

Going forward, Dougherty plans on researching whether these molecular and functional differences in the locus coeruleus of mice are duplicated in the human brain.

Story Source:

Materials provided by Cell Press. Note: Content may be edited for style and length.

Researchers define for the first time the mechanisms responsible for the mammary gland development — ScienceDaily

Publication in Nature Cell Biology: researchers at the Université libre de Bruxelles, ULB define for the first time the mechanisms responsible for the mammary gland development.

The mammary gland is the tissue that produces the milk during lactation, allowing the survival of young mammalian offspring. The mammary gland is composed of two main lineages: the basal cells, which surround the inner luminal cells. The luminal cells can be subdivided into ductal cells, and alveolar cells that produce the milk. The basal cells allow the circulation of the milk from the alveoli to the nipple region through their contractile properties. During pubertal mammary gland expansion and adult life, distinct pools of unipotent stem cells replenish the basal and luminal lineages independently of each other’s. However, it remains unclear how mammary gland initially develops. Are embryonic mammary gland progenitors multipotent, meaning that their progenitors are capable of giving rise to both basal and luminal cells? If so, when does the switch from multipotency to unipotency occur? And what are the molecular mechanisms that regulate multipotency and basal and luminal lineage segregation?

In a new study published in Nature Cell Biology, research team led by Prof. Cédric Blanpain, MD/PhD, WELBIO investigator and Professor at the Université libre de Bruxelles, Belgium, identified the mechanisms that regulate mammary gland development. Using a combination of lineage tracing, molecular profiling, single cell sequencing and functional experiments, Aline Wuidart and colleagues demonstrated that mammary gland initially develops from multipotent progenitors during the early steps of embryonic mammary gland morphogenesis whereas postnatal mammary gland development is mediated by lineage-restricted stem cells.

To understand the molecular mechanisms regulating multipotency during embryonic development, the researchers developed a novel strategy to isolate embryonic mammary gland stem cells, and assessed for the first time their molecular features using single cell sequencing in collaboration with Thierry Voet group, KUL/Sanger Institute. Interestingly, only embryonic mammary gland progenitors and not adult cells, expressed a hybrid transcriptional signature comprising markers for both luminal and basal lineages, explaining their multipotent fate at this stage of embryonic development.

Breast cancer is the most common cancer among women. By analyzing the early steps of breast cancer formation, Alexandra Van Keymeulen and Cédric Blanpain previously demonstrated that the expression of one of the most frequently mutated genes in patients with breast cancers reactivates a multipotent program in adult unipotent stem cells. In this new study, the researchers show that embryonic mammary gland progenitors express the same genes than during the reactivation of multipotency associated with breast cancer development. “It was really interesting to see that many genes found to be specifically expressed by embryonic mammary gland progenitors are expressed in aggressive human breast cancers with poor prognosis, further suggesting that the reactivation of a gene expression program characteristic of embryonic mammary gland during tumorigenesis is essential for cancer growth and invasion.” Comments Cédric Blanpain, the senior author of this study.

In conclusion, this new study identifies multipotent embryonic stem cells of the mammary gland, uncovers the molecular features associated with embryonic multipotency and identifies the molecular mechanisms regulating the switch from multipotency to unipotency during mammary gland development. The paradigm uncovered in this study has important implications for the understanding of the development of other glandular organs and tissues such as the prostate that present similar developmental switch. Finally, the mechanisms uncovered here have also implications for cancer development and progression.

Story Source:

Materials provided by Université libre de Bruxelles. Note: Content may be edited for style and length.

New tech may make prosthetic hands easier for patients to use — ScienceDaily

Researchers have developed new technology for decoding neuromuscular signals to control powered, prosthetic wrists and hands. The work relies on computer models that closely mimic the behavior of the natural structures in the forearm, wrist and hand. The technology could also be used to develop new computer interface devices for applications such as gaming and computer-aided design (CAD).

The technology has worked well in early testing but has not yet entered clinical trials — making it years away from commercial availability. The work was led by researchers in the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill.

Current state-of-the-art prosthetics rely on machine learning to create a “pattern recognition” approach to prosthesis control. This approach requires users to “teach” the device to recognize specific patterns of muscle activity and translate them into commands — such as opening or closing a prosthetic hand.

“Pattern recognition control requires patients to go through a lengthy process of training their prosthesis,” says He (Helen) Huang, a professor in the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill. “This process can be both tedious and time-consuming.

“We wanted to focus on what we already know about the human body,” says Huang, who is senior author of a paper on the work. “This is not only more intuitive for users, it is also more reliable and practical.

“That’s because every time you change your posture, your neuromuscular signals for generating the same hand/wrist motion change. So relying solely on machine learning means teaching the device to do the same thing multiple times; once for each different posture, once for when you are sweaty versus when you are not, and so on. Our approach bypasses most of that.”

Instead, the researchers developed a user-generic, musculoskeletal model. The researchers placed electromyography sensors on the forearms of six able-bodied volunteers, tracking exactly which neuromuscular signals were sent when they performed various actions with their wrists and hands. This data was then used to create the generic model, which translated those neuromuscular signals into commands that manipulate a powered prosthetic.

“When someone loses a hand, their brain is networked as if the hand is still there,” Huang says. “So, if someone wants to pick up a glass of water, the brain still sends those signals to the forearm. We use sensors to pick up those signals and then convey that data to a computer, where it is fed into a virtual musculoskeletal model. The model takes the place of the muscles, joints and bones, calculating the movements that would take place if the hand and wrist were still whole. It then conveys that data to the prosthetic wrist and hand, which perform the relevant movements in a coordinated way and in real time — more closely resembling fluid, natural motion.

“By incorporating our knowledge of the biological processes behind generating movement, we were able to produce a novel neural interface for prosthetics that is generic to multiple users, including an amputee in this study, and is reliable across different arm postures,” Huang says.

And the researchers think the potential applications are not limited to prosthetic devices.

“This could be used to develop computer-interface devices for able-bodied people as well,” Huang says. “Such as devices for gameplay or for manipulating objects in CAD programs.”

In preliminary testing, both able-bodied and amputee volunteers were able to use the model-controlled interface to perform all of the required hand and wrist motions — despite having very little training.

“We’re currently seeking volunteers who have transradial amputations to help us with further testing of the model to perform activities of daily living,” Huang says. “We want to get additional feedback from users before moving ahead with clinical trials.

“To be clear, we are still years away from having this become commercially available for clinical use,” Huang stresses. “And it is difficult to predict potential cost, since our work is focused on the software, and the bulk of cost for amputees would be in the hardware that actually runs the program. However, the model is compatible with available prosthetic devices.”

The researchers are also exploring the idea of incorporating machine learning into the generic musculoskeletal model.

“Our model makes prosthetic use more intuitive and reliable, but machine learning could allow users to gain more nuanced control by allowing the program to learn each person’s daily needs and preferences and better adapt to a specific user in the long term,” Huang says.

Microwave/RF cable assemblies meet mil/aero qualifications

W. L. Gore & Associates, Inc. (Gore) has announced that the
GORE-FLIGHT Microwave Assemblies and GORE Microwave/RF Assemblies for
military/aerospace applications have passed U.S. Army flight qualifications on
the MH-47 Rotorcraft. Gore provided a complex harness that included more than
100 of its rugged assemblies for the ALQ-211 SIRFC, a critical aircraft
survivability system used by the 160th Special Operations Aviation Regiment
(SOAR).

0618_npIN_Gore

Gore also provided a similar microwave/RF solution for Aircraft
Survivability Equipment (ASE) on the MH-60 Rotorcraft that is expected to pass
U.S. Army flight qualifications in the next several months. The company also is
working with the U.S. Army to provide high-speed data interconnects for future
APR-39 D(V) 2 radar warning receivers on the Apache D model.

Gore
offers an extensive portfolio of advanced cables, cable assemblies, and
materials designed specifically for harsh military conditions. Products include
microwave/RF assemblies, high-data-rate cables, high-power delivery cables,
aircraft sealants, and shielding materials.