Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.
“Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, ‘Hey, I’m under attack, you better protect yourself,'” says Gerald Shadel, a professor in Salk’s Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.
Most of the DNA that a cell needs to function is found inside the cell’s nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds — or even thousands — of mitochondria.
Shadel’s lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus — by releasing it from mitochondria and launching an immune response that beefs up the cell’s defenses.
In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell’s interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.
To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage — and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell’s DNA.
“Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress,” says Shadel.
Most of the time, he points out, it’s probably a good thing that the mtDNA is more prone to damage — it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin — by damaging mtDNA first and setting off molecular alarm bells — can be less effective at damaging the nuclear DNA of cancer cells.
“It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance,” Shadel says.
His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell’s nucleus to ward off damage.
Scientists have developed a new gene-therapy technique by transforming human cells into mass producers of tiny nano-sized particles full of genetic material that has the potential to reverse disease processes.
Though the research was intended as a proof of concept, the experimental therapy slowed tumor growth and prolonged survival in mice with gliomas, which constitute about 80 percent of malignant brain tumors in humans.
The technique takes advantage of exosomes, fluid-filled sacs that cells release as a way to communicate with other cells.
While exosomes are gaining ground as biologically friendly carriers of therapeutic materials — because there are a lot of them and they don’t prompt an immune response — the trick with gene therapy is finding a way to fit those comparatively large genetic instructions inside their tiny bodies on a scale that will have a therapeutic effect.
This new method relies on patented technology that prompts donated human cells such as adult stem cells to spit out millions of exosomes that, after being collected and purified, function as nanocarriers containing a drug. When they are injected into the bloodstream, they know exactly where in the body to find their target — even if it’s in the brain.
“Think of them like Christmas gifts: The gift is inside a wrapped container that is postage paid and ready to go,” said senior study author L. James Lee, professor emeritus of chemical and biomolecular engineering at The Ohio State University.
And they are gifts that keep on giving, Lee noted: “This is a Mother Nature-induced therapeutic nanoparticle.”
The study is published today (Dec. 16) in the journal Nature Biomedical Engineering.
In 2017, Lee and colleagues made waves with news of a regenerative medicine discovery called tissue nanotransfection (TNT). The technique uses a nanotechnology-based chip to deliver biological cargo directly into skin, an action that converts adult cells into any cell type of interest for treatment within a patient’s own body.
By looking further into the mechanism behind TNT’s success, scientists in Lee’s lab discovered that exosomes were the secret to delivering regenerative goods to tissue far below the skin’s surface.
The technology was adapted in this study into a technique first author Zhaogang Yang, a former Ohio State postdoctoral researcher now at the University of Texas Southwestern Medical Center, termed cellular nanoporation.
The scientists placed about 1 million donated cells (such as mesenchymal cells collected from human fat) on a nano-engineered silicon wafer and used an electrical stimulus to inject synthetic DNA into the donor cells. As a result of this DNA force-feeding, as Lee described it, the cells need to eject unwanted material as part of DNA transcribed messenger RNA and repair holes that have been poked in their membranes.
“They kill two birds with one stone: They fix the leakage to the cell membrane and dump the garbage out,” Lee said. “The garbage bag they throw out is the exosome. What’s expelled from the cell is our drug.”
The electrical stimulation had a bonus effect of a thousand-fold increase of therapeutic genes in a large number of exosomes released by the cells, a sign that the technology is scalable to produce enough nanoparticles for use in humans.
Essential to any gene therapy, of course, is knowing what genes need to be delivered to fix a medical problem. For this work, the researchers chose to test the results on glioma brain tumors by delivering a gene called PTEN, a cancer-suppressor gene. Mutations of PTEN that turn off that suppression role can allow cancer cells to grow unchecked.
For Lee, founder of Ohio State’s Center for Affordable Nanoengineering of Polymeric Biomedical Devices, producing the gene is the easy part. The synthetic DNA force-fed to donor cells is copied into a new molecule consisting of messenger RNA, which contains the instructions needed to produce a specific protein. Each exosome bubble containing messenger RNA is transformed into a nanoparticle ready for transport, with no blood-brain barrier to worry about.
“The advantage of this is there is no toxicity, nothing to provoke an immune response,” said Lee, also a member of Ohio State’s Comprehensive Cancer Center. “Exosomes go almost everywhere in the body, including passing the blood-brain barrier. Most drugs can’t go to the brain.
“We don’t want the exosomes to go to the wrong place. They’re programmed not only to kill cancer cells, but to know where to go to find the cancer cells. You don’t want to kill the good guys.”
The testing in mice showed the labeled exosomes were far more likely to travel to the brain tumors and slow their growth compared to substances used as controls.
Because of exosomes’ safe access to the brain, Lee said, this drug-delivery system has promise for future applications in neurological diseases such as Alzheimer’s and Parkinson’s disease.
“Hopefully, one day this can be used for medical needs,” Lee said. “We’ve provided the method. If somebody knows what kind of gene combination can cure a certain disease but they need a therapy, here it is.”
Autoimmune diseases are a medical conundrum. In people with these conditions, the immune system of the body, the designated defense system, starts attacking the cells or organs of its own body, mistaking the self-cells for invading disease-causing cells. Often, the cause for this spontaneous dysfunction is not clear, and hence, treatment of these diseases presents a major and ongoing challenge.
One recently discovered autoimmune disease is the IgG4-related disease (or IgG4-RD), which involves the infiltration of plasma cells that are specific to the immunoglobulin (antibody) IgG4 into the body tissue, resulting in irreversible tissue damage in multiple organs. In most patients with IgG4-RD, the blood levels of IgG4 also tend to be higher than those in healthy individuals. Previous studies show that T cells — which are white blood cells charged with duties of the immune response — play a key role in the disease mechanism. In particular, special T cells called cytotoxic T lymphocytes, or CTLs, were found in abundance from the inflamed or affected pancreas of patients, along with IgG4. But what was the exact role of CTLs?
In a new study published in International Immunology, a team of scientists from Tokyo University of Science decided to find the answer to this question. Prof. Masato Kubo, a member of this team, states that their aim was twofold. “We planned to explore how IgG4 Abs contributes to the CTL-mediated pancreas tissue damage in IgG4-RD, and also to evaluate the pathogenic function of human IgG4 Abs using the mouse model that we have established.” The latter is especially important, as IgG4 is not naturally present in mice, meaning that there is a severe lack of adequate animal models to explore this disease.
With these aims, they selected mice that have been genetically programmed to express a protein called ovalbumin (the major protein in egg white) in their pancreas. Then, they injected IgG4 that specifically targets ovalbumin into the mice. Their assumption was that IgG4 would target the pancreas and bring about IgG-4-RD-like symptoms. However, what they found was surprising. No inflammation or any other symptom typical of IgG4-RD appeared. This convinced the researchers that IgG4 alone was not the causative factor of IgG4-RD.
Next, to check if it was the CTLs that were perhaps the villain of the story, the scientists injected both IgG4 specific against ovalbumin as well as CTLs. Now, the pancreas of the mice showed tissue damage and inflammation. Thus, it was established that the presence of CTLs and IgG4 was necessary for pancreatic inflammation.
When they probed further, they found that another variation of T cells, known as T follicular helper or “TFH cells,” which develop from the natural T cells of the mice, produce self-reactive antibodies like IgG4, which induce inflammation in combination with CTLs.
Once the puzzle was pieced together, the scientists now had the opportunity to zero in on the target step for intervention; after all, if one of these steps is disrupted, the inflammation can be prevented. After much deliberation, they propose that Janus kinase, or JAK, can be a suitable target. JAK is a key component of the JAK-STAT cellular signaling pathway, and this pathway is an integral step in the conversion of natural T cells of the mice to TFH cells. If this JAK is inhibited, this conversion will not take place, meaning that even the presence of CTLs will not be able to induce inflammation.
Prof. Kubo also suggests a broader outlook, not limited to the therapeutic option explored in the study. He states, “based on our findings, the therapeutic targets for IgG4-related diseases can be the reduction of TFH cell responses and the auto-antigen specific CTL responses. These can also provide the fundamental basis for developing new therapeutic applications.”
These proposed therapeutic targets need further exploration, but once developed, they have the potential to improve the lives of millions of patients with IgG4-RD worldwide.
Wearable sensors that track heart rate or steps are popular fitness products. But in the future, working up a good sweat could provide useful information about a person’s health. Now, researchers reporting in ACS Applied Materials & Interfaces have developed a headband that measures electrolyte levels in sweat. And unlike many previous sweat sensors, the device can heal itself when cut or scratched during exercise. Watch a video of the sensor in action here.
Human sweat contains biochemical markers, such as metabolites, electrolytes and heavy metals, that can indicate a person’s health and even help diagnose some diseases. In recent years, scientists have developed sweat sensors in the form of patches, bandages and tattoos, but their performance can be impaired by natural movements such as walking, running, jumping or throwing. Also, if the sensors become scratched or broken, which can easily happen during exercise, they often cannot be repaired. Sung Yeon Hwang, Jeyoung Park, Bong Gill Choi and colleagues wanted to develop a wearable sweat sensor that could withstand vigorous exercise and quickly repair itself if damaged.
To make their self-healing sensor, the researchers coated carbon fiber thread electrodes with a citric acid-based polymer. When cut, the threads quickly rejoined through hydrogen bonding of the polymer. They sewed the threads, which could detect potassium and sodium ions, into a headband and added a wireless electronic circuit board that could transfer data to a smart phone. A human volunteer wore the headband while exercising on a stationary bike, and the sensor accurately tracked the electrolyte concentrations in their sweat over 50 minutes of exercise. During cycling, the researchers cut the sensor threads with scissors, and the threads healed and returned to normal operation in only 20 seconds.
Saccharin received a bad rap after studies in the 1970s linked consumption of large amounts of the artificial sweetener to bladder cancer in laboratory rats. Later, research revealed that these findings were not relevant to people. And in a complete turnabout, recent studies indicate that saccharin can actually kill human cancer cells. Now, researchers reporting in ACS’ Journal of Medicinal Chemistry have made artificial sweetener derivatives that show improved activity against two tumor-associated enzymes.
Saccharin, the oldest artificial sweetener, is 450 times sweeter than sugar. Recently, scientists showed that the substance binds to and inhibits an enzyme called carbonic anhydrase (CA) IX, which helps cancer cells survive in the acidic, oxygen-poor microenvironments of many tumors. In contrast, healthy cells make different — but very similar — versions of this enzyme called CA I and II. Saccharine and another artificial sweetener called acesulfame K can selectively bind to CA IX over CA I and II, making them possible anti-cancer drugs with minimal side effects. Alessio Nocentini, Claudiu Supuran and colleagues wondered whether they could make versions of the artificial sweeteners that show even more potent and selective inhibition of CA IX and another tumor-associated enzyme, CA XII.
The team designed and synthesized a series of 20 compounds that combined the structures of saccharin and acesulfame K and also added various chemical groups at specific locations. Some of these compounds showed greater potency and selectivity toward CA IX and XII than the original sweeteners. In addition, some killed lung, prostate or colon cancer cells grown in the lab but were not harmful to normal cells. These findings indicate that the widely used artificial sweeteners could be promising leads for the development of new anticancer drugs, the researchers say.
In the wake of recent disappointments over clinical trials targeting amyloid plaque build-up in Alzheimer’s disease, researchers are focusing more attention on misfolded tau protein, another culprit in brain diseases that cause dementia.
New research published in Science Translational Medicine finds that targeting abnormal tau through the suppression of a gene called MSUT2 (mammalian suppressor of tauopathy 2) shows promise.
Tau, like amyloid protein, is another substance that builds up in Alzheimer’s disease and damages brain cells.
However, clinical trials targeting tau have been far less numerous in part because tau-targeted drugs have been hard to find.
In this study, researchers concluded that suppressing MSUT2 might protect people from Alzheimer’s disease as long as the RNA binding protein PolyA Binding Protein Nuclear 1 (PABPN1) is not depleted. MSUT2 and PABPNI normally work together closely to regulate the biology of tau in the brain.
“If you inhibit MSUT2 and don’t affect PABN1, that protects against the effects of tau pathology,” said senior author Brian Kraemer, a research associate professor of medicine, Division of Gerontology and Geriatric Medicine at the University of Washington School of Medicine. He is also a scientist at the Veterans Affairs Puget Sound Health Care System.
Kraemer said his team sees their role as the person kicking the ball down field to provide other researchers and drug companies an opportunity to move the ball towards the ultimate goal: A treatment or cure for Alzheimer’s disease.
“Pharmaceutical companies have heavily invested in going after amyloid but so far these efforts haven’t moved the needle on dementia treatments,” he said. “I think the field needs to think about targeting amyloid and tau together because both amyloid and tau act together to kill neurons in Alzheimer’s disease.”
Senior author Jeanna Wheeler, a research scientist at the Seattle Institute for Biomedical and Clinical Research and the VA, said what’s novel about the study is the discovery of the role of the MSUT2 gene.
“We discovered MSUT2 originally in a completely unbiased way by looking for anything that could make worms resistant to pathological tau protein. Now we have shown that this gene can also affect tau toxicity in mice, and also that there are differences in MSUT2 in human Alzheimer’s patients,” she said. “If we can use MSUT2 in the future as a drug target, this would be a completely novel approach for treating Alzheimer’s and other related disorders.”
The study also brings more attention to the role of tau pathology in Alzheimer’s disease.
The healthy human brain contains tens of billions of specialized cells or neurons that process and transmit information. By disrupting communication among these cells, Alzheimer’s disease results in loss of neuron function and cell death.
Previous studies have shown that abnormal tau burden correlates strongly with cognitive decline in Alzheimer’s disease patients, but amyloid does not. Some dementia disorders, such as frontotemporal lobar degeneration, may have only abnormal tau with no amyloid deposits.
“If you could protect the brain from tau alone, you may provide substantial benefit for people with Alzheimer’s disease,” Kraemer said. “Likewise, targeting tau in tangle-only Alzheimer’s disease-related dementia disorders, like frontotemporal lobar degeneration, will almost certainly be beneficial for patients.”
This study follows previous work by these researchers that showed very similar results using the worm C. elegans. Worms go from egg to adult in three days so it was easier to do experiments on the biology of aging rapidly. Although worms don’t have complex cognitive functions, their movement is affected by tau buildup. Researchers found that they could cure the worm by knocking out the worm sut-2 gene.
The more recent study applied the experiment to mice, whose evolutionary distance to humans is much smaller than the distance between worms and humans.
The researchers knocked out the MSUT2 gene in mice, thereby, preventing the formation of the tau tangles that kill off brain cells. This lessened learning and memory problems as well.
While examining autopsy brain samples from Alzheimer’s patients, the researchers found that cases with more severe disease lacked both MSUT2 protein, and its partner protein, PABPN1. This finding suggests that neurons that lose the MSUT2 -PABPN1 protein partnership may simply die during a patient’s life.
Moreover, mice lacking MSUT2 but possessing a normal complement of PABPN1 were strongly protected against abnormal tau and the resulting brain degeneration. Therefore, the researchers concluded that the key to helping people with abnormal tau buildup is blocking MSUT2 while preserving PABPN1 activity.
Medicines such as insulin for diabetes and clotting factors for hemophilia are hard to synthesize in the lab. Such drugs are based on therapeutic proteins, so scientists have engineered bacteria into tiny protein-making factories. But even with the help of bacteria or other cells, the process of producing proteins for medical or commercial applications is laborious and costly.
Now, researchers at Washington University School of Medicine in St. Louis have discovered a way to supercharge protein production up to a thousandfold. The findings, published Dec. 18 in Nature Communications, could help increase production and drive down costs of making certain protein-based drugs, vaccines and diagnostics, as well as proteins used in the food, agriculture, biomaterials, bioenergy and chemical industries.
“The process of producing proteins for medical or commercial applications can be complex, expensive and time-consuming,” said Sergej Djuranovic, PhD, an associate professor of cell biology and physiology and the study’s senior author. “If you can make each bacterium produce 10 times as much protein, you only need one-tenth the volume of bacteria to get the job done, which would cut costs tremendously. This technique works with all kinds of proteins because it’s a basic feature of the universal protein-synthesizing machinery.”
Proteins are built from chains of amino acids hundreds of links long. Djuranovic and first author Manasvi Verma, an undergraduate researcher in Djuranovic’s lab, stumbled on the importance of the first few amino acids when an experiment for a different study failed to work as expected. The researchers were looking for ways to control the amount of protein produced from a specific gene.
“We changed the sequence of the first few amino acids, and we thought it would have no effect on protein expression, but instead, it increased protein expression by 300%,” Djuranovic said. “So then we started digging in to why that happened.”
The researchers turned to green fluorescent protein, a tool used in biomedical research to estimate the amount of protein in a sample by measuring the amount of fluorescent light produced. Djuranovic and colleagues randomly changed the sequence of the first few amino acids in green fluorescent protein, generating 9,261 distinct versions, identical except for the very beginning.
The brilliance of the different versions of green fluorescent protein varied a thousandfold from the dimmest to the brightest, the researchers found, indicating a thousandfold difference in the amount of protein produced. With careful analysis and further experiments, Djuranovic, Verma and their collaborators from Washington University and Stanford University identified certain combinations of amino acids at the third, fourth and fifth positions in the protein chain that gave rise to sky-high amounts of protein.
Moreover, the same amino-acid triplets not only ramped up production of green fluorescent protein, which originally comes from jellyfish, but also production of proteins from distantly related species like coral and humans.
The findings could help increase production of proteins not only for medical applications, but in food, agriculture, chemical and other industries.
“There are so many ways we could benefit from ramping up protein production,” Djuranovic said. “In the biomedical space, there are many proteins used in drugs, vaccines, diagnostics and biomaterials for medical devices that might become less expensive if we could improve production. And that’s not to mention proteins produced for use in the food industry — there’s one called chymosin that is very important in cheese-making, for example — the chemical industry, bioenergy, scientific research and others. Optimizing protein production could have a broad range of commercial benefits.”
An experimental vaccine against the Zika virus reduced the amount of virus in pregnant rhesus macaques and improved fetal outcomes. The work could help support development and approval of the experimental Zika DNA vaccine VRC5283, which is currently in early stage trials in humans. The results are published Dec. 18 in Science Translati
This study marks the first test of a Zika vaccine given before conception with exposure to the virus during pregnancy, said Koen Van Rompay, virologist at the California National Primate Research Center at the University of California, Davis. Zika virus infection of pregnant women is associated with a high risk of adverse fetal effects, including fetal death, microcephaly and other abnormalities, collectively termed congenital Zika syndrome. No approved vaccine is available yet.
The new study was designed to mimic a real-world scenario where women could be vaccinated months or years before becoming pregnant.
UC Davis researchers worked in collaboration with scientists from the National Institute of Allergy and Infectious Diseases, or NIAID, including Barney Graham, deputy director of the NIAID Vaccine Research Center and Ted Pierson, chief of the NIAID Laboratory of Viral Diseases. The team vaccinated female monkeys with VRC5283. After vaccination, depending on their reproductive cycles, the female animals were housed with males and allowed to procreate. Thirteen vaccinated animals and twelve unvaccinated controls became pregnant.
The investigators exposed the pregnant animals to Zika virus at intervals representing first and second trimesters.
Vaccinated females had less virus in their blood and the virus persisted for a shorter duration after exposure. Two unvaccinated animals lost the fetus early in pregnancy due to Zika virus infection; there was no early fetus loss in the vaccinated group.
At the end of pregnancy, the researchers looked for Zika virus in tissues from the mothers and fetuses. Eleven of 12 fetuses in the unvaccinated control group had detectable Zika virus RNA. No Zika virus RNA was detected in the 13 fetuses from the vaccinated group, suggesting that the vaccine prevented transmission of virus to the fetus. Antibodies against Zika virus in the vaccinated mother animals correlated with protection against the virus.
Preventing Zika transmission
The results suggest that VRC5283 vaccine may prevent mother-to-fetus transmission of Zika virus in humans as well, Van Rompay said. The candidate vaccine is currently in global phase IIb trials conducted by the VRC to test its safety and ability to elicit an immune response in humans. Additional clinical trials to determine efficacy would be needed to support licensure of the vaccine. Results from the animal studies will help support the case for approving the vaccine.
Ongoing work with this animal model of Zika virus infection includes evaluation of the ability of passive antibody to the virus to protect against Zika virus infection in pregnancy. Because it takes some weeks for antibodies to develop after a vaccination, passive antibody transfer might be used to immediately treat a pregnant woman who is at risk of getting infected or has symptoms of Zika virus infection.
UC Davis researchers are also looking at how Zika virus affects the development of young macaques. Rhesus macaques do not develop the same head malformation (microcephaly) seen in some human infants, Van Rompay said, but this may be a relatively rare complication. It is thought that there could be many more infants exposed to Zika virus before birth who may show more subtle developmental deficits.
“In our previous studies, we found microscopic brain lesions in fetuses exposed to Zika virus,” Van Rompay said. By carefully monitoring macaques that were exposed to the virus before birth for a long time after birth, the UC Davis researchers hope to pick up on other problems that might also show up in children.
Compulsive drinking may be due to dysfunction in a specific brain pathway that normally helps keep drinking in check. The results are reported in the journal Biological Psychiatry.
In the United States, 14 million adults struggle with alcohol use disorder (AUD) — formerly known as alcoholism. This disorder makes individuals unable to stop drinking even when they know the potential risks to health, jobs, and relationships.
“Difficulty saying no to alcohol, even when it could clearly lead to harm, is a defining feature of alcohol use disorders,” said Andrew Holmes, PhD, senior investigator of the study and Chief of the Laboratory on Behavioral and Genomic Neuroscience at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). “This study takes us a step further in understanding the brain mechanisms underlying compulsive drinking.”
Many complex parts of behavior — emotion, reward, motivation, anxiety — are regulated by the cortex, the outer layers of the brain that are responsible for complex processes like decision-making. Unlike drugs like cocaine, alcohol has broad effects on the brain, which makes narrowing down a target for therapeutic treatment much more difficult.
“We want to understand how the brain normally regulates drinking, so we can answer questions about what happens when this regulation isn’t happening as it should,” said Lindsay Halladay, PhD, Assistant Professor of Psychology and Neuroscience at Santa Clara University, and lead author of the study.
To study how the brain regulates drinking, Halladay and colleagues trained mice in the lab to press a lever for an alcohol reward. Once trained, the mice were presented with a new, conflicting situation: press the same lever for alcohol and receive a light electric shock to their feet, or avoid that risk but forfeit the alcohol. After a short session, most mice quickly learn to avoid the shock and choose to give up the alcohol.
Halladay’s team first used surgically-implanted electrodes to measure activity in regions of the cortex during that decision.
“We found a group of neurons in the medial prefrontal cortex that became active when mice approached the lever but aborted the lever press,” said Halladay. “These neurons only responded when the mice did not press the lever, apparently deciding the risk of shock was too great, but not when mice chose alcohol over the risk of shock. This means that the neurons we identified may be responsible for putting the brakes on drinking when doing so may be dangerous.”
The medial prefrontal cortex (mPFC) plays a role in many forms of decision-making and communicates with many regions of the brain, so Halladay’s team explored those external connections.
The team used optogenetics, a viral engineering technique that allowed them to effectively shut down precise brain pathways by shining light in the brain. They shut down activity of cells in the mPFC that communicate with the nucleus accumbens, an area of the brain important for reward, and found that the number of risky lever presses increased.
“Shutting down this circuit restored alcohol-seeking despite the risk of shock,” said Halladay. “This raises the possibility that alcohol use disorder stems from some form of dysfunction in this pathway.”
Understanding compulsive drinking in some people relies on identifying the neural pathway that keeps drinking in check.
“Current treatments just aren’t effective enough,” said Halladay. “Nearly half of all people treated for AUD relapse within a year of seeking treatment.”
Once scientists understand exactly how wiring in the brain is different for individuals with AUD compared to those without the disorder, more effective treatments can be developed.
Soft pressure sensors have received significant research attention in a variety of fields, including soft robotics, electronic skin, and wearable electronics. Wearable soft pressure sensors have great potential for the real-time health monitoring and for the early diagnosis of diseases.
A KAIST research team led by Professor Inkyu Park from the Department of Mechanical Engineering developed a highly sensitive wearable pressure sensor for health monitoring applications. This work was reported in Advanced Healthcare Materials on November 21 as a front cover article.
This technology is capable of sensitive, precise, and continuous measurement of physiological and physical signals and shows great potential for health monitoring applications and the early diagnosis of diseases.
A soft pressure sensor is required to have high compliance, high sensitivity, low cost, long-term performance stability, and environmental stability in order to be employed for continuous health monitoring. Conventional solid-state soft pressure sensors using functional materials including carbon nanotubes and graphene have showed great sensing performance. However, these sensors suffer from limited stretchability, signal drifting, and long-term instability due to the distance between the stretchable substrate and the functional materials.
To overcome these issues, liquid-state electronics using liquid metal have been introduced for various wearable applications. Of these materials, Galinstan, a eutectic metal alloy of gallium, indium, and tin, has great mechanical and electrical properties that can be employed in wearable applications. But today’s liquid metal-based pressure sensors have low-pressure sensitivity, limiting their applicability for health monitoring devices.
The research team developed a 3D-printed rigid microbump array-integrated, liquid metal-based soft pressure sensor. With the help of 3D printing, the integration of a rigid microbump array and the master mold for a liquid metal microchannel could be achieved simultaneously, reducing the complexity of the manufacturing process. Through the integration of the rigid microbump and the microchannel, the new pressure sensor has an extremely low detection limit and enhanced pressure sensitivity compared to previously reported liquid metal-based pressure sensors. The proposed sensor also has a negligible signal drift over 10,000 cycles of pressure, bending, and stretching and exhibited excellent stability when subjected to various environmental conditions.
These performance outcomes make it an excellent sensor for various health monitoring devices. First, the research team demonstrated a wearable wristband device that can continuously monitor one’s pulse during exercise and be employed in a noninvasive cuffless BP monitoring system based on PTT calculations. Then, they introduced a wireless wearable heel pressure monitoring system that integrates three 3D-BLiPS with a wireless communication module.
Professor Park said, “It was possible to measure health indicators including pulse and blood pressure continuously as well as pressure of body parts using our proposed soft pressure sensor. We expect it to be used in health care applications, such as the prevention and the monitoring of the pressure-driven diseases such as pressure ulcers in the near future. There will be more opportunities for future research including a whole-body pressure monitoring system related to other physical parameters.”