The discovery, reported online June 6, 2022, in Molecular Psychiatry, illuminates the molecular details of the brain’s response to alcohol withdrawal, and suggests that the immune protein, colony stimulating factor 1 (CSF1), could be a target of future treatments for alcohol use disorder (AUD).

“Alcohol withdrawal activates the stress system in the brain, which contributes to relapse, and in this study, we linked this stress response to CSF1, a neuroimmune mediator, opening up new opportunities for therapeutic intervention,” says study senior author Marisa Roberto, PhD, professor and Schimmel Family Chair in the Department of Molecular Medicine at Scripps Research.

The study’s first author, who performed many of the experiments, is Reesha R. Patel, PhD, a former postdoctoral researcher in the Roberto lab.

Alcohol is by far the most used and abused recreational drug. According to the 2019 National Survey on Drug Use and Health, nine million men and more than five million women in the United States have an alcohol use disorder (AUD), which is defined as an inability to control alcohol use despite its negative impact on the user’s health, social life and/or employment. Drug treatments, talk-therapy and support group-based treatments are available, but relapse is common, mainly due to the limited understanding of the brain-circuit dysfunctions underlying AUD.

Scientists know that relapse-promoting alcohol withdrawal symptoms include rising feelings of anxiety, caused at least in part by the release of stress molecules such as corticotropin-releasing factor (CRF) within the brain. CRF stimulates receptors on neurons in the prefrontal cortex, and in the limbic system, a set of more primitive brain structures that process emotions. If scientists could fully identify and characterize these CRF-sensitive neuronal populations, they could understand better how anxiety occurs during withdrawal and potentially devise effective treatments to block it.

Toward that end, Roberto and her team, in the new study, identified a population of neurons in the medial prefrontal cortex (mPFC) of mice that are sensitive to CRF because they express a CRF receptor called CRF1. The scientists showed that these neurons are involved in altering mood and behavior during alcohol exposure and withdrawal.

The team’s initial experiments revealed that deletion of these CRF-sensitive neurons makes the mice less anxious, suggesting that the neurons normally mediate anxiety-like behaviors.

The researchers subsequently found that these CRF-sensitive mPFC neurons become less excitable — less likely to fire signals to other neurons when stimulated — in alcohol-dependent mice that experience alcohol withdrawal. In contrast, nearby mPFC neurons lacking CRF receptors become more excitable.

“These CRF-sensitive mPFC neurons appear to constitute a unique neuronal population that undergoes profound neuroadaptations with chronic alcohol exposure,” says study co-author Pauravi Gandhi, PhD, a postdoctoral research associate in the Roberto lab.

Intriguingly, the researchers found that alcohol withdrawal, even as it dialed down the excitability of the CRF-sensitive neurons, also induced large increases in CSF1 gene expression within these neurons. CSF1 is an immune protein best known for its role in stimulating stem cells to mature into large white blood cells called macrophages. In the brain, CSF1 is thought to have a similar role in sustaining brain-resident immune cells called microglia. Moreover, prior research in mice has suggested that under conditions of chronic stress, CSF1 production rises in the mPFC, driving microglia to prune connections between neurons, which in turn causes signs of anxiety and depression.

Looking more closely at CSF1’s role in alcohol withdrawal, Roberto and colleagues artificially increased CSF1 production in CRF-sensitive mPFC neurons in mice, and observed that the animals exhibited many of the same neuronal and behavioral changes seen in alcohol withdrawal — suggesting that elevated CSF1 levels in mPFC may be a key driver of alcohol-withdrawal signs and symptoms.

“Targeting CSF1 therefore may be a good strategy for treating AUD, and we’re now eager to test that in our preclinical models,” Patel says.

In a new study, University of Chicago scientists find that holes can also improve technology, including medical devices. Published in Nature Materials, the paper describes an entirely new way to make a solar cell: by etching holes in the top layer to make it porous. The innovation could form the basis for a less-invasive pacemaker, or similar medical devices. It could be paired with a small light source to reduce the size of the bulky batteries that are currently implanted along with today’s pacemakers.

“We hope this opens many possibilities for further improvements in this field,” said Aleksander Prominski, the first author on the paper.

Light work

Prominski is a member of the lab of University of Chicago chemist Bozhi Tian, which specializes in creating ways to connect biological tissue and artificial materials — such as wires to modulate brain signals and surfaces for medical implants.

One of the areas they’re interested in is making devices that can be powered by light. We’re most familiar with this technology in the form of solar cells, but they can also use any light source, including artificial ones. When operating in the body, such devices are known as photoelectrochemical cells and can be powered from a tiny optical fiber implanted in the body.

Normally, solar cells require two layers, which can be achieved either by combining the silicon with another material such as gold, or by mixing different kinds of atoms into each silicon layer.

But UChicago scientists in the Tian lab found they could create a solar cell out of pure silicon if they made one layer porous, like a sponge.

The resulting soft, flexible cell can be less than five microns across, which is about the size of a single red blood cell. It can then be paired with an optical fiber, which can be made as thin as a strand of human hair — significantly reducing the overall size of an implant, making it more body-friendly and less likely to cause side effects.

The porous cell has multiple advantages over the ways to manufacture traditional solar cells, streamlining the production process while maintaining the efficacy of the final product.

“You can make them in a matter of minutes, and the process doesn’t require high temperatures or toxic gases,” said Prominski.

Added study co-author Jiuyun Shi: “When we measured them, we saw the photocurrent was really high — two orders of magnitude higher than our previous designs.”

Then, to boost the material’s ability to stimulate heart or nerve cells, they treat it with oxygen plasma to oxidize the surface layer. This step is counterintuitive for chemists, because silicon oxide most often works as an insulator, and “you don’t want the photoelectrochemical effect to be impeded by any insulating materials,” said Tian. In this case, however, oxidization actually helps by making the silicon material hydrophilic — attracted to water — which boosts the signal to biological tissues. “Finally, by adding a few-atoms-thick layer of metal oxide, you can further enhance the device properties,” said Pengju Li, another study co-author.

Because all of the components can be made to be biodegradable, the scientists can imagine the technology being used for short-term cardiac procedures. Instead of a second surgery for removal, the parts would degrade naturally after a few months. The innovative approach might also be particularly useful for a procedure called cardiac resynchronization therapy which seeks to correct arrhythmias where the right and left chambers of the heart do not beat in time, because the devices could be placed in multiple areas of the heart to improve coverage.

Prominski is also excited about possible applications for nerve stimulation. “You could imagine implanting such devices in people who have chronic nerve degeneration in the wrists or hands, for example, in order to provide pain relief,” he said.

This novel way of making solar cells could also be of interest for sustainable energy or other non-medical applications. Because these solar cells are designed to work best in a liquid environment, UChicago scientists think they could be used in applications such as artificial leaves and solar fuels.

Tian’s team is working with cardiac researchers at the University of Chicago Medicine to further develop the technology for eventual use in humans. They are also collaborating with the UChicago Polsky Center for Entrepreneurship and Innovation to commercialize the discovery.

Jiping Yue, Yiliang Lin, Jihun Park, and Menahem Rotenberg were also co-authors on the study.

The research used the resources of the Pritzker Nanofabrication Facility at the Pritzker School of Molecular Engineering; the Illinois Innovation Network; the Northwestern University Atomic and Nanoscale Characterization Experimental Center and Northwestern Materials Research Science and Engineering Center; and the University of Chicago Materials Research Science and Engineering Center.

Along some fault lines, which are the boundaries of tectonic plates, a fine-grained gravel is formed as the plates grind against one another. The influence of this gravel on earthquakes has long been the subject of scientific speculation. In a new paper appearing in the journal Nature on June 1, the Caltech researchers show that the fine gravel, known as rock gouge, first halts earthquake propagation, but then triggers the rebirth of earthquakes to generate powerful ruptures.

“Our novel experimental approach has enabled us to look into the earthquake process up close, and to uncover key features of rupture propagation and friction evolution in rock gouge,” says Vito Rubino, research scientist and lead author of the Nature paper. “One of the main findings of our study is that fault sections previously thought to act as barriers against dynamic rupture may in fact host earthquakes, as a result of the activation of co-seismic friction weakening mechanisms.”

In the paper, Rubino and his co-authors Nadia Lapusta, the Lawrence A. Hanson, Jr., Professor of Mechanical Engineering and Geophysics, and Ares Rosakis, Theodore von Kármán Professor of Aeronautics and Mechanical Engineering, show that so-called “stable” or “creeping” faults are not actually immune to major ruptures after all, as previously suspected. Such faults occur when tectonic plates slide past one another slowly, without generating big quakes (for example, the currently creeping section of the San Andreas Fault in central California).

Instead, rock gouge has a complex behavior. It first acts as a barrier to the rupture, absorbing energy and blocking its progress. But, when the plates slide past each other with high enough velocity, the rock gouge interface weakens and dramatically reduces friction between the two plates, causing the re-emergence of the quake. This process is known as “renucleation.”

“Based on the previous rich body of rock-friction experiments, we know that rock gouge can either strengthen with fault slip and act as a barrier, or weaken and promote earthquake rupture,” Lapusta says. “However, these behaviors are typically considered to be separated in space, with weakening and strengthening occurring on different fault locations. Our experiments show how these behaviors can combine on the same fault locations during the same slip event, over the timescales of dynamic rupture, leading to intermittent slip and potentially turning a fault barrier into an earthquake-prone region.”

The Nature study explores the role and reaction of rock gouge, a micrometer-sized granular material, to seismic activity. To simulate the effect of rock gouge on an earthquake’s propagation, the team used Caltech’s so-called seismological wind tunnel, founded by Rosakis and former Caltech Seismological Laboratory director Hiroo Kanamori, John E. and Hazel S. Smits Professor of Geophysics, Emeritus. The facility, in existence since 1999, allows engineers and scientists to study major earthquakes on a miniature scale.

To simulate an earthquake, the team first cut in half a transparent meter-sized block of a type of plastic known as Homalite. The bulk properties of Homalite enable dynamic rupture nucleation within samples as small as tens of centimeters in diameter; studying these effects in rock would require samples that are tens of meters in size.

The researchers then placed the two halves of the Homalite together under high pressure and shear (a situation in which the two halves want to slide against one another in opposite directions), simulating tectonic pressure that slowly builds up along a fault line. Between the pieces, fine-grained quartz powder was embedded as a stand-in for fault gouge. Next, the team put a small wire fuse between the two halves; its location was the “epicenter” of the earthquake they planned to simulate. As the simulated quake progressed, high-speed imaging technology was used to record its evolution, one millionth of a second at a time.

“Back in the late 1990s, when we were designing the ‘seismological wind tunnel,’ we could never have imagined its success in discovering such a rich spectrum of physical phenomena relating to frictional earthquake source processes and that such phenomena could rigorously be scaled to explain natural earthquake behavior occurring at massively different length scale around the globe,” Rosakis says. “This is a testament of the tremendous power of the discipline of mechanics.”

Next, the team plans to study the effects of fluids, which are naturally present in Earth’s crust, on the frictional behavior of rock gouge.

The Nature paper is titled “Intermittent lab earthquakes in dynamically weakening fault gouge.” This research was funded by the National Science Foundation (NSF), the U.S. Geological Survey, the NSF-IUCRC program at Caltech’s Center for Geomechanics and Mitigation of Geohazards (GMG), and the Southern California Earthquake Center (SCEC).

The scientists of the “Biology and Mars Experiment” (BIOMEX) project had already sent kombucha cultures to the International Space Station (ISS) in 2014 with the support of the European Space Agency. The aim was to learn more about the robustness of cellulose as a biomarker, the genomic architecture of kombucha, and its survival behaviour under extraterrestrial conditions. After one and a half years under simulated Martian conditions outside the ISS, the samples were reactivated on Earth and cultivated for another two and a half years.

The head of the University of Göttingen’s Institute of Veterinary Medicine, Professor Bertram Brenig, was responsible for the sequencing and bioinformatic analysis of the metagenomes of the reactivated cultures and individual kombucha cultures in a team with researchers from the University of Minas Gerais in Brazil. “Based on our metagenomic analysis, we found that the simulated Martian environment drastically disrupted the microbial ecology of kombucha cultures. However, we were surprised to discover that the cellulose-producing bacteria of the genus Komagataeibacter survived.” The results suggest that the cellulose produced by the bacteria is probably responsible for their survival in extraterrestrial conditions. This also provides the first evidence that bacterial cellulose could be a biomarker for extraterrestrial life and cellulose-based membranes or films could be a good biomaterial for protecting life and producing consumer goods in extraterrestrial settlements.

Another interesting aspect of these experiments could be the development of novel drug delivery systems, for example for the development of medicine suitable for use in space. Another focus was on investigations into changes in antibiotic resistance: the research team was able to show that the total number of antibiotic and metal resistance genes — meaning that these microorganisms might survive despite antibiotics or metals in the environment — were enriched in the exposed cultures. “This result shows that the difficulties associated with antibiotic resistance in medicine in space should be given special attention in the future,” the scientists said.

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The federally funded review, which will be updated on an ongoing basis, was published today in the Annals of Internal Medicine.

Researchers did find evidence to support a short-term benefit in treating neuropathic pain — caused by damage to peripheral nerves, such as diabetic neuropathy resulting in pain described as burning and tingling, involving two FDA-approved synthetic products with 100% tetrahydrocannabinol, or THC: dronabinol (under the trade name Marinol) and nabilone (Cesamet). Both products also lead to notable side effects including sedation and dizziness, according to the review.

Another product, a sublingual spray of equal parts THC and cannabidiol, or CBD, extracted from the cannabis plant, known as nabiximols, also showed evidence of some clinical benefit for neuropathic pain, although that product is not available in the U.S. This product also led to side effects, such as nausea, sedation and dizziness.

“In general, the limited amount of evidence surprised all of us,” said lead author Marian S. McDonagh, Pharm.D., emeritus professor of medical informatics and clinical epidemiology in the OHSU School of Medicine. “With so much buzz around cannabis-related products, and the easy availability of recreational and medical marijuana in many states, consumers and patients might assume there would be more evidence about the benefits and side effects.

“Unfortunately, there is very little scientifically valid research into most these products,” she said. “We saw only a small group of observational cohort studies on cannabis products that would be easily available in states that allow it, and these were not designed to answer the important questions on treating chronic pain.”

Voters in Oregon, Washington and 20 other states have legalized medical and recreational marijuana, however the researchers found many of the products now available at U.S. dispensaries have not been well studied.

“For some cannabis products, such as whole-plant products, the data are sparse with imprecise estimates of effect and studies had methodological limitations,” the authors write.

This situation makes it difficult to guide patients.

“Cannabis products vary quite a bit in terms of their chemical composition, and this could have important effects in terms of benefits and harm to patients,” said co-author Roger Chou, M.D., director of OHSU’s Pacific Northwest Evidence-based Practice Center. “That makes it tough for patients and clinicians since the evidence for one cannabis-based product may not be the same for another.”

The living review, including a visual abstract summary of the findings, will also be shared on a new web-based tool launched by OHSU and VA Portland Health Care System early this year to help clinicians and researchers evaluate the latest evidence around the health effects of cannabis. Known as Systematically Testing the Evidence on Marijuana, or STEM, the project includes “clinician briefs” to help health care workers translate the clinical implications.

“This new living evidence review is exactly the type of resource clinicians need to clarify for patients the areas of potential promise, the cannabis formulations that have been studied and, importantly, the major gaps in knowledge,” said co-author Devan Kansagara, M.D., M.C.R., professor of medicine in the OHSU School of Medicine and a staff physician at the VA Portland.

Reviewers searched more than 3,000 studies in the scientific literature as of January of this year and landed on a total of 25 with scientifically valid evidence — 18 randomized controlled studies and seven observational studies of at least four weeks.

The effects of cannabis and related products are based on their ability to mimic the body’s own endocannabinoid system. The system is composed of receptors and enzymes in the nervous system that regulate bodily functions and can affect the sensation of pain. In the evidence review, researchers sorted the types of product into high, comparable and low ratios of THC to CBD and compared their reported benefits and side effects.

Dronabinol and nabilone fit into the high THC to CBD ratio category, with 100% THC (no CBD), showing the most benefit among the products studied, with meta-analysis of the six randomized controlled studies demonstrating statistically valid benefits for easing neuropathic pain compared to a placebo.

“Honestly, the best advice is to talk to your primary care physician about possible treatments for chronic pain,” McDonagh said. “If you want to consider cannabis, you need to talk to your doctor.”

In addition to McDonagh, Chou and Kansagara, co-authors included Benjamin J. Morasco, Ph.D., Jesse Wagner, M.A., Azrah Y. Ahmed, B.A., and Rongwei Fu, Ph.D.

The project was funded by Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, contract number 75Q80120D00006. Statements in the report should not be construed as endorsement by the AHRQ or the Department of Health and Human Services.

The National Cancer Institute cites infection with H. pylori as the primary identified cause of certain types of stomach cancer. H. pylori is a bacterium that grows in the mucosa, or membrane layer that lines the stomach.

“This study is proposing that if you are carrying this particular allele, you are more likely to have an aggressive type of response to the bacteria that can result in complications,” said the study’s senior author, Juanita L. Merchant, MD, PhD, Regents Professor of Medicine and chief of the Division of Gastroenterology at the UArizona College of Medicine — Tucson.

In the United States, H. pylori is more prevalent in Hispanics, African Americans and the elderly. Dr. Merchant cited data suggesting that 1-3% of people with H. pylori will develop gastric cancer and that the cure rate is around 30%, which is low compared with some other types of cancer.

Current diagnosis of stomach or gastric cancer requires the patient to undergo an upper endoscopy, where a doctor looks for signs of cancer and takes a tissue sample for analysis.

For years, Dr. Merchant and colleagues have been investigating new ways to diagnose stomach cancer in its earliest possible stages. In 2020, they published research on a promising biomarker that appears in some patients before stomach cancer develops.

The new study focused on the molecular pathways that control the activation of immune cells in response to H. pylori infection, specifically the action of toll-like receptor 9 (TLR9).

Located within immune cells, TLR9 signals the immune system when to fight an infection. However, H. pylori infection can constantly trigger TLR9 activation over long periods of time, leading to the chronic inflammation. The long-term presence of inflammation caused by H. pylori infection is believed to be one of the triggers for cancer developing in the stomach.

“This addresses the question of what role the immune microenvironment has in gastric cancer,” said Dr. Merchant, who is a research member of the UArizona Cancer Center. “We have shown that these immune cells do play an important role.”

Researchers found that the chronic activation of TLR9 in the stomach triggers a series of events that includes increased production of interferon α, a signaling protein that can change the genetic signature of specialized immune cells known as myeloid-derived suppressor cells, or MDSCs. Prior research has linked MDSCs with H. pylori infection.

Dr. Merchant and her team focused on each step of the pathway and identified a specific genetic change — allele rs5743836 TLR9 minor C — that was linked to higher levels of TLR9 and interferon α and a greater incidence of gastric tumors. The allele is a single nucleotide polymorphism, or SNP, which is a genetic change in the DNA between genes.

“Because TLR9 and the SNP can be tested by DNA, they could be used as biomarkers to help us identify which patient populations are going to be more susceptible to the cellular changes that might lead to cancer based on their genetic background,” Dr. Merchant explained. “Those are the patients who could benefit from increased endoscopic surveillance.”

Eventually, the findings may also lead to new therapeutic options for patients.

“We have previously found a real-time biomarker in a blood test, and now we have something we can see in DNA,” Dr. Merchant said. “Our next step is to look at therapy options.”