Cell membrane proteins hide secret gateways that can be used to modify cell behavior. This has been demonstrated in a study led by the Hospital del Mar Research Institute and published in Nature Communications, with participation from research centers in Spain, Switzerland, the United Kingdom, Germany, France, Poland, the Netherlands, Denmark, Hungary, Italy, Sweden, China, and the United States. The findings may facilitate the creation of new medications or improve the mechanisms of existing ones.

The study’s findings are based on computer simulations that achieved an unprecedented level of detail.

Researchers were able to observe, at atomic scale and in real time, how membrane lipids interact with G protein-coupled receptors (GPCRs) in their natural environment.

These interactions reveal new ways to modulate cellular functions that would otherwise remain invisible.

“We have discovered new gateways for drugs to modulate proteins that regulate cellular activity,” explains Dr. Jana Selent, coordinator of the GPCR Drug Discovery Research Group within the Biomedical Informatics Research Program (GRIB) at the Hospital del Mar Research Institute, a joint group with Pompeu Fabra University.

GPCRs are important because a significant portion of existing drugs target them to act on cells.

In fact, 34% of FDA-approved drugs are based on these receptors.

“Having detailed information about the specific site where these drugs act within the cell will accelerate the development of targeted therapies,” adds Dr. Selent.

Work in Progress

Although the study published is based on data from 190 experiments covering 60% of known GPCRs, the work continues to uncover the mechanisms used by these proteins to regulate cell function.

So far, researchers have confirmed that beyond the known access points, there are others only visible through computer simulations.

These newly identified pathways could be leveraged to develop innovative therapeutic treatments.

According to Dr. David Aranda, postdoctoral researcher at GRIB and lead author of the study, these are “more specific gateways for each receptor — a more direct way to modulate cell behavior.”

In many cases, it was known that a drug acted on cells, but not how.

These results shed light on this aspect of cellular dynamics, making it possible to identify “targets that help create more selective, more precise medications, thereby reducing possible side effects. This could allow us to go beyond current methods used in treating multiple conditions,” he adds.

This information, along with future findings, is freely available for use by any laboratory working on developing or improving medications.

Plastic containers and packaging are everywhere, as many people rely on them for food storage, convenience, and hydration. Plastics have improved modern life in countless ways, but the ultimate price of this convenience is only now coming clearly into focus.

We have reached the point as a society where researchers have begun looking beyond the environmental hazards of plastic pollution to uncover hidden connections between plastic exposure and human well-being.

Questions are emerging about how microplastics might be affecting our bodies and whether this is something we should address.

Some everyday items, such as water bottles, may contribute far more than trash. They could be releasing tiny plastic particles that slip into our bodies.

Early studies suggest that plastic particles are influencing human blood pressure, a condition linked to serious cardiovascular problems.

According to Dr. Johanna Fischer from the Department of Medicine at Danube Private University in Austria, a few recent findings have sparked new debates about what happens when microplastics flow through our bloodstream.

Tiny pieces of plastic wreaking havoc

Microplastics measure less than 5 mm, arising from the breakdown of larger plastics or from everyday sources like car tires and synthetic clothing.

They have been detected in food, water, and the air. Scientists have identified them in the placenta, in certain organs, and even in the bloodstream.

Their presence has raised concerns because they might trigger inflammation or hormonal imbalances. By entering daily routines unnoticed, these microscopic bits could pose health hazards that are still under investigation.

Annovis Bio, Inc. (NYSE: ANVS) (“Annovis” or the “Company”), a late-stage clinical drug platform company pioneering transformative therapies for neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), today announced that on March 26, 2025, it received notice (the “Notice”) from the New York Stock Exchange (NYSE) that it is no longer in compliance with the NYSE continued listing standards set forth in Section 802.01B of the NYSE’s Listed Company Manual due to the fact that the Company’s average global market capitalization over a consecutive 30 trading-day period was less than $50 million while its stockholders’ equity was less than $50 million.

The Notice does not affect the Company’s business operations or its reporting obligations with the Securities and Exchange Commission, and it does not conflict with or cause an event of default under any of the Company’s material debt or other agreements.

As set forth in the Notice, as of March 25, 2025, the 30 trading-day average market capitalization of the Company was approximately $37.9 million and the Company’s last reported stockholders’ equity as of December 31, 2024 was $9.3 million.

The Company has notified the NYSE that it will submit a plan within 45 days of the Notice advising the NYSE of definitive action it has taken, or is taking, to bring it into conformity with Section 802.01B within 18 months of receipt of the Notice. The NYSE will review the Company’s plan and, within 45 days, make a determination as to whether the Company has made a reasonable demonstration of its ability to come into conformity with Section 802.01B within 18 months. If the Company’s plan is not submitted on a timely basis or is not accepted, the NYSE will initiate delisting proceedings. If the NYSE accepts the Company’s plan, the Company’s common stock will continue to be listed and traded on the NYSE during the cure period, subject to the Company’s compliance with the plan and other continued listing standards. The NYSE will review the Company on a quarterly basis to confirm compliance with the plan. If the Company fails to comply with the plan or does not meet continued listing standards at the end of the 18-month cure period, it will be subject to the prompt initiation of NYSE suspension and delisting procedures.

The Notice has no immediate impact on the listing of the Company’s common stock, which will continue to be “ANVS”, subject to the Company’s continued compliance with the plan and other listing requirements of the NYSE. However, the common stock trading symbol will have an added designation of “.BC” to indicate that the status of the common stock is below criteria with the NYSE continued listing standards. The “.BC” indicator will be removed at such time as the Company regains compliance.

Cautionary Note Regarding Forward-Looking Statements
This press release contains, and oral statements made from time to time by our representatives may contain, “forward-looking statements.” Forward-looking statements include statements identified by words such as “could,” “may,” “might,” “will,” “intends,” “plans,” “seeks,” “believes,” “estimates,” “expects,” “continues,” “projects” and similar references to future periods, or by the inclusion of forecasts or projections. Forward-looking statements are based on our current expectations and assumptions regarding capital market conditions, our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, our actual results may differ materially from those contemplated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, the Company’s ability to develop a plan to regain compliance with the continued listing criteria of the NYSE; the NYSE’s acceptance of such plan; the Company’s ability to execute such plan and to continue to comply with applicable listing standards within the available cure period; risks arising from the potential suspension of trading of the Company’s common stock on the NYSE; regional, national or global political, economic, business, competitive, market and regulatory conditions, including risks regarding our ability to manage inventory or anticipate consumer demand; changes in consumer confidence and spending; our competitive environment; our failure to open new profitable stores or successfully enter new markets and other factors set forth under “Risk Factors” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2024. Any forward-looking statement made in this report speaks only as of the date on which it is made. The Company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.

Howard Marks put it nicely when he said that, rather than worrying about share price volatility, ‘The possibility of permanent loss is the risk I worry about… and every practical investor I know worries about.’ So it might be obvious that you need to consider debt, when you think about how risky any given stock is, because too much debt can sink a company. We can see that ABL Bio Inc. (KOSDAQ:298380) does use debt in its business. But should shareholders be worried about its use of debt?

What Risk Does Debt Bring?

Debt assists a business until the business has trouble paying it off, either with new capital or with free cash flow. Ultimately, if the company can’t fulfill its legal obligations to repay debt, shareholders could walk away with nothing. While that is not too common, we often do see indebted companies permanently diluting shareholders because lenders force them to raise capital at a distressed price. Of course, debt can be an important tool in businesses, particularly capital heavy businesses. When we think about a company’s use of debt, we first look at cash and debt together.

What Is ABL Bio’s Debt?

The chart below, which you can click on for greater detail, shows that ABL Bio had ₩43.0b in debt in December 2024; about the same as the year before. However, it does have ₩141.5b in cash offsetting this, leading to net cash of ₩98.5b.

How Strong Is ABL Bio’s Balance Sheet?

We can see from the most recent balance sheet that ABL Bio had liabilities of ₩63.4b falling due within a year, and liabilities of ₩1.34b due beyond that. Offsetting these obligations, it had cash of ₩141.5b as well as receivables valued at ₩827.2m due within 12 months. So it can boast ₩77.6b more liquid assets than total liabilities.

This surplus suggests that ABL Bio has a conservative balance sheet, and could probably eliminate its debt without much difficulty. Succinctly put, ABL Bio boasts net cash, so it’s fair to say it does not have a heavy debt load! When analysing debt levels, the balance sheet is the obvious place to start. But ultimately the future profitability of the business will decide if ABL Bio can strengthen its balance sheet over time. So if you want to see what the professionals think, you might find this free report on analyst profit forecasts to be interesting.

In the last year ABL Bio had a loss before interest and tax, and actually shrunk its revenue by 49%, to ₩33b. To be frank that doesn’t bode well.

So How Risky Is ABL Bio?

Statistically speaking companies that lose money are riskier than those that make money. And in the last year ABL Bio had an earnings before interest and tax (EBIT) loss, truth be told. And over the same period it saw negative free cash outflow of ₩78b and booked a ₩56b accounting loss. However, it has net cash of ₩98.5b, so it has a bit of time before it will need more capital. Overall, its balance sheet doesn’t seem overly risky, at the moment, but we’re always cautious until we see the positive free cash flow. When analysing debt levels, the balance sheet is the obvious place to start. But ultimately, every company can contain risks that exist outside of the balance sheet. For example, we’ve discovered 1 warning sign for ABL Bio that you should be aware of before investing here.

When all is said and done, sometimes its easier to focus on companies that don’t even need debt. Readers can access a list of growth stocks with zero net debt 100% free, right now.

The pleasure we get from eating junk food—the dopamine rush—is often blamed as the cause of overeating and rising obesity rates in our society. But paradoxically, anecdotal evidence suggests that people with obesity may take less pleasure in eating than do individuals with normal weight. Brain scans of obese individuals show reduced activity in pleasure-related brain regions when presented with food, a pattern also observed in animal studies.

Research in mice by scientists at the University of California (UC), Berkeley, has now revealed an unsuspected brain mechanism that may explain why a chronic high-fat diet (HFD) can reduce the desire for high-fat, sugary foods, even when these foods remain easily accessible.

The researchers propose that this lack of desire in individuals with obesity is due to a loss of pleasure in eating caused by long-term consumption of high-calorie foods. Losing this pleasure may actually contribute to the progression of obesity. Their findings indicate that a decline in neurotensin—a brain peptide that interacts with the dopamine network—may represent a possible underlying cause of this phenomenon.

The results suggest that pleasure in eating, even eating calorie-rich high fat, high sugar foods, is key for maintaining a healthy weight in a society that abounds with cheap, high-fat food. The results point to a potential strategy to restore pleasure in eating in a way that helps reduce overall consumption. The researchers found that this effect is driven by a reduction in neurotensin in a specific brain region that connects to the dopamine network. Importantly, they demonstrate that restoring neurotensin levels—either through dietary changes or genetic manipulations that enhance neurotensin production—can reinstate the pleasure in eating and promote weight loss.

“Imagine eating an amazing dessert at a great restaurant in Paris—you experience a burst of dopamine and happiness,” said Neta Gazit Shimoni, PhD, a UC Berkeley postdoctoral fellow. “We found that this same feeling occurs in mice on a normal diet, but is missing in those on a high-fat diet. They may keep eating out of habit or boredom, rather than genuine enjoyment.”

Added research lead Stephan Lammel, PhD, a UC Berkeley professor in the department of neuroscience and a member of the Helen Wills Neuroscience Institute, “A natural inclination toward junk food is not inherently bad—but losing it could further exacerbate obesity. A high-fat diet changes the brain, leading to lower neurotensin levels, which in turn alters how we eat and respond to these foods. We found a way to restore the desire for high-calorie foods, which may actually help with weight management.”

While findings in mice don’t always translate directly to humans, this discovery could open new avenues for addressing obesity by restoring food-related pleasure and breaking unhealthy eating patterns. Lammel, together with co-lead first authors Gazit Shimoni, and former UC Berkeley graduate student Amanda Tose, reported on their findings in Nature, in a paper titled, “Changes in neurotensin signaling drive hedonic devaluation in obesity,” in which they concluded, “Together, our findings identify a neural circuit mechanism that links the devaluation of hedonic foods with obesity.”

“Excessive consumption of high-calorie foods is a key contributor to the development and progression of obesity in humans and animals,” the authors wrote. Doctors and researchers have struggled to understand and treat obesity, as countless fad diets and eating regimens have failed to produce long-term results. The recent success of GLP-1 agonists like Ozempic, which curb appetite by increasing feelings of fullness, stands out among many failed approaches.

Lammel studies brain circuits, particularly the dopamine network, which plays a crucial role in reward and motivation. Dopamine is often associated with pleasure, reinforcing our desire to seek rewarding experiences, such as consuming high-calorie foods.

While raising mice on a high-fat diet, Gazit Shimoni noticed a striking paradox. While they were in their home cages, these mice strongly preferred high-fat chow, which contained 60% fat, over normal chow with only 4% fat, leading them to gain excessive weight. However, when they were taken out of their home cages and given free access to high-calorie treats such as butter, peanut butter, jelly, or chocolate, they showed much less desire to indulge than did normal-diet mice, who immediately ate everything they were offered. The animals on a chronic HFD “… paradoxically exhibited a reduced drive to opportunistically consume high-calorie foods in an acute feeding assay, even when no effort was required to obtain the food,” the team wrote.

Gazit Shimoni further stated, “If you give a normal, regular-diet mouse the chance, they will immediately eat these foods. We only see this paradoxical attenuation of feeding motivation happening in mice on a high-fat diet.” The researchers discovered that this effect had been reported in past studies, but no one had followed up to find out why, and how the effect connects to the obesity phenotype observed in these mice. “This paradoxical decrease in hedonic feeding has been reported previously, but its neurobiological basis remains unclear,” the investigators stated.

To investigate the phenomenon further, Lammel and team used optogenetics, a technique that allows scientists to control brain circuits with light. They found that in normal-diet mice, stimulating a brain circuit that connects to the dopamine network increased their desire to eat high-calorie foods, but in obese mice, the same stimulation had no effect, suggesting that something must have changed. In their paper, the investigators further explained that “… in mice on regular diet, neurons in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA) encoded hedonic feeding behaviors.” In contrast, they reported, “In HFD mice, this behavior was reduced and uncoupled from neural activity.”

The reason, they discovered, was that neurotensin was reduced so much in obese mice that it prevented dopamine from triggering the usual pleasure response to high-calorie foods. “Neurotensin is this missing link,” Lammel said. “Normally, it enhances dopamine activity to drive reward and motivation. But in high-fat diet mice, neurotensin is downregulated, and they lose the strong desire to consume high-calorie foods—even when easily available.”

The researchers then tested ways to restore neurotensin levels. When obese mice were switched back to a normal diet for two weeks, their neurotensin levels returned to normal, dopamine function was restored, and they regained interest in high-calorie foods.

When neurotensin levels were artificially restored using a genetic approach, the mice not only lost weight, but also showed reduced anxiety and improved mobility. Their feeding behavior also normalized, with increased motivation for high-calorie foods and a simultaneous reduction of their total food consumption in their home cages. “Our results demonstrate that overexpression of NTS mitigates HFD-induced changes in hedonic feeding, anxiety, mobility, and home cage food consumption,” the authors stated.

They suggest that their results demonstrate how “disruptions in NTS signaling contribute to disordered consumption of calorie-rich foods.” Given the role of these foods in driving the obesity epidemic, they suggested, “… targeting NTS signaling in the NAcLat→VTA pathway may offer a promising strategy to regulate food intake and support healthy weight maintenance without disrupting other essential NTS-mediated functions.”

Lammel commented, “Bringing back neurotensin seems to be very, very critical for preventing the loss of desire to consume high-calorie foods. It doesn’t make you immune to getting obese again, but it would help to control eating behavior, to bring it back to normal.”

Although directly administering neurotensin could theoretically restore feeding motivation in obese individuals, neurotensin acts on many brain areas, raising the risk of unwanted side effects. To overcome this, the researchers used gene sequencing, a technique that allowed them to identify specific genes and molecular pathways that regulate neurotensin function in obese mice. This discovery provides crucial molecular targets for future obesity treatments, paving the way for more precise therapies that could selectively enhance neurotensin function without broad systemic effects.

“We now have the full genetic profile of these neurons and how they change with high-fat diets,” Lammel said. “The next step is to explore pathways upstream and downstream of neurotensin to find precise therapeutic targets.”

Lammel and Gazit Shimoni plan to expand their research to explore neurotensin’s role beyond obesity, investigating its involvement in diabetes and eating disorders. “The bigger question is whether these systems interact across different conditions,” Gazit Shimoni said. “How does starvation affect dopamine circuits? What happens in eating disorders? These are the questions we’re looking at next.”

Scientists from the J. Craig Venter Institute (JCVI), the Friedrich-Loeffler-Institut (FLI), and the International Livestock Research Institute (ILRI) say they have developed a reverse genetics system for African swine fever virus (ASFV).

The team published its study, “A synthetic genomics-based African swine fever virus engineering platform,” in Science Advances.

The new system is expected to aid researchers in developing vaccines and in studying the pathogenesis and biology of ASFV, a highly contagious, deadly viral disease affecting domesticated and wild pigs, especially prevalent in Africa, Europe, Asia, and the Caribbean.

A recent study estimates if ASFV reached the United States it could result in economic losses exceeding $50 billion over a ten-year period.

Sanjay Vashee, PhD, JCVI, senior author of the paper remarked, “By developing a synthetic genomics-based reverse genetics system for ASFV, we are not only advancing our understanding of this virus but also creating tools that can be applied to other emerging viral threats. This research has the potential to significantly reduce the economic losses caused by ASFV in the global swine industry, providing much-needed solutions to control and prevent the spread of the disease.”

The reverse genetic system allows scientists to quickly generate genetically modified versions of ASFV and involves several steps. First, scientists construct synthetic DNA, which is a lab-made version of the virus’s genetic material. Fragments of ASFV are modified and then assembled into full-length genomes in yeast using its recombination machinery. The modified genomes are then transferred to E. coli which makes isolating them in larger amounts possible.

The synthetic DNA is then transfected into mammalian host cells which are subsequently infected with a self-helper virus. This self-helper virus is an inhibited version of ASFV which has been modified using CRISPR/Cas9 technology, a powerful gene-editing tool that can precisely cut DNA at specific locations. The alterations ensure that the self-helper virus cannot replicate on its own. Despite this inhibition, the self-helper virus still provides the necessary proteins and machinery required for the synthetic DNA to replicate and assemble into new virus particles.

This process results in the production of live recombinant viruses that contain the specific genetic modifications introduced in the synthetic DNA. These recombinant viruses can then be used for further study or vaccine development.

Devastating economic losses

“Globally, ASFV outbreaks have caused devastating economic losses amounting to billions of dollars, severely impacting the pork industry, food security, and livelihoods. In Africa, the impact could be dire given the presence of multiple genotypes of the virus and the widespread lack of adequate biosecurity measures to control the disease,” said Hussein Abkallo, PhD, a researcher at ILRI and one of the authors of the paper. “This platform gives hope of developing new, targeted vaccines that can protect animal health to reduce mortality as well as the environmental footprint of the livestock sector by preventing unnecessary losses.”

The synthetic genomics-based reverse genetics system developed for ASFV can be applied to other viruses with non-infectious genomes, offering significant potential for research and vaccine development. For example, it could be applied to lumpy skin disease virus, a double-stranded DNA virus that primarily affects cattle causing significant economic harm.

This methodology could also be adapted for emerging RNA viruses such as Zika, chikungunya, Mayaro, and Ebola viruses, which have caused significant outbreaks and pose serious threats to global health. By leveraging synthetic genomics, researchers can rapidly develop reverse genetics tools for these and new emerging viruses, facilitating the study of their biology and the creation of effective vaccines and treatments.

Merck & Co. has agreed to license the oral small molecule Lipoprotein(a) [Lp(a)] inhibitor HRS-5346 from Jiangsu Hengrui Pharmaceuticals, through a licensing agreement that could generate up to $2 billion plus for the Chinese drug developer.

Hengrui Pharma has granted Merck exclusive rights to develop, manufacture, and commercialize HRS-5346 worldwide, except in Greater China where Hengrui will retain rights. At China’s Peking University Third Hospital, HRS-5346 is under study in a Phase II trial (NCT06816264) designed to assess the drug’s efficacy and safety in adults with elevated Lp(a) at high risk for cardiovascular events.

Dean Y. Li, MD, PhD, president, Merck Research Laboratories, hailed HRS-5346 in a statement as “an important addition that expands and complements our cardiometabolic pipeline.”

“Elevated blood concentrations of Lp(a) provide a well-documented risk factor for atherosclerotic cardiovascular disease, affecting as many as 1 in 5 adults globally,” Li stated.

Merck agreed to pay Hengrui $200 million upfront and up to $1.77 billion in payments tied to achieving development, regulatory, and commercial milestones, plus royalties on net sales of HRS-5346, if approved.

The collaboration agreement positions Merck to challenge two other pharma giants that aim to treat cardiovascular diseases by inhibiting Lp(a), a form of low-density lipoprotein (LDL) that plays a key role in the transport of cholesterol in the bloodstream.

Last November, Eli Lilly announced positive Phase II data showing three dosages of its oral, once daily muvalaplin (10 mg, 60 mg, and 240 mg) to have met the primary endpoint of a Phase II trial (NCT05565742) by showing significant reductions in Lp(a) levels vs placebo. Reductions were 47.6% (10 mg), 81.7% (60 mg), and 85.8% (240 mg) with an intact Lp(a) assay, and 40.4% (10 mg), 70.0% (60 mg), and 68.9% (240 mg) with an apolipoprotein A [apo(a)] assay.

$2B+ dyslipidemia partnership

And last October, AstraZeneca inked a potentially $2 billion-plus collaboration deal of its own to advance the development of YS2302018, a small molecule Lp(a) inhibitor designed to treat dyslipidemia. The pharma giant exclusively licensed rights to the preclinical candidate from Chinese-based CSPC Pharmaceutical Group. Under the companies’ agreement, AstraZeneca agreed to pay CSPC $100 million upfront, up to $1.92 billion tied to achieving development and commercialization milestones, plus tiered royalties.

Other pharmas targeting Lp(a) within their pipelines include Amgen and Novartis.

As for Merck and Hengrui, their collaboration deal is expected to close in the second quarter, subject to approval under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions. Merck said it expected to record a pre-tax charge of $200 million, or approximately $0.06 per share, to be included in GAAP and non-GAAP results in the quarter during which the transaction will close.

Investors reacted to news of the deal by sending Hengrui shares on the Shanghai Stock Exchange up 1.17%, to CNY 44.87 ($6.18) at the close of trading today. Merck shares on the New York Stock Exchange nearly 5% from yesterday’s close of $92.31, to $88.03 as of 1:11 p.m. ET.

“We are pleased to partner with Merck, a global leader in cardiovascular care. We believe Merck’s clinical expertise and global scale will help accelerate the development of HRS-5346 and potentially provide more patients with an additional option to reduce their risk of atherosclerosis,” added Frank Jiang, MD, PhD, Hengrui’s executive vice president and chief strategy officer.

After meals, the intestines use peristalsis to move food through the gut using coordinated contractions and relaxations of smooth muscle. Results from a new study in mice done by scientists at Harvard Medical School (HMS), the Icahn School of Medicine at Mount Sinai, and their collaborators show that a pressure-sensing protein called Piezo1 in intestinal nerve cells plays a key role in coordinating these movements and preventing inflammation in the gut. Details are published in a new Cell paper titled, “Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force.”

If the findings can be replicated in humans, scientists believe that they could inform the design of new treatments for intestinal inflammation in IBD patients as well as for disorders of gut motility such as diarrhea and constipation. Ruaidhrí Jackson, PhD, an assistant professor of immunology at HMS and co-senior author on the study, noted that the findings show how the nervous and immune systems interact in the gut to maintain healthy function and protect against inflammation. The results also add to a growing body of research showing that these two systems engage in a powerful interplay in various organs, including the brain, lungs, and skin.

The question is how the intestines can move independently without input from the central nervous system. Previous studies have shown that enteric neurons—nerve cells contained completely within the intestines—interact with smooth muscle cells to drive peristalsis, but exactly what happens at the interface has been unclear.

Jackson had previously studied the role of the Piezo1 protein in immune cells that sense the mechanical force generated by breathing. He and other colleagues published a study in Nature in 2019 that highlighted how the protein can spur inflammation in the lungs when it senses mechanical pressure. He wondered if this protein could also be somehow involved in digestive peristalsis.

To explore this idea, researchers in the current study analyzed gene activity in mouse and human gut neurons. They found evidence that the gene that produces Piezo1 is highly active in excitatory gut neurons, which are responsible for triggering muscle contractions in the intestine by releasing the chemical messenger acetylcholine.

To better understand the role of the protein, the researchers tested mouse intestinal tissue under varying pressure conditions. In normal mice, the intestines contracted when pressure increased. In mice that were genetically altered to lack the gene for the protein, scientists observed that the tissue failed to contract under pressure. This confirmed that Piezo1 acts as a pressure sensor, helping regulate gut movement.

For their next set of experiments, the researchers used genetically modified mice whose gut neurons could be altered by light. When Piezo1-expressing neurons were activated by light, the mice expelled a small glass bead from their intestines twice as fast as normal mice. When the researchers used chemicals to turn off Piezo1 neurons in the gut, digestion in these mice slowed notably.

Once they confirmed the role of Piezo1 in gut movement, the researchers then assessed the impact of exercise and gut inflammation due to intestinal bowel disease (IBD) on the protein’s activity. Running on a treadmill increased the movement of waste through the intestines in mice with functional Piezo1 protein. These mice had bowel movements after just 10 minutes of exercise. Mice who lacked the protein did not have a similar increase in intestinal motility. It suggests that the gene for Piezo1 senses the increased intestinal pressure from exercise.

To test Piezo1’s role in IBD, the researchers created mouse models of the disease. Mice with IBD whose guts had intact Piezo1 produced a bowel movement more quickly, compared with animals in which Piezo1 was inactivated. In addition, turning off the gene also worsened IBD symptoms. Compared with mice that had intact Piezo1 genes, animals without working Piezo1 lost more weight and gradually lost the layer of protective intestinal mucus and mucus-making cells that shield the walls of the colon.

The scientists hypothesize that the worsened inflammation could be due to the loss of acetylcholine, which is responsible for nerve signaling and smooth muscle movement and also acts as an anti-inflammatory agent. Jackson suspects that IBD-linked inflammation might spur Piezo1 to cause enteric neurons to generate excess acetylcholine in an effort to tamp down inflammation, and this results in the increased intestinal motility characteristic of this condition.

Modulating Piezo1 activity might be a way to fight IBD inflammation, Jackson said. A possible treatment could target Piezo1 in gut neurons to release acetylcholine. This strategy would be markedly different from the way most IBD drugs work, which is by suppressing key inflammatory proteins. He and his colleagues plan to explore these kinds of therapies in future studies.

A drug-resistant strain of bacteria inhabiting hospital settings has evolved to utilize an antimicrobial genetic tool. Vancomycin-resistant Enterococcus faecium (VREfm) is responsible for many lethal infections and has been shown by researchers at the University of Pittsburgh (UPitt) to be equally lethal to other bacterial species.

The findings, published in Nature Microbiology in a study titled, “Bacteriocin production facilitates nosocomial emergence of vancomycin-resistant Enterococcus faecium,” suggest that VREfm have the ability to produce bacteriocin, an antimicrobial that can kill or inhibit other bacteria.

“Our lab has a front-row seat to the parade of pathogens that move through the hospital setting,” said senior author Daria Van Tyne, PhD, associate professor of medicine in UPitt’s Division of Infectious Diseases.

The Enhanced Detection System for Healthcare-Associated Transmission (EDS-HAT) was developed at UPitt and the University of Pittsburgh Medical Center (UPMC) to track infectious disease outbreaks using patient data. This machine learning system analyzes data from whole genome sequencing in conjunction with electronic health records to detect healthcare-associated outbreaks and investigate transmission routes.

“Once these strains are in an institutional setting—such as a hospital—and are matched up against other strains of VRE in a patient’s gut, they take over. It’s a ‘kill your buddies and eat their food’ scenario,” said first author Emma Mills, a graduate student in the Van Tyne lab.

VREfm is one of the deadliest hospital pathogens, killing approximately 40% of those infected. Given VREfm’s high mortality rate and resistance to treatment with common antibiotics, tracking its evolution is critical. The researchers leveraged EDS-HAT to study VREfm to help better understand its growth mechanism and elucidate strategies to reduce its spread and treat infected patients.

Over 700 samples of VREfm from UPMC were collected over a six-year period from 2017–2022 and analyzed with EDS-HAT to trace the evolution of VREfm within the hospital. The team found that while about eight VREfm strains were initially present in 2017, two specific strains began to dominate in 2018, and by the end of 2022, these strains accounted for 80% of VREfm infections. The key to their success was determined as the ability of these strains to produce bacteriocin T8, allowing these strains to outcompete others.

After expanding their analysis globally and analyzing a publicly available collection of 15,631 VREfm genomes collected between 2002 and 2022, the team found parallel results in the larger data set.

“This was a completely unexpected discovery—I was surprised to see such a dramatic signal,” said Mills.

The results confirmed that the bacteriocin-producing strains were not only overtaking the bacterial populations in UPMC but were also emerging as dominant strains globally.

Van Tyne commented: “When we took a step back and zoomed out, it quickly became apparent that big changes were afoot with one of the world’s more difficult-to-treat bacteria.”

While there is an increasing restriction of diversity of VREfm strains, it seems that clinically, the virility of the bacteriocin-producing strains has not increased. Patients are not more susceptible to increased illness or death from these strains. This could simplify the development of therapeutic measures.

“We may soon have only one single target for which to design therapeutics such as antibiotics or phage therapy,” pointed out Van Tyne. “It also suggests that bacteriocins are very potent, and perhaps we could weaponize them for our own purposes.”

The findings highlight the importance of tracking bacterial evolution and resistance mechanisms. By understanding VREfm’s evolution, researchers may be able to anticipate future threats and develop countermeasures before they become widespread.

As aging bodies decline, the brain loses the ability to cleanse itself of waste, a scenario that scientists think could be contributing to neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. Researchers at Washington University School of Medicine in St. Louis report they have found a way around that problem by targeting the network of vessels that drain waste from the brain. Their study results indicated that rejuvenating those vessels improves memory in old mice.

The study could lay the groundwork for developing therapies for age-related cognitive decline that overcome the challenges faced by conventional treatments that struggle to pass through the blood-brain barrier to reach the brain.

“The physical blood-brain barrier hinders the efficacy of therapies for neurological disorders,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “By targeting a network of vessels outside of the brain that is critical for brain health, we see cognitive improvements in mice, opening a window to develop more powerful therapies to prevent or delay cognitive decline.”

Kipnis and colleagues reported on their results in Cell, in a paper titled, “Meningeal lymphatics-microglia axis regulates synaptic physiology,” in which they concluded that the study “… underscores the potential of enhancing meningeal lymphatic function to mitigate age-related synaptic and cognitive deficits.”

Kipnis is an expert in the field of neuroimmunology, which studies how the immune system affects the brain in health and disease. A decade ago, Kipnis’ lab discovered in mice and humans a network of vessels surrounding the brain—known as the meningeal lymphatics—that drains fluid and waste into the lymph nodes, where many immune system cells reside and monitor for signs of infection, disease, or injury. “Meningeal lymphatic vessels, located in the dura mater of the meninges, drain cerebrospinal fluid (CSF) together with its content of central nervous system (CNS)-derived waste primarily into deep cervical lymph nodes (dCLNs),” the authors wrote. Kipnis and colleagues also have previously shown that some investigational Alzheimer’s therapies are more effective in mice when paired with a treatment that improves drainage of fluid and debris from the brain.

Beginning at about age 50 years, as part of normal aging people start to experience a decline in brain fluid flow. The authors also pointed out that, “Since the discovery of meningeal lymphatic vessels, accumulating evidence from mouse models and humans has linked their dysfunction to various neurodegenerative conditions.” And while previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, “… the neural mechanisms underlying these changes have remained elusive.”

For their newly reported study, Kipnis collaborated with Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology, to ask if enhancing the function of an aged drainage system can improve memory.

To test the memory of mice, the researchers placed two identical black rods in the cage for twenty minutes for old mice to explore. The next day, the mice received one of the black rods again and a new object, a silver rectangular prism. Mice that remember playing with the black rod will spend more time with the new object. But old mice spend a similar amount of time playing with both objects.

Study first author Kyungdeok Kim, PhD, a postdoctoral fellow in the Kipnis lab, then boosted the functioning of the lymphatic vessels in old mice with a treatment that stimulates vessel growth, enabling more waste to drain out of the brain. He found that, compared with older mice given no treatment, those older mice with rejuvenated lymphatic vessels spent more time with the new object, an indicator of improved memory. “We demonstrated that enhancing meningeal lymphatics can reverse aging-related memory deficits and restore decreased cortical inhibitory tone,” the authors wrote.

“A functioning lymphatic system is critical for brain health and memory,” said Kim. “Therapies that support the health of the body’s waste management system may have health benefits for a naturally aging brain.”

When the lymphatic system is so impaired that waste builds up in the brain, the burden of cleaning falls to the brain’s resident immune cells, called microglia. But this local cleaning crew fails to keep up and gets exhausted, Kipnis explained.

The new study found that the overwhelmed cells produce a distress signal, the immune protein interleukin 6 (IL-6), that acts on brain cells to promote cognitive decline in mice with damaged lymphatic vessels. Examining the brains of such mice the researchers found that neurons had an imbalance in the types of signals they receive from surrounding brain cells. In particular, neurons received fewer signals that function like noise-canceling headphones among the cacophony of neuron communications. This imbalance, caused by increased IL-6 levels in the brain, led to changes in how the brain is wired and affected proper brain function. “Our data suggest that the observed reduction in inhibitory inputs is mediated by an excess of IL-6, a proinflammatory cytokine associated with various neuropsychiatric and neurodegenerative conditions,” the team wrote.

In addition to improving memory in the aged mice, the lymphatic vessel-boosting treatment also caused levels of IL-6 to drop, restoring the noise-canceling system of the brain. “In addition, we observed reduced levels of Il6 (along with Tnfa) in VEGFC-treated aged mice,” the authors further noted. The findings point to the potential of improving the health of the brain’s lymphatic vessels to preserve or restore cognitive abilities.

Noting limitations of their study, the authors concluded: “Taken together, our findings highlight the essential role of meningeal lymphatics in maintaining the homeostasis of cortical networks … our study underscores the potential of enhancing meningeal lymphatic function to mitigate age-related synaptic and cognitive deficits.”

Kipnis said, “As we mark the 10th anniversary of our discovery of the brain’s lymphatic system, these new findings provide insight into the importance of this system for brain health. Targeting the more easily accessible lymphatic vessels that are located outside the brain may prove to be an exciting new frontier in the treatment of brain disorders. We may not be able to revive neurons, but we may be able to ensure their most optimal functioning through modulation of meningeal lymphatic vessels.”