Good noise, bad noise: White noise improves hearing

Noise is not the same as noise — and even a quiet environment does not have the same effect as white noise. With a background of continuous white noise, hearing pure sounds becomes even more precise, as researchers from the University of Basel have shown in a study in Cell Reports. Their findings could be applied to the further development of cochlear implants.

Despite the importance of hearing in human communication, we still understand very little of how acoustic signals are perceived and how they are processed to allow us to make sense of them. One thing is clear though: the more precisely we can distinguish sound patterns, the better our hearing is. But how does the brain manage to distinguish between relevant and less relevant information — especially in an environment with background noise?

Exploring the “auditory brain”

Researchers led by Prof. Dr. Tania Rinaldi Barkat from the Department of Biomedicine at the University of Basel have investigated the neuronal foundation of sound perception and sound discrimination in a challenging sound environment. The focus was on research into the auditory cortex — the “auditory brain,” that is, the area of the brain that processes acoustic stimuli. The resulting activity patterns stem from measurements in a mouse brain.

As is well known, the distinction between sounds becomes more difficult the closer they are in the frequency spectrum. Initially, the researchers assumed that additional noise could make such a hearing task even more difficult. However, the opposite was observed: The team was able to demonstrate that the brain’s ability to distinguish subtle tone differences improved when white noise was added to the background. Compared to a quiet environment, the noise thus facilitated auditory perception.

Noise reduces neuronal activity

The data of the research group showed that white noise significantly inhibited the activity of the nerve cells in the auditory cortex. Paradoxically, this suppression of the neuronal excitation led to a more precise perception of the pure tones. “We found that less overlap occurred between populations of neurons during two separate tone representations,” explains Professor Tania Barkat. “As a result, the overall reduction in neuronal activity produced a more distinct tone representation.”

To confirm that the auditory cortex and not another area of the brain was responsible for the change in sound perception, the researchers used the light-controlled technique optogenetic. Their findings could possibly be used to improve auditory perception in situations where sounds are difficult to distinguish. According to Barkat, it is conceivable that cochlear implants could be stimulated with an effect similar to white noise in order to improve the frequency resolution and thus the hearing result of their users.

Measuring up: how does the UK compare internationally on cancer survival?

Our ambition is that 3 in 4 people will survive their cancer by 2034. And while cancer outcomes may differ from country to country, the goal of improving cancer survival is one that’s reflected across the world.

A good way for countries to monitor their progress in improving cancer care is by comparing how many people get cancer (incidence), how many survive (survival) and how many die from their cancer (mortality) to see how they measure up. If survival is higher, and incidence and mortality are lower, it’s clear that a country is on the right track.

“No one country manages cancer perfectly,” says John Butler, a consultant specialising in gynaecological cancer surgery. “ But international studies enable countries to learn lessons from one another to with the aim of improving their own cancer policies.”

And in the latest study, published in Lancet Oncology by the International Cancer Benchmarking Partnership, some promising trends have emerged. Survival has improved for the 7 cancer types studied in all countries between 1995 and 2014.

But the figures also underline how much progress still needs to be made in the UK to equal the best outcomes globally. With the exception of ovarian and oesophageal, the UK has the lowest survival figures for the cancers studied.

What do the latest figures show?

Big, international studies like this are a task for the International Cancer Benchmarking Partnership (ICBP). Led by clinicians, researchers and policymakers from around the world, the team compare trends in cancer survival, incidence and mortality rates across 7 countries with similar healthcare systems: UK, Australia, Canada, New Zealand, Denmark, Norway and Ireland. Something that’s never been done before.

Comparisons like this can be tricky – mainly because countries collect and record data in slightly different ways, something the ICBP is looking at in more detail. But despite the challenges, the latest figures from the ICBP are the best available and will only get better as more analysis is done.

The team has been collecting data from 7 cancer types – ovary, lung, colon, rectum, pancreas, oesophagus and stomach – since 1995.

And the latest figures, covering 1995 to 2014, reveal some stark differences in cancer survival between countries. Generally, cancer survival is higher in Australia, Canada and Norway than in Denmark, Ireland, New Zealand and the UK.

Similar trends can be seen for individual cancer types, like lung cancer. From the graphs we can see that Australia has the highest lung cancer survival, and Ireland has made the greatest increase in survival over time. But despite big improvements in lung cancer survival, the UK remains bottom of the list for this cancer type.

Why is the UK lagging behind?

There are many, complex reasons that could explain why we have lower survival compared to other countries.

Butler, the lead clinical advisor for ICBP, says there are some factors that will affect survival in all cancer types. “The UK health system is under great pressure, with increasing demands on cancer diagnostics and more urgent referrals”. And that could affect survival figures. Diagnosing and treating cancer early gives patients the best chance of surviving their cancer, but it relies on having enough NHS staff and funding in place to make this a reality – something the NHS doesn’t currently have.

But there are also more specific reasons that may explain differences between countries for some cancers.
Take ovarian cancer for example. Patients diagnosed in the UK appear to be diagnosed at similar stages to other countries, but survival is lower. This suggests there could be improvements in how these patients are treated.

And as Butler elaborated, this is amplified in older patients.

Older patients are more likely to have other health problems, which often make it more challenging to perform surgery or deliver chemotherapy. More is needed to be done to understand these patients’ complex needs and improve treatments for them, as we’ve blogged about before, as well as to understand why this is an issue particularly for the UK.

But when looking at survival as a whole, it’s useful to consider where we started. In 1995, the UK had some of the lowest survival estimates of the seven countries studied. This means that even though we have made improvements in certain cancers, we’re starting from a lower baseline. Which makes it that much harder for us to catch up with the countries who have higher survival.

And it’s where comparing our progress to other countries can help.

What can we learn from other countries?

Denmark was in a similar place to the UK with their survival in 1995. But as Jesper Fisker, chief executive officer of the Danish Cancer Society, told us “There’s been great progress in Danish cancer survival – which is the result of massive efforts and investments in the cancer field over the past 20 years”.

They’ve also made major strides towards centralising their cancer services, meaning cancer patients are treated in fewer, more specialised centres, with the best clinicians for their cancer type.

And it’s paid off – Denmark has seen real improvements in cancer survival – such as increasing their 1-year survival of lung cancer from 27.5% to 46.2% (from 1995-1999 to 2010-2014). The UK has made similar efforts to improve cancer services, with some success, but much more needs to be done.

And it’s not quite as straightforward as it sounds. While Denmark has made big improvements overall, this has not been universal for every cancer type. The same is true for all the countries studied and it’s something the ICBP is working to understand. They’re looking into variations in access people have to diagnostic tests, scans and treatment, as well as differences in healthcare systems that could help to explain the disparity.

Progress for the UK

On the bright side, the UK has made particularly good progress in increasing cancer survival in rectal, ovarian, and oesophageal cancers.

For example, from 1995 to 1999, 48 in 100 patients were estimated to survive their rectal cancer for at least 5 years. This has now increased to 62 in 100 patients for 2010-2014, only 8.7% behind Australia, who had the highest rectal cancer survival of the countries studied.

Butler called the progress “encouraging” and said there were lots of factors that could be behind the improvements. England produced its first national cancer plan in 2000 and appointed a national cancer director, who helps provide advice and leadership for our cancer services. Since then there’s been more guidance and greater scrutiny of how cancer services are performing, as well as more funding.

There’s also been a move towards cancers being treated in specialised centres, where there will be more relevant cancer expertise.

How can the UK catch up?

But despite the improvements, there’s clearly more work to be done in the UK.

For Butler, investigations into how well cancer services are performing could be a good way to start. For example, national audits in the UK for lung cancer have increased the number of people having surgery, as well as the number of specialised lung cancer surgeons. Replicating this approach could help the NHS direct its efforts to improve outcomes for other types of cancer.

And while the UK government have introduced a range of policies between 1995 and 2014 to improve cancer services and speed up diagnosis and treatment, these have added to the strain on NHS services.

It’s crucial that investment into cancer services is increased to match the ever-growing demand. As Butler told us, “one of the biggest challenges the UK faces is capacity of diagnostic services.”

Trump signs order aimed at development of better flu vaccines

Reporting By Deena Beasley; Editing by Sonya Hepinstall

(Reuters) – U.S. President Donald Trump on Thursday signed an executive order aimed at spurring the development of better vaccines to protect against seasonal influenza as well as a potential pandemic flu outbreak.

The order does not allocate additional funding for now, but calls for an evaluation of current flu vaccine manufacturing abilities and a task force report including cost estimates, administration officials said on a call with reporters.
Each year the seasonal flu, which can kill tens of thousands of Americans, costs the United States about $50 billion, including lost productivity, one administration official said. A serious flu pandemic would push those costs to between $1.8 billion and $3.8 billion, he said.

Manufacturers such as GlaxoSmithKline Plc and Sanofi SA make millions of doses of flu vaccine for the U.S. market alone, growing the virus in chicken eggs. Usually the doses, which protect against strains that experts predicted the previous February, are ready in time and in sufficient quantity for the winter flu season.
But if the strain that appears during flu season was not the one experts forecast, the vaccines might not work. The appearance of H1N1 swine flu in 2009-2010 took experts by surprise, and the flu was already on its second wave before a vaccine was ready; an estimated 61 million people in the U.S. got swine flu and thousands died.

The Department of Health and Human Services will coordinate government efforts to modernize influenza vaccine production. The focus will be on recombinant technologies to quickly produce reliable vaccines as well as “universal” vaccines that would elicit immunity against parts of the virus that do not change from year to year.

NHS to fund ‘life changing’ haemophilia drug

Mark Gould

Thursday, 22 August 2019

NHS England is to fund what it says will be “life changing treatment” for around 2,000 people with severe Haemophilia A, which will dramatically cut their risk of life-threatening bleeds and reduce treatment time.

The new treatment is part of a package of measures set out in the NHS Long Term Plan which will save lives through access to the most advanced medical interventions.

A new drug – emicizumab (also referred to as Hemlibra®) – mimics the action of the blood protein factor VIII to avoid uncontrolled bleeding, while cutting treatment times from multiple time-consuming infusions every week to a single injection given once-a-week or fortnight.

Many young children are affected by the condition and NHS England says parents sometimes struggle to administer the current infusion several times a month.

Simon Stevens, NHS chief executive, said: “Giving patients access to world class, trailblazing drugs and therapies is a key part of the NHS Long Term Plan which aims to save thousands more lives.

“As a parent I know that cuts and scrapes happen to kids all the time, but for many families these routine accidents can be distressing and life-threatening, so this new treatment will change lives and lift a weight from thousands of parents.

“This treatment has the potential to significantly improve the lives of people with haemophilia, especially children – reducing treatment time and even ending the dangerous bleeds which can lead to life-threatening cuts and life-changing damage.”

Liz Carroll, chief executive of The Haemophilia Society, said: “This decision is fantastic news for our community. Current treatments can require intravenous infusions multiple times a week which can place a significant burden on people with haemophilia and their carers. This decision will mean that people will have the opportunity to have treatment less frequently without intravenous access which will enable many to live their lives more freely.’’

Gene mutation evolved to cope with modern high-sugar diets

The gene variant became more common in humans after cooking and farming became widespread, and might now help people avoid diabetes, according to the findings published in eLife.

“We found that people differ in how efficiently their bodies can manage blood sugar levels, resulting from an evolutionary process that seems to have been brought about by changing diets,” said the study’s lead author, Professor Frances Brodsky, Director of UCL Biosciences.

The researchers were investigating the CLTCL1 gene, which directs production of the CHC22 protein that plays a key role in regulating a glucose transporter in our fat and muscle cells.

After people eat, the hormone insulin reacts to higher levels of blood glucose by releasing the transporter to remove glucose from the blood, taking it into muscle and fat tissue. Between meals, with the help of the CHC22 protein, the glucose transporter remains inside muscle and fat so that some blood sugar will continue to circulate.

The research team, consisting of specialists in population genetics, evolutionary biology, ancient DNA and cell biology, analysed human genomes as well as those of 61 other species, to understand how the gene producing CHC22 has varied throughout evolutionary history.

In humans, by looking at the genomes of 2,504 people from the global 1000 Genomes Project, they found that almost half of the people in many ethnic groups have a variant of CHC22 that is produced by a mutated gene, which became more common as people developed cooking and farming.

The researchers also looked at genomes of ancient humans, and found that the newer variant is more common in ancient and modern farming populations than in hunter-gatherers, suggesting that increased consumption of carbohydrates could have been the selective force driving the genetic adaptation.

By studying cells, the researchers found that the newer CHC22 variant is less effective at keeping the glucose transporter inside muscle and fat between meals, meaning the transporter can more readily clear glucose out of the blood. People with the newer variant will therefore have lower blood sugar.

“The older version of this genetic variant likely would have been helpful to our ancestors as it would have helped maintain higher levels of blood sugar during periods of fasting, in times when we didn’t have such easy access to carbohydrates, and this would have helped us evolve our large brains,” said first author Dr Matteo Fumagalli, who began the study at UCL before moving to Imperial College London.

“In more recent years, with our high-carb diets that often provide us too much sugar, the newer variant may be advantageous,” Dr Fumagalli added.

The researchers say that while this genetic variant does not play a direct role in the development of diabetes, having the older variant may make people more likely to develop diabetes, and it may also exacerbate insulin resistance involved in diabetes.

“People with the older variant may need to be more careful of their carb intake, but more research is needed to understand how the genetic variant we found can impact our physiology,” added Professor Brodsky.

Co-author Professor Mark Thomas (UCL Genetics, Evolution & Environment) added: “Our analyses strongly suggest that we have found yet another example of how prehistoric changes in dietary habits have shaped human evolution. Understanding how we have adapted to these changes doesn’t only inform us about why people lived or died in the past, but also helps us to better understand the relationship between diet, health and disease today.”

The study was funded by the National Institutes of Health (USA), Wellcome and the Medical Research Council (UK).

Genetic therapy heals damage caused by heart attack

Researchers from King’s College London have found that therapy that can induce heart cells to regenerate after a heart attack.

Myocardial infarction, more commonly known as a heart attack, caused by the sudden blocking of one of the cardiac coronary arteries, is the main cause of heart failure, a condition that now affects over 23 million population in the world, according to the World Health Organisation.

At present, when a patient survives a heart attack, they are left with permanent structural damage to their heart through the formation of a scar, which can lead to heart failure in the future. In contrast to fish and salamander, which can regenerate the heart throughout life.

In this study, published today in Nature, the team of investigators delivered a small piece of genetic material, called microRNA-199, to the heart of pigs, after a myocardial infarction which resulted in the almost complete recovery of cardiac function at one month later.

Lead author Professor Mauro Giacca, from King’s College London said: “It is a very exciting moment for the field. After so many unsuccessful attempts at regenerating the heart using stem cells, which all have failed so far, for the first time we see real cardiac repair in a large animal.”

This is the first demonstration that cardiac regeneration can be achieved by administering an effective genetic drug that stimulates cardiac regeneration in a large animal, with heart anatomy and physiology like that of humans.

“It will take some time before we can proceed to clinical trials” explained Professor Giacca.

“We still need to learn how to administer the RNA as a synthetic molecule in large animals and then in patients, but we already know this works well in mice.”

New microscopy technique peers deep into the brain

In order to understand the brain, scientists must be able to see the brain — cell by cell, and moment by moment. However, because brains comprise billions of microscopic moving parts, faithfully recording their activity comes with many challenges. In dense mammalian brains, for example, it is difficult to track rapid cellular changes across multiple brain structures — particularly when those structures are located deep within the brain.

A novel microscopy technique, developed by Rockefeller scientists, integrates new and existing approaches to help build a more cohesive picture of the brain. Described in Cell, the technology captures cellular activity across large volumes of neural tissue, with impressive speed and at new depths.

Laser focused

For decades, brain imaging has been plagued by trade-offs. Some techniques produce beautiful images but fail to record neural activity in real time. Others can keep up with the brain’s speed but have poor spatial resolution. And although there are tactics that successfully combine rapidity and image quality, they typically capture only a small number of cells.

“This is in part because the limits that govern these tradeoffs have not been explored or pushed in a systematic and integrated manner,” says Alipasha Vaziri, head of the Laboratory of Neurotechnology and Biophysics.

Hoping to end the era of trade-offs, Vaziri recently endeavored to improve upon a technique known as two-photon (2p) microscopy. It involves the application of a laser that causes bits of brain tissue to fluoresce, or light up; and for many researchers, 2p has long been the gold standard for probing cellular activity in the brain.

Yet, this technique has limitations. Standard 2p microscopy requires point-by-point scanning of a given region, which results in slow imaging. To resolve this issue, Vaziri and his colleagues implemented a novel strategy that permits recording from multiple brain regions in parallel, while carefully controlling the size and shape of each spot recorded.

Another weakness of traditional 2p is that it measures only the surface, or cortex, of the brain, neglecting structures buried deep within the organ, such as the hippocampus, which is involved in storing memories.

“One of the biggest challenges in neuroscience is developing imaging techniques that measure the activity of deep brain regions while maintaining high resolution,” says Vaziri.

Taking up this challenge, he decided to make use of a newer technology: three-photon (3p) microscopy. Whereas 2P doesn’t reach beyond the surface, or cortex, of a mouse brain, 3p penetrates deeper regions. Called hybrid multiplexed sculpted light microscopy, or HyMS, Vaziri’s latest innovation applies 2P and 3P concurrently, allowing researchers to generate a picture of rapid cellular activity across multiple layers of brain tissue.

Deep dive

In addition to its hybrid laser strategy, HyMS also integrates other recent technical and conceptual advancements in the field — a synergistic approach that, Vaziri says, guided the development of the technology. The goal, he says, was to maximize the amount of biological information that could be obtained through multi-photon excitation microscopy while minimizing the heat produced by this method. And when testing their new system, the scientists certainly obtained a lot of information.

HyMS boasts the highest frame rate of available 3p techniques, which means it can capture biological changes at record speed. And whereas previous techniques scanned only a single plane of tissue, this technology can obtain information from the entire tissue sample and allows users to record from as many as 12,000 neurons at once. Another advantage of HyMS is its ability to simultaneously measure activity from brain areas at different depths. Since different layers of the brain constantly exchange signals, says Vaziri, tracking the interplay between these regions is key to understanding how the organ functions.

“Before, people hadn’t even been able to look at the activity of neurons over the entire depth of the cortex, which has multiple layers, all at the same time,” he says. “With this technology you can actually see what the information flow looks like within the cortex, and between cortical and subcortical structures.”

In addition to probing new depths, HyMS allows researchers to record brain activity from animals as they actively engage with their environment. In a recent experiment, for example, the researchers used the technology to record signals from thousands of mouse neurons as an animal walked on a treadmill or listened to sounds. The fact that they were able to obtain good recordings suggests that the technique may be used to monitor large cell populations as animals perform diverse tasks — an application that could help elucidate neural mechanisms underlying various aspects of behavior and cognition.

Further, says Vaziri, techniques like HyMS will be vital to researchers hoping to better understand how brains process information. Neurons in the brain are densely interconnected and information is often represented not by individual cells, but by states of the network.

“To understand the dynamics of a network,” he says, “you need to get accurate measurements of big portions of the brain at a single-neuron level. That’s what we’ve done here.”

New pill can deliver insulin through the stomach

An MIT-led research team has developed a drug capsule that could be used to deliver oral doses of insulin, potentially replacing the injections that people with type 1 diabetes have to give themselves every day.

About the size of a blueberry, the capsule contains a small needle made of compressed insulin, which is injected after the capsule reaches the stomach. In tests in animals, the researchers showed that they could deliver enough insulin to lower blood sugar to levels comparable to those produced by injections given through skin. They also demonstrated that the device can be adapted to deliver other protein drugs.

“We are really hopeful that this new type of capsule could someday help diabetic patients and perhaps anyone who requires therapies that can now only be given by injection or infusion,” says Robert Langer, the David H. Koch Institute Professor, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, and a visiting scientist in MIT’s Department of Mechanical Engineering, where he is starting as a faculty member in 2019, is also a senior author of the study. The first author of the paper, which appears in the Feb. 7 issue of Science, is MIT graduate student Alex Abramson. The research team also includes scientists from the pharmaceutical company Novo Nordisk.

Self-orientation

Several years ago, Traverso, Langer, and their colleagues developed a pill coated with many tiny needles that could be used to inject drugs into the lining of the stomach or the small intestine. For the new capsule, the researchers changed the design to have just one needle, allowing them to avoid injecting drugs into the interior of the stomach, where they would be broken down by stomach acids before having any effect.

The tip of the needle is made of nearly 100 percent compressed, freeze-dried insulin, using the same process used to form tablets of medicine. The shaft of the needle, which does not enter the stomach wall, is made from another biodegradable material.

Within the capsule, the needle is attached to a compressed spring that is held in place by a disk made of sugar. When the capsule is swallowed, water in the stomach dissolves the sugar disk, releasing the spring and injecting the needle into the stomach wall.

The stomach wall has no pain receptors, so the researchers believe that patients would not be able to feel the injection. To ensure that the drug is injected into the stomach wall, the researchers designed their system so that no matter how the capsule lands in the stomach, it can orient itself so the needle is in contact with the lining of the stomach.

“As soon as you take it, you want the system to self-right so that you can ensure contact with the tissue,” Traverso says.

The researchers drew their inspiration for the self-orientation feature from a tortoise known as the leopard tortoise. This tortoise, which is found in Africa, has a shell with a high, steep dome, allowing it to right itself if it rolls onto its back. The researchers used computer modeling to come up with a variant of this shape for their capsule, which allows it to reorient itself even in the dynamic environment of the stomach.

“What’s important is that we have the needle in contact with the tissue when it is injected,” Abramson says. “Also, if a person were to move around or the stomach were to growl, the device would not move from its preferred orientation.”

Once the tip of the needle is injected into the stomach wall, the insulin dissolves at a rate that can be controlled by the researchers as the capsule is prepared. In this study, it took about an hour for all of the insulin to be fully released into the bloodstream.

Easier for patients

In tests in pigs, the researchers showed that they could successfully deliver up to 300 micrograms of insulin. More recently, they have been able to increase the dose to 5 milligrams, which is comparable to the amount that a patient with type 1 diabetes would need to inject.

After the capsule releases its contents, it can pass harmlessly through the digestive system. The researchers found no adverse effects from the capsule, which is made from biodegradable polymer and stainless steel components.

Maria José Alonso, a professor of biopharmaceutics and pharmaceutical technology at the University of Santiago de Compostela in Spain, describes the new capsule as a “radically new technology” that could benefit many patients.

“We are not talking about incremental improvements in insulin absorption, which is what most researchers in the field have done so far. This is by far the most realistic and impactful breakthrough technology disclosed until now for oral peptide delivery,” says Alonso, who was not involved in the research.

The MIT team is now continuing to work with Novo Nordisk to further develop the technology and optimize the manufacturing process for the capsules. They believe this type of drug delivery could be useful for any protein drug that normally has to be injected, such as immunosuppressants used to treat rheumatoid arthritis or inflammatory bowel disease. It may also work for nucleic acids such as DNA and RNA.

“Our motivation is to make it easier for patients to take medication, particularly medications that require an injection,” Traverso says. “The classic one is insulin, but there are many others.”

The research was funded by Novo Nordisk, the National Institutes of Health, a National Science Foundation Graduate Research Fellowship, Brigham and Women’s Hospital, a Viking Olaf Bjork Research Scholarship, and the MIT Undergraduate Research Opportunities Program.

Other authors of the paper include Ester Caffarel-Salvador, Minsoo Khang, David Dellal, David Silverstein, Yuan Gao, Morten Revsgaard Frederiksen, Andreas Vegge, Frantisek Hubalek, Jorrit Water, Anders Friderichsen, Johannes Fels, Rikke Kaae Kirk, Cody Cleveland, Joy Collins, Siddartha Tamang, Alison Hayward, Tomas Landh, Stephen Buckley, Niclas Roxhed, and Ulrik Rahbek.

Scientists discover how neuroactive steroids dampen inflammatory signaling in cells

For the first time, scientists discovered how neuroactive steroids naturally found in the brain and bloodstream inhibit the activity of a specific kind of protein called Toll-like receptors (TLR4), which have been known to play a role in inflammation in many organs, including the brain.

This UNC School of Medicine-University of Maryland collaboration, published in Nature Scientific Reports, shows how the neurosteroid allopregnanolone prevents the activation of pro-inflammatory proteins important for gene regulation, as well as the creation of cytokines, which are known to be involved in many different inflammatory conditions. Inflammatory cell signaling in the brain is heightened in many neuropsychiatric conditions, including alcohol use disorder, depression, and posttraumatic stress. It is also seen in sepsis, epilepsy, multiple sclerosis, and Alzheimer’s disease.

“It has been very difficult to treat brain disease that involves inflammation, but allopregnanolone’s inhibition of TLR4 signaling activation in macrophages and the brain provides hope that we can develop better therapies to help millions of people suffering with these conditions,” said senior author A. Leslie Morrow, PhD, the John Andrews Distinguished Professor in the Departments of Psychiatry and Pharmacology at the UNC School of Medicine.

Neuroactive steroids, which are naturally occurring steroids in the brain and elsewhere in the body, have many functions critical for life and health. These steroids decline with aging and are deficient in many neuropsychiatric conditions, such as depression. Morrow and her colleagues have proposed that treatment with these compounds may prevent uncontrolled TLR4 signaling in conditions where this signaling contributes to disease.

Recent studies showed that the neurosteroid compounds pregnenolone and allopregnanolone have therapeutic effects in depression, schizophrenia and PTSD. But until now, scientists didn’t understand how. The UNC-Maryland study suggests that inhibition of inflammatory signaling may contribute to these effects, and inhibition of TLR4 signaling may be a new target for these conditions.

In collaboration with Laure Aurelian, PhD, at the University of Maryland, Morrow and colleagues found that allopregnanolone inhibits TLR4 activation in macrophages, which are found in white blood cells and part of the immune system, including in the brain. In particular, the researchers found that allopregnanolone prevents TLR4 binding to MD2 proteins that work together to produce transcription factors that regulate the genes responsible for inflammatory responses in cells and tissues. Allopregnanolone also tamps down chemokines and cytokines, such as NFkB, HMGB1, MCP-1 and TNF-a, all of which are part of the immune system and involved in many different inflammatory diseases.

Morrow and colleagues found that pregnenolone also inhibited TLR4 signaling in macrophage cells. “Pregnenolone’s effects in the brain were less pronounced,” Morrow said. “But inhibition of peripheral inflammation protects the brain as well because systemic inflammation affects organs throughout the body indirectly.”

Now that scientists have identified this inhibitory mechanism that dampens inflammatory signals responsible for brain inflammation, researchers can create new compounds to fill this particular role of neurosteroids without unwanted side effects. In addition, researchers can now plan clinical studies to determine the best doses, formulations, and modes of administration for different conditions.

David Rubinow, MD, chair of the department of psychiatry at UNC-Chapel Hill, who was not involved in the study, said, “This great example of collaborative and translational research provides physiologic insights with great potential for spawning new, more effective primary and adjunctive treatments for the many individuals suffering from brain disorders characterized by so-called neuroinflammation.”

Scientists design ‘smart’ wound healing technique

New research, published in the journal Advanced Materials, paves the way for “a new generation of materials that actively work with tissues to drive [wound] healing.”

As more and more surgical procedures are performed in the United States, the number of surgical site infections is also on the rise.

Chronic wounds that do not heal — such as those that occur in diabetes — often host a wide range of bacteria in the form of a biofilm.

Such biofilm bacteria are often very resilient to treatment, and antimicrobial resistance only increases the possibility that these wounds become infected.

According to recent estimates, chronic wounds affect approximately 5.7 million people in the U.S. Some chronic wounds can result in amputations, as is the case with diabetic ulcers.

On a global level, researchers approximate that every 30 seconds a chronic, nonhealing diabetic ulcer causes an amputation.

In this context, there is a dire need for innovative, effective wound healing methods. New research shows promise in this regard, as scientists have devised a molecule that helps harness the body’s natural healing powers.

The molecules are called traction force-activated payloads (TrAPs). They are growth factors that help materials such as collagen interact with the body’s tissues more naturally.

Ben Almquist, Ph.D., a lecturer in the department of engineering at Imperial College London in the United Kingdom, led the new research.

TrAP technology and wound healing

Materials such as collagen are often used in wound healing. For instance, collagen sponges can treat burn injuries, and collagen implants can help bones regenerate.

But how does collagen interact with tissue? In so-called scaffold implants, cells move through the collagen structure, pulling the scaffold along with them. This triggers healing proteins, such as growth factors, that help the tissue regenerate.

In the new study, Almquist and the team engineered TrAP molecules to recreate this natural process. The scientists “folded” DNA strands into aptamers, which are three-dimensional shapes that bind to proteins.

Then, they designed a “handle” for cells to grip. They attached cells to one end of the handle and a collagen scaffold to the other end.

Lab tests revealed that the cells dragged the TrAPs along as they moved through the collagen implants. In turn, this activated growth proteins that triggered the healing process within the tissue.

The scientists explain that this technique recreates healing processes that exist throughout the natural world. “Using cell movement to activate healing is found in creatures ranging from sea sponges to humans,” says Almquist.

“Our approach mimics them and actively works with the different varieties of cells that arrive in our damaged tissue over time to promote healing,” he adds.

A ‘new generation’ of healing materials

The research also revealed that tweaking the cellular handle changes the type of cells that can attach and hold on to the TrAPs.

In turn, this enables TrAPs to release personalized regenerative proteins based on the cells that have attached to the handle.

This adaptability to different types of cells means that the technique can be applied to various types of wounds — ranging from bone fractures to scar tissue injuries caused by heart attacks and from nerve damage to diabetic ulcers.

Finally, aptamers are already approved as drugs for human clinical use, which could mean that the TrAP technique may become widely available sooner rather than later.

“The TrAP technology provides a flexible method to create materials that actively communicate with the wound and provide key instructions when and where they are needed,” explains Almquist.

“This sort of intelligent, dynamic healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds,” he adds.

The researcher concludes, “[t]his technology has the potential to serve as a conductor of wound repair, orchestrating different cells over time to work together to heal damaged tissues.”