The research is published Aug. 2 in Science Advances.

The compound targets gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome and other illnesses that can turn deadly. It was developed through a collaboration between the labs of Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology, and Michael Caparon, PhD, a professor of molecular microbiology, and Fredrik Almqvist, a professor of chemistry at the University of Umeå in Sweden.

A new type of antimicrobial would be good news for clinicians seeking effective treatments against pathogens that are becoming more resistant to currently available drugs, and thus much more dangerous.

“All of the gram-positive bacteria that we’ve tested have been susceptible to that compound. That includes enterococci, staphylococci, streptococci, C. difficile, which are the major pathogenic bacteria types,” said Caparon, the co-senior author. “The compounds have broad-spectrum activity against numerous bacteria.”

It’s based on a type of molecule called ring-fused 2-pyridone. Initially, Caparon and Hultgren had asked Almqvist to develop a compound that might prevent bacterial films from attaching to the surface of urethral catheters, a common cause of hospital-associated urinary tract infections. Discovering that the resulting compound had infection-fighting properties against multiple types of bacteria was a happy accident.

The team named their new family of compounds GmPcides (for gram-positive-icide). In past work, the authors showed that GmPcides can wipe out bacteria strains in petri dish experiments. In this latest study, they decided to test it on necrotizing soft-tissue infections, which are fast-spreading infections usually involving multiple types of gram-positive bacteria, for which Caparon already had a working mouse model. The best known of these, necrotizing fasciitis or “flesh-eating disease,” can quickly damage tissue severely enough to require limb amputation to control its spread. About 20% of patients with flesh-eating disease die.

This study focused on one pathogen, Streptococcus pyogenes, which is responsible for 500,000 deaths every year globally, including flesh-eating disease. Mice infected with S. pyogenes and treated with a GmPcide fared better than did untreated animals in almost every metric. They had less weight loss, the ulcers characteristic of the infection were smaller, and they fought off the infection faster.

The compound appeared to reduce the virulence of the bacteria and, remarkably, speed up post-infection healing of the damaged areas of the skin.

It is not clear how GmPcides accomplish all of this, but microscopic examination revealed that the treatment appears to have a significant effect on bacterial cell membranes, which are the outer wrapping of the microbes.

“One of the jobs of a membrane is to exclude material from the outside,” Caparon said. “We know that within five to ten minutes of treatment with GmPcide, the membranes start to become permeable and allow things that normally should be excluded to enter into the bacteria, which suggests that those membranes have been damaged.”

This can disrupt the bacteria’s own functions, including those that cause damage to their host, and make the bacteria less effective at combating the host’s immune response to infections.

In addition to their antibacterial effectiveness, GmPcides appear to be less likely to lead to drug-resistant strains. Experiments designed to create resistant bacteria found very few cells able to withstand treatment and thus pass on their advantages to the next generation of bacteria.

Caparon explained that there is a long way to go before GmPcides are likely to find their way into local pharmacies. Caparon, Hultgren and Almqvist have patented the compound used in the study and licensed it to a company, QureTech Bio, in which they have an ownership stake, with the expectation that they will be able to collaborate with a company that has the capacity to manage the pharmaceutical development and clinical trials to potentially bring GmPcides to market.

Hultgren said that the kind of collaborative science that created GmPcides is what is needed to treat intractable problems like antimicrobial resistance.

“Bacterial infections of every type are an important health problem, and they are increasingly becoming multi-drug resistant and thus harder to treat,” he said. “Interdisciplinary science facilitates the integration of different fields of study that can lead to synergistic new ideas that have the potential to help patients.”

The latest study conducted in the center, housed in the College of Agricultural Sciences, investigated how eating behavior changes when consumers are served a dip with a salty snack. The findings, available online now and to be published in the November issue of Food Quality and Preference, suggest that they eat more — a lot more. The chips and dip together yielded a 77% greater caloric intake, and a faster total eating rate compared to the just chips, no-dip control.

However, there was no difference in chip intake, pointed out study corresponding author John Hayes, professor of food science and director of the Penn State Sensory Evaluation Center.

“The most striking findings of our study is that people didn’t eat fewer chips when dip was available — they ate the same amount of chips, plus the dip,” he said. “This lack of compensation means that adding dip to chips can substantially increase overall energy intake without people realizing it.”

Intuitively, many people would guess that if we add something extra to a snack, like dip, people will compensate, and eat less of the main item, Hayes explained.

“But our research shows this is not the case with chips and dip,” he said. “Our participants consumed the same amount of chips regardless of whether dip was present, leading to much greater energy intake when dip was available.”

The study, which was led by research assistant Madeline Harper, who recently graduated from Penn State with a master’s degree in food science, assessed 46 adult participants. In two visits to the Sensory Evaluation Center, they were served 70 grams of ranch-flavored chips, or about 2.5 servings, with or without about a third of a cup of ranch dip. Participants ate as much as they wanted.

Their intake was measured, and all eating sessions were video recorded and annotated for number of bites and active eating time. Researchers used that information to calculate measures of “eating microstructure,” including eating rate and bite size.

Harper suggested that the greater intake of the chips and dip snack was facilitated by a larger bite size resulting from dip inclusion. On average per eating session, participants consumed 345 calories of chips and dip compared to 195 calories of chips alone.

The study was novel, Harper noted, because little research has been conducted on the effect of external sources of oral lubrication like dips on oral processing of salty snacks.

“Clearly, it has an influence on food intake, especially while snacking,” she said. “However, in this chips-and-dip snack, the greater intake resulting from dip inclusion may have been facilitated by a larger total snack bite size, as opposed to faster chip eating rate.”

Even though snacking is a major source of energy in the typical American diet, it remains understudied, Hayes said, adding that understanding eating behavior around snacking is crucial to address issues of overeating and obesity.

“This research opens up new avenues for exploring how the physical properties of foods can influence our eating behaviors and ultimately, our energy intake,” he said. “If we can slow people down, we can influence energy consumption without giving up the pleasure from food.”

Paige Cunningham, postdoctoral scholar in the Department of Food Science and the Department of Nutritional Sciences at Penn State, contributed to the research.

The U.S. Department of Agriculture’s National Institute of Food and Agriculture supported this research.

Medulloblastoma is the most common malignant brain tumor in children. Survival rates vary according to which one of the four subtypes a patient has, but the worst survival rates, historically at about 40%, are for Group 3, which this research focused on.

Jezabel Rodriguez Blanco, Ph.D., an assistant professor who holds dual appointments at MUSC Hollings Cancer Center and the Darby Children’s Research Institute at MUSC, led the research, published in the Journal of Clinical Investigation.

Her research focused on the drug triptolide, which is extracted from a vine used in traditional Chinese medicine, and its water-soluble prodrug version, Minnelide. A prodrug is an inactive medication that the body converts into an active drug through enzymatic or chemical reactions.

MYC is an oncogene, or gene that has the potential to cause cancer. MYC is dysregulated, or out of control, in about 70% of human cancers, and it shows up in much higher levels in Group 3 medulloblastoma than in the other medulloblastoma subgroups. Despite its well-known role in cancer, this oncogene historically has been considered impossible to target with drugs.

Despite its poor druggability, previous research in other cancers had shown that triptolide and its derivatives had the ability to target MYC. When Blanco was still a postdoctoral fellow at the University of Miami, her mentor, David Robbins, Ph.D., attended a presentation by the research team that showed that the more copies of MYC that a tumor has, the better that triptolide works.

“He came to me, and he told me, ‘You know, as Group 3 medulloblastoma has many MYC copies, you should get some research models and try the drug,” Blanco recalled. She started the project from scratch. “I started talking to people, getting cell lines and animal models, learning how to propagate them, getting the drug, using it.”

Blanco received a three-month grant intended for cancer center trainees to develop ideas. Then her lab at the time was awarded a one-year grant from the Southeastern Brain Tumor Foundation in 2018. Since then, she’s received no additional funding specific to this project. Even as she started her faculty position at MUSC and began to focus most of her research on the Sonic Hedgehog subgroup of medulloblastoma, she continued to work on the Group 3 research as a side project. She knew how well triptolide was working in these hard-to-treat tumors, and she did not want her initial results to fall through the cracks.

Determining the mechanism of action has been the most challenging part of the project, she noted, due to the drug’s multiple effects, and there could still be additional mechanisms beyond those that Blanco identified.

“It was affecting MYC gene expression by affecting the RNA pol II activity, and then it was affecting how long the protein lasts. So, the fact that it’s working through two different mechanisms on this oncogene may explain why it’s so effective in tumors that have extra copies of MYC,” she said, explaining that RNA polymerase II is a protein that helps to make copies of DNA instructions, which are used to produce proteins in the cell.

Despite the challenges of narrowing down the mechanism of action specific to the cancer, it was quite clear that however it worked, it did work, she said.

The efficacy was 100 times higher in the Group 3 tumors with extra MYC copies than in the Sonic Hedgehog tumors with normal levels of MYC, she said. She found that Minnelide reduced tumor growth and the spread of cancer cells to the thin tissues that cover the brain and spinal cord, called leptomeninges. It also increased the efficacy of the chemotherapy drug cyclophosphamide, which is currently used in treatment.

Blanco decided to move forward with publication rather than waiting to write a manuscript that answered all possible questions. Knowing that most parents whose children receive a Group 3 medulloblastoma diagnosis will lose their child in less than two years was the incentive she needed to push this work out.

“There was a point at which I could not hold these data anymore because it was working so well that it needed to go out,” she said. “The preclinical models were showing such a nice efficacy that it was like, ‘OK, I cannot keep on holding this work, digging deeper into the mechanism of action because the kids that have Group 3 medulloblastoma are dying while we are doing those experiments.”

Minnelide has been tested or is currently in testing in phase I and phase II clinical trials of adults with different types of cancer, including pancreatic cancer, where it showed some efficacy.

Blanco is hopeful that, with this new research on Group 3 medulloblastoma, a clinical trial for children with this disease can be launched.

That would make the tropical Andes the first region in the world known to pass that threshold as a result of the steadily warming global climate. It also makes them possible harbingers of what’s to come for glaciers globally.

“We think these are the canary in the coal mine. The tropics would probably be the first place you’d expect ice to disappear, and that’s what we’re seeing,” says Shaun Marcott, a professor of geoscience at UW-Madison. Marcott guided the research with colleagues at Boston College and Tulane University. Andrew Gorin, a former Boston College graduate student who is now at University of California, Berkeley, led the study, which appears in the Aug. 2, 2024, issue of the journal Science.

Glaciers grow slowly over time in regions where summer weather isn’t warm enough to melt all of the previous winter’s snowfall. Over time, unmelted snow collects and gets compacted and begins to move under its own weight, resulting in the year-round ice that defines a glacier.

Satellite imagery and on-the-ground observations have provided conclusive evidence for decades that high-altitude glaciers in the Andes are steadily shrinking as warmer temperatures cause them to melt more quickly than falling snow can replenish them.

What has remained unclear, though, is whether the glaciers’ dwindling footprints are anomalously small compared to the rest of the period that began at the end of the last ice age, known as the Holocene. Meanwhile, glaciers in other parts of the world were smaller at some points in the early Holocene, when the global climate was warmer and drier than recent millennia.

“We knew that glaciers ebbed and flowed in the past, so we wanted to learn how the behavior of glaciers today — melting due to human-caused climate change — stacks up against their long-term fluctuations,” says Andy Jones, a UW-Madison doctoral student and study co-author.

To answer this question, the team of scientists analyzed the geochemistry of bedrock from areas near the edges of four glaciers in the high tropical Andes, choosing sites that satellite imagery showed were exposed by melting ice in only the last two or three decades.

The team specifically looked for evidence of two unique isotopes — basically chemical flavors — of a pair of elements with the bedrock’s quartz crystals: beryllium-10 and carbon-14. These isotopes are only present in rock that has spent time at or near the Earth’s surface as they result from interactions between the rock and cosmic rays, which are high-energy particles that constantly rain down on the planet from outer space.

Bedrock accumulates beryllium-10 and carbon-14 once it’s exposed to the surface, so measuring the isotopes’ concentrations in rock crystals near glaciers can be useful for understanding the previous extent of ice coverage. The team found “remarkably low” concentrations of both isotopes in nearly all samples, suggesting that melting ice has exposed bedrock near the glaciers for the first time only recently in most of the sampled locations.

Additional analyses — and the fact that the extremely low concentrations were consistent across sample sites — made the researchers confident that melting ice, rather than erosion, exposed the bedrock.

“It’s highly unlikely this is from erosion,” says Marcott. “Because the multiple locations we went to all show the same thing.”

This consistency points to a single likely conclusion, according to Marcott: The world’s tropical glaciers, more than 99% of which are located in the Andes, are the first to shrink beyond what’s been seen in the recent geologic past.

“Glaciers are very sensitive to the climate system that they live in,” says Marcott. “They really are the place you would look to see some of the first big changes resulting from a warming climate. You can look to these glaciers and imagine what we might be looking at going into the future in other places like the Western United States, which is a no-ice scenario.”

This research was supported by the National Science Foundation (EAR-1805620; EAR-1805133; EAR-1805892).

In electronic technologies, key material properties change in response to stimuli like voltage or current. Scientists aim to understand these changes in terms of the material’s structure at the nanoscale (a few atoms) and microscale (the thickness of a piece of paper). Often neglected is the realm between, the mesoscale — spanning 10 billionths to 1 millionth of a meter.

Scientists at the U.S. Department of Energy’s (DOE) Argonne National Laboratory, in collaboration with Rice University and DOE’s Lawrence Berkeley National Laboratory, have made significant strides in understanding the mesoscale properties of a ferroelectric material under an electric field. This breakthrough holds potential for advances in computer memory, lasers for scientific instruments and sensors for ultraprecise measurements.

The ferroelectric material is an oxide containing a complex mixture of lead, magnesium, niobium and titanium. Scientists refer to this material as a relaxor ferroelectric. It is characterized by tiny pairs of positive and negative charges, or dipoles, that group into clusters called “polar nanodomains.” Under an electric field, these dipoles align in the same direction, causing the material to change shape, or strain. Similarly, applying a strain can alter the dipole direction, creating an electric field.

“If you analyze a material at the nanoscale, you only learn about the average atomic structure within an ultrasmall region,” said Yue Cao, an Argonne physicist. “But materials are not necessarily uniform and do not respond in the same way to an electric field in all parts. This is where the mesoscale can paint a more complete picture bridging the nano- to microscale.”

A fully functional device based on a relaxor ferroelectric was produced by professor Lane Martin’s group at Rice University to test the material under operating conditions. Its main component is a thin film (55 nanometers) of the relaxor ferroelectric sandwiched between nanoscale layers that serve as electrodes to apply a voltage and generate an electric field.

Using beamlines in sectors 26-ID and 33-ID of Argonne’s Advanced Photon Source (APS), Argonne team members mapped the mesoscale structures within the relaxor. Key to the success of this experiment was a specialized capability called coherent X-ray nanodiffraction, available through the Hard X-ray Nanoprobe (Beamline 26-ID) operated by the Center for Nanoscale Materials at Argonne and the APS. Both are DOE Office of Science user facilities.

The results showed that, under an electric field, the nanodomains self-assemble into mesoscale structures consisting of dipoles that align in a complex tile-like pattern (see image). The team identified the strain locations along the borders of this pattern and the regions responding more strongly to the electric field.

“These submicroscale structures represent a new form of nanodomain self-assembly not known previously,” noted John Mitchell, an Argonne Distinguished Fellow. “Amazingly, we could trace their origin all the way back down to underlying nanoscale atomic motions; it’s fantastic!”

“Our insights into the mesoscale structures provide a new approach to the design of smaller electromechanical devices that work in ways not thought possible,” Martin said.

“The brighter and more coherent X-ray beams now possible with the recent APS upgrade will allow us to continue to improve our device,” said Hao Zheng, the lead author of the research and a beamline scientist at the APS. “We can then assess whether the device has application for energy-efficient microelectronics, such as neuromorphic computing modeled on the human brain.” Low-power microelectronics are essential for addressing the ever-growing power demands from electronic devices around the world, including cell phones, desktop computers and supercomputers.

This research is reported in Science. In addition to Cao, Martin, Mitchell and Zheng, authors include Tao Zhou, Dina Sheyfer, Jieun Kim, Jiyeob Kim, Travis Frazer, Zhonghou Cai, Martin Holt and Zhan Zhang.

Funding for the research came from the DOE Office of Basic Energy Sciences and National Science Foundation.

“These findings add to growing evidence of increased cancer risk in post-Baby Boomer generations, expanding on previous findings of early-onset colorectal cancer and a few obesity-associated cancers to encompass a broader range of cancer types,” said Dr. Hyuna Sung, lead author of the study and a senior principal scientist of surveillance and health equity science at the American Cancer Society. “Birth cohorts, groups of people classified by their birth year, share unique social, economic, political, and climate environments, which affect their exposure to cancer risk factors during their crucial developmental years. Although we have identified cancer trends associated with birth years, we don’t yet have a clear explanation for why these rates are rising.”

In this analysis, researchers obtained incidence data from 23,654,000 patients diagnosed with 34 types of cancer and mortality data from 7,348,137 deaths for 25 types of cancer for individuals aged 25-84 years for the period Jan 1, 2000, to Dec 31, 2019, from the North American Association of Central Cancer Registries and the U.S. National Center for Health Statistics, respectively. To compare cancer rates across generations, they calculated birth cohort-specific incidence rate ratios and mortality rate ratios, adjusted for age effect and period effect, by birth years, separated by five-year intervals, from 1920 to 1990.

Researchers found that incidence rates increased with each successive birth cohort born since approximately 1920 for eight of 34 cancers. In particular, the incidence rate was approximately two-to-three times higher in the 1990 birth cohort than in the 1955 birth cohort for pancreatic, Kidney, and small intestinal cancers in both male and female individuals; and for liver cancer in female individuals. Additionally, incidence rates increased in younger cohorts, after a decline in older birth cohorts, for nine of the remaining cancers including breast cancer (estrogen-receptor positive only), uterine corpus cancer, colorectal cancer, non-cardia gastric cancer, gallbladder cancer, ovarian cancer, testicular cancer, anal cancer in male individuals, and Kaposi sarcoma in male individuals. Across cancer types, the incidence rate in the 1990 birth cohort ranged from 12% for ovarian cancer to 169% for uterine corpus cancer higher than the rate in the birth cohort with the lowest incidence rate. Notably, mortality rates increased in successively younger birth cohorts alongside incidence rates for liver cancer (female only), uterine corpus, gallbladder, testicular, and colorectal cancers.

“The increase in cancer rates among this younger group of people indicate generational shifts in cancer risk and often serve as an early indicator of future cancer burden in the country. Without effective population-level interventions, and as the elevated risk in younger generations is carried over as individuals age, an overall increase in cancer burden could occur in the future, halting or reversing decades of progress against the disease,” added Dr. Ahmedin Jemal, senior vice president, surveillance and health equity science at the American Cancer Society and senior author of the study. “The data highlights the critical need to identify and address underlying risk factors in Gen X and Millennial populations to inform prevention strategies.”

“The increasing cancer burden among younger generations underscores the importance of ensuring people of all ages have access to affordable, comprehensive health insurance, a key factor in cancer outcomes,” said Lisa Lacasse, president of the American Cancer Society Cancer Action Network (ACS CAN). “To that end, ACS CAN will continue our longstanding work to urge lawmakers to expand Medicaid in states that have yet to do so as well as continue to advocate for making permanent the enhanced Affordable Care Act tax subsidies that have opened the door to access to care for millions.”

The rapid advancement of AI technology, including applications like generative AI, has pushed the scalability of existing digital hardware (CPUs, GPUs, ASICs, etc.) to its limits. Consequently, there is active research into analog hardware specialized for AI computation. Analog hardware adjusts the resistance of semiconductors based on external voltage or current and utilizes a cross-point array structure with vertically crossed memory devices to process AI computation in parallel. Although it offers advantages over digital hardware for specific computational tasks and continuous data processing, meeting the diverse requirements for computational learning and inference remains challenging.

To address the limitations of analog hardware memory devices, the research team focused on Electrochemical Random Access Memory (ECRAM), which manage electrical conductivity through ion movement and concentration. Unlike traditional semiconductor memory, these devices feature a three-terminal structure with separate paths for reading and writing data, allowing for operation at relatively low power.

In their study, the team successfully fabricated ECRAM devices using three-terminal-based semiconductors in a 64×64 array. Experiments revealed that the hardware incorporating the team’s devices demonstrated excellent electrical and switching characteristics, along with high yield and uniformity. Additionally, the team applied the Tiki-Taka algorithm, a cutting-edge analog-based learning algorithm, to this high-yield hardware, successfully maximizing the accuracy of AI neural network training computations. Notably, the researchers demonstrated the impact of the “weight retention” property of hardware training on learning and confirmed that their technique does not overload artificial neural networks, highlighting the potential for commercializing the technology.

This research is significant because the largest array of ECRAM devices for storing and processing analog signals reported in the literature to date is 10×10. The researchers have now successfully implemented these devices on the largest scale, with varied characteristics for each device.

Professor Seyoung Kim of POSTECH remarked, “By realizing large-scale arrays based on novel memory device technologies and developing analog-specific AI algorithms, we have identified the potential for AI computational performance and energy efficiency that far surpass current digital methods.”

The research was conducted with support from the Ministry of Trade, Industry and Energy, the Public-Private Partnership for Semiconductor Talent Training Program supported by the Korea Planning & Evaluation Institute of Industrial Technology (KEIT) and Korea Semiconductor Industry Association, and EDA Tool of the IDEC.