The researchers argue that a sizable proportion of drugs and other compounds can bind to melanin pigments in the skin, leading to differences in how bioavailable and efficacious these drugs and other compounds are in people with varying skin tones.

“Our review paper concludes that melanin, the pigment responsible for skin color, shows a surprising affinity for certain drug compounds,” said Simon Groen, an assistant professor of evolutionary systems biology in the Institute of Integrative Genome Biology at the University of California, Riverside, and a coauthor on the paper. “Melanin’s implications for drug safety and dosing have been largely overlooked, raising alarming questions about the efficacy of standard dosing since people vary a lot in skin tones.”

According to Groen and coauthor Sophie Zaaijer, a consultant and researcher affiliated with UC Riverside who specializes in diversity, equity, and inclusion (DEI) in preclinical R&D and clinical trials, current FDA guidelines for toxicity testing fail to adequately address the impact of skin pigmentation on drug interactions.

“This oversight is particularly concerning given the push for more diverse clinical trials, as outlined in the agency’s Diversity Action Plan,” Zaaijer said. “But current early-stage drug development practices still primarily focus on drug testing in white populations of Northern European descent.”

In one example, the researchers found evidence of nicotine affinity for skin pigments, potentially affecting smoking habits across people with a variety of skin tones and raising questions about the efficacy of skin-adhered nicotine patches for smoking cessation.

“Are we inadvertently shortchanging smokers with darker skin tones if they turn to these patches in their attempts to quit?” Groen said.

Groen and Zaaijer propose utilizing a new workflow involving human 3D skin models with varying pigmentation levels that could offer pharmaceutical companies an efficient method to assess drug binding properties across different skin types.

“Skin pigmentation should be considered as a factor in safety and dosing estimates,” Zaaijer said. “We stand on the brink of a transformative era in the biomedical industry, where embracing inclusivity is not just an option anymore but a necessity.”

According to the researchers, skin pigmentation is just one example. Genetic variations among minority groups can lead to starkly different drug responses across races and ethnicities, affecting up to 20% of all medications, they said.

“Yet, our molecular understanding of these differences remains very limited,” Zaaijer said.

The researchers acknowledge that transformations enhancing inclusivity — encompassing race, ethnicity, sex, and age — demand a comprehensive overhaul of all FDA guidelines on clinical endpoints to align with the FDA’s Diversity Action Plan.

“It’s a monumental task, requiring clear lines of communication between academics, industry researchers, clinicians, and regulators,” Zaaijer said. “The future of medicine relies on our capacity to connect these currently isolated operational teams.”

The researchers point out that a shift towards inclusive drug development is set to take place as instigated by a new law, the Food and Drug Omnibus Reform Act, enacted in 2022.

“The FDA published their draft guidelines recently,” Zaaijer said. “Once final in a few months, they will mandate considering patient diversity in clinical trials and preclinical R&D. The next step is to provide guidance on what pharmacokinetic variables should be tested in drug R&D pipelines in their pursuit to equitable drugs.”

The researchers hope to activate the pharmaceutical industry and academia to start doing systematic experimental evaluations in preclinical research in relation to skin pigmentation and drug kinetics.

They also encourage patients, their advocacy groups, and clinical trial participants to ask questions related to ancestry-specific drug efficacy and safety, such as, “Has this drug been tested to see if it’s safe for people from different ancestral backgrounds, including mine?” Clinicians and pharmaceutical representatives should be able to provide an easy-to-understand document outlining the results of the various tests, the researchers said.

They acknowledge that in the current state of drug development this will be hard.

“In terms of risk profile testing, drugs are most often tested on one or a few human cell models that mostly come from donors of Northern European descent,” Zaaijer said. “Drugs are then tested in a rodent model. If these tests are successful, drug companies push the drug through to clinical trials. But are drugs ready to be given to a diverse patient group if they haven’t first been tested, for example, on human cell models of different ancestries? Would you bungee jump off a bridge if you know the ropes have not been tested for your weight category? Unlikely. So why is this currently acceptable with drugs?”

Groen explained that in different ancestral backgrounds certain genetic variants are more prevalent. Those variants can affect how a drug is metabolized and how it behaves in a body, he said.

“If different ancestral backgrounds are taken into consideration in the early stages of drug discovery, then diverse groups of people may have more trust in the drug development process and enroll in clinical trials because they will be better informed of any potential associated risks,” he said.

The researchers sampled groundwater in two different watersheds adjacent to the Fayetteville Works fluorochemical plant in Bladen County.

“There’s a huge area of PFAS contaminated groundwater — including residential and agricultural land — which impacts the population in two ways,” says David Genereux, professor of marine, earth and atmospheric sciences at NC State and leader of the study.

“First, there are over 7,000 private wells whose users are directly affected by the contamination. Second, groundwater carrying PFAS discharges into tributaries of the Cape Fear River, which affects downstream users of river water in and near Wilmington.”

The researchers tested the samples they took to determine PFAS types and levels, then used groundwater age-dating tracers, coupled with atmospheric contamination data from the N.C. Department of Environmental Quality and the rate of groundwater flow, to create a model that estimated both past and future PFAS concentrations in the groundwater discharging to tributary streams.

They detected PFAS in groundwater up to 43 years old, and concentrations of the two most commonly found PFAS — hexafluoropropylene oxide-dimer acid (HFPO−DA) and perfluoro-2-methoxypropanoic acid (PMPA) — averaged 229 and 498 nanograms per liter (ng/L), respectively. For comparison, the maximum contaminant level (MCL) issued by the U.S. Environmental Protection Agency for HFPO-DA in public drinking water is 10 ng/L. MCLs are enforceable drinking water standards.

“These results suggest it could take decades for natural groundwater flow to flush out groundwater PFAS still present from the ‘high emission years,’ roughly the period between 1980 and 2019,” Genereux says. “And this could be an underestimate; the time scale could be longer if PFAS is diffusing into and out of low-permeability zones (clay layers and lenses) below the water table.”

The researchers point out that although air emissions of PFAS are substantially lower now than they were prior to 2019, they are not zero, so some atmospheric deposition of PFAS seems likely to continue to feed into the groundwater.

“Even a best-case scenario — without further atmospheric deposition — would mean that PFAS emitted in past decades will slowly flush from groundwater to surface water for about 40 more years,” Genereux says. “We expect groundwater PFAS contamination to be a multi-decade problem, and our work puts some specific numbers behind that. We plan to build on this work by modeling future PFAS at individual drinking water wells and working with toxicologists to relate past PFAS levels at wells to observable health outcomes.”

The solutions to these long-standing problems could further enhance our understanding of symmetries of structures and objects in nature and science, and of long-term behavior of various random processes arising in fields ranging from chemistry and physics to engineering, computer science and economics.

Pham Tiep, the Joshua Barlaz Distinguished Professor of Mathematics in the Rutgers School of Arts and Science’s Department of Mathematics, has completed a proof of the 1955 Height Zero Conjecture posed by Richard Brauer, a leading German-American mathematician who died in 1977. Proof of the conjecture — commonly viewed as one of the most outstanding challenges in a field of math known as the representation theory of finite groups — was published in the September issue of the Annals of Mathematics.

“A conjecture is an idea that you believe has some validity,” said Tiep, who has thought about the Brauer problem for most of his career and worked on it intensively for the past 10 years. “But conjectures have to be proven.I was hoping to advance the field. I never expected to be able to solve this one.”

In a sense, Tiep and his colleagues have been following a blueprint of challenges Brauer laid out for them in a series of mathematical conjectures posed and published in the 1950-60s.

“Some mathematicians have this rare intellect,” Tiep said of Brauer. “It’s as though they came from another planet or from another world. They are capable of seeing hidden phenomena that others can’t.”

In the second advance, Tiep solved a difficult problem in what is known as the Deligne-Lusztig theory, part of the foundational machinery of representation theory. The breakthrough touches on traces, an important feature of a rectangular array known as a matrix. The trace of a matrix is the sum of its diagonal elements. The work is detailed in two papers, one was published in Inventiones mathematicae, vol. 235 (2024), the second in Annals, vol. 200 (2024).

“Tiep’s high-quality work and expertise on finite groups has allowed Rutgers to maintain its status as a top world-wide center in the subject,” said Stephen Miller, a Distinguished Professor and Chair of the Department of Mathematics. “One of the great accomplishments in 20^th century mathematics was the classification of the so-called but perhaps misleadingly named ‘simple’ finite groups, and it is synonymous with Rutgers — it was led from here and many of the most interesting examples were discovered here. Through his amazing stretch of strong work, Tiep brings international visibility to our department.”

Insights from the solution are likely to greatly enhance mathematicians’ understanding of traces, Tiep said. The solution also provides insights that could lead to breakthroughs in other important problems in mathematics, including conjectures posed by the University of Florida mathematician John Thompson and the Israeli mathematician Alexander Lubotzky, he added.

Both breakthroughs are advances in the field of representation theory of finite groups, a subset of algebra. Representation theory is an important tool in many areas of math, including number theory and algebraic geometry as well as in the physical sciences, including particle physics. Through mathematical objects known as groups, representation theory also has been used to study symmetry in molecules, encrypt messages and produce error-correcting codes.

Following the principles of representation theory, mathematicians take abstract shapes that exist in Euclidean geometry — some of them extremely complex — and transform them into arrays of numbers. This can be achieved by identifying certain points that exist in each three- or higher-dimensional shape and converting them to numbers placed in rows and columns.

The reverse operation must work, too, Tiep said: One needs to be able to reconstitute the shape from the sequence of numbers.

Unlike many of his colleagues in the physical sciences who often employ complex devices to advance their work, Tiep said he uses only a pen and paper to conduct his research, which so far has resulted in five books and more than 200 papers in leading mathematical journals.

He jots down math formulas or sentences indicating chains of logic. He also engages in continual conversations — in person or on Zoom — with colleagues as they proceed step by step through a proof.

But progress can come from internal reflection, Tiep said, and ideas burst forth when he is least expecting it.

“Maybe I’m walking with our children or doing some gardening with my wife or just doing something in the kitchen,” he said. “My wife says she always knows when I’m thinking about math.”

On the first proof, Tiep collaborated with Gunter Malle of Technische Universität Kaiserslautern in Germany, Gabriel Navarro of Universitat de València in Spain and Amanda Schaeffer Fry, a former graduate student of Tiep’s who is now at the University of Denver.

For the second breakthrough, Tiep worked with Robert Guralnick of the University of Southern California and Michael Larsen of Indiana University. On the first of two papers that tackle the mathematical problems on traces and solve them, Tiep worked with Guralnick and Larsen. Tiep and Larsen are co-authors of the second paper.

“Tiep and coauthors have obtained bounds on traces which are about as good as we could ever expect to obtain,” Miller said. “It’s a mature subject which is important from many angles, so progress is hard — and applications are many.”

Now, new research reveals that these tiny suitors are leveraging a flexible network of modular brain circuits to quickly adapt to different mating signals. The study, published in Nature, is the first to describe how diverse species of fruit flies plug new sensory inputs, such as pheromones, into a set of basic brain circuits without needing to develop new neural pathways from scratch.

The findings offer a larger framework for understanding how brain wiring can change to influence behavioral evolution. “The diversity of behaviors across the animal kingdom is enormous, but the underlying mechanisms of how nervous systems are shaped by evolution have been very difficult to unravel,” says Vanessa Ruta, head of the Laboratory of Neurophysiology and Behavior. “Here we uncovered what we believe is a key neural mechanism that gives brain circuits the flexibility to rewire across species.”

Plug-and-play

One of the great mysteries of behavioral evolution is how, as species diversify, brain circuits keep pace with the rapid changes in social signals that allow individuals to find their ideal mates. Courtship behaviors, for instance, evolve quickly, making it difficult to imagine that the fly brain completely reinvents itself every time a new pheromone enters the Drosophila repertoire.

But until now, it was not possible to identify where evolution acts in the nervous system to alter behavior, and so the key features of what makes such circuits so adaptable remained a mystery. Ruta’s group turned to fruit flies, where closely related species share similar brains but rely on vastly different cues for mating rituals. D. simulans, for instance, mainly relies on visual cues to find a mate, while D. yakuba evolved a novel capacity to use pheromones to find a mate even in complete darkness. These and other variations presented an opportunity to study how similar brains detect and perceive different social cues.

“We started looking for parts of the brain that might be primed for flexibility,” says Rory Coleman, first author on the study and a postdoctoral fellow in the Ruta lab. “We were searching for features that might make the circuit intrinsically adaptable, potential evolutionary hotspots driving behavioral diversification.”

After comparing pheromone-sensing circuits across multiple species — using behavioral assays, genetic tools, neuroimaging, and CRISPR genome editing — they ultimately singled out sensory neurons in the male forelegs and P1 neurons in the higher brain as key to modulating courtship across species. The team found that the basic neural building blocks of male mating behaviors, such as the P1 neurons, are present across species, but different sensory signals can be flexibly wired into this node. This allows fly species to develop different mating strategies without rewiring their entire brains.

For instance, the researchers found that P1 neurons were activated in response to entirely different types of pheromones in D. melanogaster and D. yakuba. Yet the role of P1 neurons in initiating courtship was still conserved across both species. “One important discovery from our work is that there are discrete nodes within the brains of each of these species that can flexibly integrate new sensory modalities,” Ruta says. “This flexibility allows conserved nodes like the P1 neurons to still initiate courtship in different species but respond to the distinct cues of their females.”

A social brain

This research falls under the umbrella of Rockefeller’s Price Family Center for the Social Brain, an initiative focusing on understanding the neuronal, cellular, and molecular foundations of social behavior. In addition to shedding light on flexibility in the face of new sensory inputs, the present work also illustrates an experimental approach for studying how social behaviors evolve across species. “Our results demonstrate that Drosophila is a powerful system for studying behavioral evolution,” Ruta says.

By examining how variations in neural circuits shape behaviors like mating, the lab hopes to advance our understanding of the complex interplay between brain function and social behaviors, providing a framework for understanding how social circuits are built to produce adaptive behaviors in the human brain. And while the brain structures of flies and humans differ substantially, it is likely some of the underlying principles of how neural circuits evolve and adapt are conserved across species

“We hope that comparative evolutionary studies like this one will reveal the core rules shaping how neural circuits have been built across the animal kingdom, including in humans,” Coleman says. “Many neurological disorders are thought to arise from the miswiring of circuits” Ruta adds. “By examining neural circuits through the lens of evolution, we hope to shed light on which neural motifs can change and how they can be altered, not through the ravages of disease, but as a consequence of evolutionary selection.”

With MS, the body’s immune system attacks myelin, the fatty, white substance that insulates and protects the nerves. MS is chronic and can be unpredictable and disabling.

“People with MS undergo an increased number of tests to monitor MS, making it more likely to detect other diseases,” said study author Emmanuelle Leray, PhD, of Rennes University in France. “We found an association between some types of cancer and MS which may have different explanations depending on a person’s age and the types of cancer. Overall, our study found the increased risk of cancer was quite small.”

For the study, researchers reviewed 10 years of data in the French national health care database. Researchers identified 140,649 people with MS and matched them for factors such as age, sex and residence to 562,596 people without MS. All participants were cancer free three years before the study. They were followed for an average of eight years.

During the study, 8,368 people with MS and 31,796 people without MS developed cancer.

Researchers determined there were 799 cancers per 100,000 person-years for people with MS and 736 cancers per 100,000 person-years for people without MS. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

Researchers found people with MS had a 6% increased risk of developing any type of cancer regardless of age, sex and residence. They also found cancer risk was higher in those under 55 and lower in people 65 and older when compared to people without MS.

Researchers then looked at cancer types. People with MS had a 71% increased risk for bladder cancer, a 68% increased risk for brain cancer and a 24% increased risk for cervical cancer. However, they also had a 20% lower risk of prostate cancer, a 10% lower risk of colorectal cancer and a 9% lower risk of breast cancer.

“While our study found a higher risk for brain cancer, it may be due in part to earlier detection in those with MS since they regularly have brain scans which may detect cancers earlier, before a person has symptoms,” said Leray. “Frequent urinary tract infections in people with MS and the use of immunosuppressant drugs may contribute to their higher risk of bladder and cervical cancers.”

Leray added, “The lower risk for colorectal and breast cancers may be due in part to fewer people with MS getting screened for cancer in older age when they may be experiencing more MS symptoms. More research is needed, including studies that look at more closely at how cancer screenings may play a role.”

A limitation of the study was that researchers were unable to adjust for factors such as education, income, smoking and alcohol consumption since this information was not available in the national database.

The study was supported by the Rennes Institute of Clinical Neurosciences and the EDMUS-ARSEP Foundation.