Publisher Health

Researchers from the University of Michigan have found that an extra copy of a gene in Down syndrome patients causes improper development of neurons in mice.
The gene in question, called Down syndrome cell adhesion molecule, or DSCAM, is also implicated in other human neurological conditions, including autism spectrum disorders, bipolar disorder and intractable epilepsy.
The cause of Down syndrome is known to be an extra copy of chromosome 21, or trisomy 21. But because this chromosome contains more than 200 genes — including DSCAM — a major challenge in Down syndrome research and treatments is determining which gene or genes on the chromosome contribute to which specific symptoms of the syndrome.
“The ideal path for treatment would be to identify the gene that causes a medical condition, and then target this gene or other genes that it works with to treat that aspect of Down syndrome,” said Bing Ye, a neuroscientist at the U-M Life Sciences Institute and lead author of the study.
“But for Down syndrome, we can’t just sequence patient genomes to find such genes, because we’d find at least 200 different genes that are changed. We have to dig deeper to figure out which of those genes causes which problem.”
For this work, researchers turn to animal models of Down syndrome. By studying mice that have a third copy of the mouse equivalent of chromosome 21, Ye and his team have now demonstrated how an extra copy of DSCAM contributes to neuronal dysfunction. Their findings are described in an April 20 study in PLOS Biology.

Each neuron has two sets of branches that extend out from the cell center: dendrites, which receive signals from other nerve cells, and axons, which send signals to other neurons. Ye and colleagues previously determined that overabundance of the protein encoded by DSCAM can cause overgrowth of axons in fruit fly neurons.
Guided by their research in flies, the team has now found that a third copy of DSCAM in mice leads to increased axon growth and neuronal connections (called synapses) in the types of neurons that put the brakes on other neurons’ activities. These changes lead to greater inhibition of other neurons in the cerebral cortex — a part of the brain that is involved in sensation, cognition and behavior.
“It’s known that these inhibitory synapses are changed in Down syndrome mouse models, but the gene that underlies this change is unknown,” said Ye, who is also a professor of cell and developmental biology at the U-M Medical School. “We show here that the extra copy of DSCAMis the primary cause of the excessive inhibitory synapses in the cerebral cortex.”
The team demonstrated that in mice that had only two copies of DSCAM, but three copies of the other genes that are similar to human chromosome 21 genes, axon growth appeared normal.
“These results are striking because, although these mice have an extra copy of about a hundred genes, normalization of this single gene, DSCAM, rescues normal inhibitory synaptic function,” said Paul Jenkins, assistant professor of pharmacology and psychiatry at the Medical School and co-corresponding author of the study.
“This suggests that modulation of DSCAM expression levels could be a viable therapeutic strategy for repairing synaptic deficits seen in Down syndrome. In addition, given that alterations of DSCAM levels are associated with other brain disorders like autism spectrum disorder and bipolar disorder, these results shed insight into potential mechanisms underlying other human diseases.”
The research was supported by the National Institutes of Health, the Brain Research Foundation and the University of Michigan. All procedures performed in mice were approved by the Institutional Animal Care and Use Committee at the University of Michigan and performed in accordance with institutional guidelines.
Study authors are Hao Liu, René Caballero-Florán, Ty Hergenreder, Tao Yang, Jacob Hull, Geng Pan, Ruonan Li, Macy W. Veling, Lori Isom, Kenneth Kwan, Paul Jenkins, and Bing Ye of U-M; Z. Josh Huang of Duke University; and Peter Fuerst of the University of Idaho.

Scientists often act as detectives, piecing together clues that alone may seem meaningless but together crack the case. Professor Reuben Shaw has spent nearly two decades piecing together such clues to understand the cellular response to metabolic stress, which occurs when cellular energy levels dip. Whether energy levels fall because the cell’s powerhouses (mitochondria) are failing or due to a lack of necessary energy-making supplies, the response is the same: get rid of the damaged mitochondria and create new ones.
Now, in a study published in Science on April 20, 2023, Shaw and team cracked the case on this process of removal and replacement. It turns out that a protein called FNIP1 is the critical link between a cell sensing low energy levels and eliminating and replacing damaged mitochondria.
“This is a final puzzle piece that connects decades of studies from labs all over the world. It solves one of the final mysteries about how the signal to make new mitochondria is tied to the original signal that energy levels are low,” says Shaw, senior author and director of Salk’s Cancer Center. “This discovery that FNIP1 is at the heart of the metabolic stress response will help us understand healthy aging, cancerous tumors, neurodegenerative diseases, and so much more. This is a fundamental cellular process that ties into many diseases and will be in textbooks for years to come.”
Nearly 15 years ago, Shaw’s lab discovered that an enzyme called AMPK was responsible for starting the removal process of damaged mitochondria. Later, the team showed that a part of this removal process is the cell breaking damaged mitochondria into hundreds of fragments, then sorting through those fragments to remove the damaged parts and repurpose the functional parts. But the question remained — how is the repair of damaged powerhouses connected to the signal to start making new powerhouses from scratch?
When mitochondria are damaged, or when sugar (glucose) or oxygen levels fall in the cell, energy levels quickly fall. After an energy decrease as small as 10 percent, AMPK is triggered. AMPK communicates with another protein, called TFEB, to instruct genes to make 1) lysosomes (cellular recycling centers) to remove damaged mitochondria, and 2) replacement mitochondria. But how AMPK and TFEB communicated was unclear.
When a new suspect, FNIP1, joined in on the metabolic stress mystery, the answer was finally within reach. FNIP1 is the most recently discovered protein of the AMPK, TFEB, FNIP1 trio. For years, researchers were only able to connect FNIP1 to AMPK, and thus thought it may be a throwaway clue or a red herring — instead, it was the clue that cracked the case.
“Many years ago, we suspected the FNIP1 protein might be important for AMPK-TFEB communication that led to mitochondria synthesis and replacement in the cell during metabolic stress, but we didn’t know how FNIP1 was involved,” says first author Nazma Malik, a postdoctoral fellow in Shaw’s lab. “If correct, this finding would finally link AMPK and TFEB, which would both enrich our understanding of metabolism and cellular communication and provide a novel target for therapeutics.”
To determine whether FNIP1 was the missing link between AMPK and TFEB, the researchers compared unaltered human kidney cells with two altered types of human kidney cells: one that lacked AMPK entirely, and another that lacked only the specific parts of FNIP1 that AMPK talks to. The team discovered that AMPK signals FNIP1, which then opens the gate to let TFEB into the nucleus of the cell. Without FNIP1 receiving the signal from AMPK, TFEB remains trapped outside the nucleus, and the entire process of breaking down and replacing damaged mitochondria is not possible. And without this robust response to metabolic stress, our bodies — along with the many plants and animals whose cells also rely on mitochondria — would not be able to function effectively.
“Watching this project evolve over the last 15 years has been a rewarding experience,” says Shaw, holder of the William R. Brody Chair. “I am proud of my dedicated, talented team, and I cannot wait to see how this monumental finding will influence future research — at Salk and beyond.”
Other authors include Bibiana I. Ferreira, Pablo E. Hollstein, Stephanie D. Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S. Shadel, and Uri Manor of the Salk Institute.
The work was supported by the National Institutes of Health (R35CA220538, P01CA120964, R01DK080425, NCI CCSG P30 CA014195, and R21 DC018237), the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), an American Heart Association and Paul G. Allen Frontiers Group award (19PABH134610000), the Salk Institute’s National Cancer Institute Cancer Center (CCSG P30 CA014195) and Nathan Shock Center for Aging Research (P30 AG068635), the Waitt Foundation, the National Science Foundation (NeuroNex award 2014862), and the Glenn Foundation.

The skin is an appealing route for drug delivery because it allows drugs to go directly to the site where they’re needed, which could be useful for wound healing, pain relief, or other medical and cosmetic applications. However, delivering drugs through the skin is difficult because the tough outer layer of the skin prevents most small molecules from passing through it.
In hopes of making it easier to deliver drugs through the skin, MIT researchers have developed a wearable patch that applies painless ultrasonic waves to the skin, creating tiny channels that drugs can pass through. This approach could lend itself to delivery of treatments for a variety of skin conditions, and could also be adapted to deliver hormones, muscle relaxants, and other drugs, the researchers say.
“The ease-of-use and high-repeatability offered by this system provides a game-changing alternative to patients and consumers suffering from skin conditions and premature skin aging,” says Canan Dagdeviren, an associate professor in MIT’s Media Lab and the senior author of the study. “Delivering drugs this way could offer less systemic toxicity and is more local, comfortable, and controllable.”
MIT research assistants Chia-Chen Yu and Aastha Shah are the lead authors of the paper, which appears in Advanced Materials, as part of the journal’s “Rising Stars” series, which showcases the outstanding work of researchers in the early stages of their independent careers. Other MIT authors include Research Assistant Colin Marcus and postdoc Md Osman Goni Nayeem. Nikta Amiri, Amit Kumar Bhayadia, and Amin Karami of the University of Buffalo are also authors of the paper.
A boost from sound waves
The researchers began this project as an exploration of alternative ways to deliver drugs. Most drugs are delivered orally or intravenously, but the skin is a route that could offer much more targeted drug delivery for certain applications.

“The main benefit with skin is that you bypass the whole gastrointestinal tract. With oral delivery, you have to deliver a much larger dose in order to account for the loss that you would have in the gastric system,” Shah says. “This is a much more targeted, focused modality of drug delivery.”
Ultrasound exposure has been shown to enhance the skin’s permeability to small-molecule drugs, but most of the existing techniques for performing this kind of drug delivery require bulky equipment. The MIT team wanted to come up with a way to perform this kind of transdermal drug delivery with a lightweight, wearable patch, which could make it easier to use for a variety of applications.
The device that they designed consists of a patch embedded with several disc-shaped piezoelectric transducers, which can convert electric currents into mechanical energy. Each disc is embedded in a polymeric cavity that contains the drug molecules dissolved in a liquid solution. When an electric current is applied to the piezoelectric elements, they generate pressure waves in the fluid, creating bubbles that burst against the skin. These bursting bubbles produce microjets of fluid that can penetrate through the skin’s tough outer layer, the stratum corneum.
“This works open the door to using vibrations to enhance drug delivery. There are several parameters that result in generation of different kinds of waveform patterns. Both mechanical and biological aspects of drug delivery can be improved by this new toolset,” Karami says.
The patch is made of PDMS, a silicone-based polymer that can adhere to the skin without tape. In this study, the researchers tested the device by delivering a B vitamin called niacinamide, an ingredient in many sunscreens and moisturizers.

In tests using pig skin, the researchers showed that when they delivered niacinamide using the ultrasound patch, the amount of drug that penetrated the skin was 26 times greater than the amount that could pass through the skin without ultrasonic assistance.
The researchers also compared the results from their new device to microneedling, a technique sometimes used for transdermal drug delivery, which involves puncturing the skin with miniature needles. The researchers found that their patch was able to deliver the same amount of niacinamide in 30 minutes that could be delivered with microneedles over a six-hour period.
Local delivery
With the current version of the device, drugs can penetrate a few millimeters into the skin, making this approach potentially useful for drugs that act locally within the skin. These could include niacinamide or vitamin C, which is used to treat age spots or other dark spots on the skin, or topical drugs used to heal burns.
With further modifications to increase the penetration depth, this technique could also be used for drugs that need to reach the bloodstream, such as caffeine, fentanyl, or lidocaine. Dagdeviren also envisions that this kind of patch could be useful for delivering hormones such as progesterone. In addition, the researchers are now exploring the possibility of implanting similar devices inside the body to deliver drugs to treat cancer or other diseases.
The researchers are also working on further optimizing the wearable patch, in hopes of testing it soon on human volunteers. They also plan to repeat the lab experiments they did in this study, with larger drug molecules.
“After we characterize the drug penetration profiles for much larger drugs, we would then see which candidates, like hormones or insulin, can be delivered using this technology, to provide a painless alternative for those who are currently bound to self-administer injections on a daily basis,” Shah says.
The research was funded by the National Science Foundation, a 3M Non-Tenured Faculty Award, the Sagol Weizmann-MIT Bridge Program, Texas Instruments, Inc., the MIT Media Lab Consortium, and a K. Lisa Yang Bionics Center Graduate Fellowship.

Marijuana (cannabis) is well known for giving people the “munchies.” Not only does it make people want to eat more, but it also makes them crave the tastiest, most high-calorie foods. Now a new study in the journal Current Biology on April 20 shows that well-studied nematode worms (C. elegans) react to those chemicals known as cannabinoids in precisely the same way.
“Cannabinoids make nematodes hungrier for their favored foods and less hungry for their non-favored foods,” says Shawn Lockery from the University of Oregon in Eugene. “Thus, the effects of cannabinoids in nematodes parallels the effects of marijuana on human appetites.
“Nematodes diverged from the lineage leading to mammals more than 500 million years ago,” he added. “It is truly remarkable that the effects of cannabinoids on appetite are preserved through this length of evolutionary time.”
Lockery explained that the new study was inspired in 2015, when cannabis became legal in Oregon. “At the time, our laboratory at the University of Oregon was deeply involved in assessing nematode food preferences as part of our research on the neuronal basis of economic decision-making,” he said. “In almost literally a ‘Friday afternoon experiment’ — read: ‘let’s dump this stuff on to see what happens’ — we decided to see if soaking worms in cannabinoids alters existing food preferences. It does, and the paper is the result of many years of follow-up research.”
Cannabinoids are known to act by binding to cannabinoid detector proteins called cannabinoid receptors in the brain, nervous system, and other parts of the body. Those receptors in the body normally respond to related molecules that are naturally present in the body, known as endocannabinoids. The endocannabinoid system plays important roles in eating, anxiety, learning and memory, reproduction, metabolism, and more.
At the molecular level, the cannabinoid system in nematodes looks a lot like that in people and other animals. It begged the question as to whether the so-called hedonic feeding effects of cannabinoids also would be conserved across species.

In the new study, the researchers first showed that worms react to the endocannabinoid anandamide by eating more. They also ate more of their favorite food. The researchers found that those effects of the endocannabinoids depended on the presence of the worms’ cannabinoid receptors.
In further studies, they genetically replaced the C. elegans cannabinoid receptor with the human cannabinoid receptor to see what would happen, and they found that the animals responded normally to cannabinoids. The discovery emphasizes the commonality of cannabinoid effects in nematodes and humans, the researchers say. They report that the effects of anandamide also depend on neurons that play a role in food detection.
“We found that the sensitivity of one of the main food-detecting olfactory neurons in C. elegans is dramatically altered by cannabinoids,” Lockery said. “Upon cannabinoid exposure, it becomes more sensitive to favored food odors and less sensitive to non-favored food odors. This effect helps explain changes in the worm’s consumption of food, and it is reminiscent of how THC makes tasty food even tastier in humans.”
The findings in worms are not only entertaining, Lockery says, but they also have significant practical implications.
“Cannabinoid signaling is present in the majority of tissues in our body,” he said. “It therefore could be involved in the cause and treatment of a wide range of diseases. The fact that the human cannabinoid receptor gene is functional in C. elegans food-choice experiments sets the stage for rapid and inexpensive screening for drugs that target a wide variety of proteins involved in cannabinoid signaling and metabolism, with profound implications for human health.”
The researchers note that big outstanding questions remain, including how cannabinoids change the sensitivity of C. elegans olfactory neurons, which don’t have cannabinoid receptors. They’re also curious to study the effects of psychedelics on nematodes.
“Perhaps we can find a new set of similarities between humans and worms, now in the case of drugs that alter perception and psychological well-being,” Lockery says.

Chitin (kai’tin) and healthy fats from insects appear to contribute to healthy gut microbiota and are strong sources of protein and nutrients, according to a paper co-authored by a Colorado State University researcher and published in Nature Food.
Tiffany Weir, an associate professor in CSU’s Department of Food Science and Human Nutrition, co-authored the paper with the University of Wisconsin’s Valerie Stull. They pioneered human research on cricket consumption’s effect on gut microbiota.
Weir said that her and Stull’s earlier research helped spawn Weir’s latest study of how cricket-derived chitin in designer chocolate patties may increase positive prebiotic effects on individuals with irritable bowel syndrome.
“Edible insects and insect fibers may be unusual in the American diet, but they are commonplace around the globe, as insects are part of many traditional cuisines,” Stull said. “They are gaining attention as an environmentally friendly source of animal protein.”
A previous study referenced in the paper estimated 3,000 ethnic groups in 130 countries eat insects mostly harvested in the wild. But insect farming also is growing in popularity as it uses less water, land and feed and emits fewer greenhouse gases.
“Although reduced environmental impacts of insect rearing compared to traditional livestock have been a key selling point for insect-based products, there are also underexplored and under-appreciated nutritional benefits,” Weir said. “Insects are touted as a good source of protein, but the fiber component, chitin, is not found in other animal foods, and the omega-3 content may be higher than what is found in many plant foods. “These components may provide unique benefits for the gut by encouraging healthy gut microbiota and reducing intestinal inflammation.”
Weir said that the paper is a perspective piece summarizing current knowledge on the topic and highlighting gaps in related research.
Among the paper’s key points: The types of insects eaten in the areas where 2 billion people live are beetles, caterpillars, wasps, bees, ants, grasshoppers, true bugs; and termites. Though nutrition varies, insects are considered a reliable source of bioavailable animal protein that contain all essential amino acids needed for human nutrition, especially those in cereal- and legume-based diets. Studies identifying risks of insect consumption such as allergens and contaminants have been done, but there is little evidence entomophagy (eating insects) presents any bigger risk to consumers than other animal food sources. Recent studies show human cell types produce enzymes to break down chitin, which can be absorbed during the digestion process. Weir and Stull’s previous study showed that 25 grams of daily cricket powder was associated with an increase of beneficial bacteria in the intestines, though the authors say more research is needed. Insect consumption has the potential to positively influence global challenges of malnutrition, while reducing the risk of disease and any world food shortage. Promising evidence of the impact of insects/chitin on gut health has been tempered by study limitations, so the authors call for large, well-controlled human studies in targeted populations.”Low-cost insect farming could help vulnerable communities meet their nutritional needs and improve food security, especially in contexts where entomophagy is already practiced,” the paper said in its closing paragraphs. “Not only are insects generally an environmentally friendly animal protein source requiring fewer resources than conventional livestock, but some species are also adept recyclers that can consume and convert low-value organic byproducts and wastes, including food waste, into nutritious, high-quality food or animal feed.”
Added Stull: “Initial reports suggest several benefits from including insects in the diet, but more research — especially human intervention studies — is needed.”

Cedars-Sinai investigators are developing a novel way to treat amyotrophic lateral sclerosis (ALS) and retinitis pigmentosa using engineered stem cells that may eventually lead to personalized treatments.
The new approach uses cells derived from human induced pluripotent stem cells (iPSCs) that are renewable and scalable, and also can delay the progression of these neurodegenerative diseases in rodents.
This research, published in the journal Stem Cell Reports, marks an important first step toward achieving more personalized therapies for people with these debilitating conditions that currently have no cures.
“In the past, we have had an enormous success using expanded populations of neural progenitor cells derived from human brain tissue combined with gene therapy in developing new treatments for patients with ALS,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine.
The team previously showed that neural progenitor cells can be engineered to produce a protein called glial cell line-derived neurotrophic factor (GDNF), which helps sustain diseased neurons.
This product was safely transplanted in the spinal cord of patients with ALS in a recently completed trial. And after a one-time treatment, the cells can survive and produce the critical GDNF protein for over three years, thereby potentially protecting motor neurons that die in ALS. These neural progenitor cells are also used in an ongoing trial for retinitis pigmentosa.

“However, the cell lines we are using in the clinic are coming from a single source and are going to eventually run out. We just don’t have endless product,” said Svendsen, who is also the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine at Cedars-Sinai. “Induced pluripotent stem cells provide a renewable source and allow us to develop a more sustainable product that can be engineered to release powerful growth factors.”
Scientists are finding cell and gene therapies to hold great promise in treating a variety of diseases, including hard-to-treat neurodegenerative diseases like ALS and retinitis pigmentosa. After transplantation, stem cells generate support cells that release the engineered drug to provide support to degenerating neurons. Yet limitations that can hinder widespread use and commercialization of these therapies include insufficient tissue availability and potential rejection of the cells by the patient.
“Being able to minimize immune interactions by engineering a patient’s own cells and then turning that into a precision medicine therapy has very strong potential,” said Alexander Laperle, PhD, a project scientist in the Svendsen Laboratory and co-first author of the study.
To test the iPSC-based therapy, the team engineered iPSC-derived neural progenitor cells to produce GDNF, to see if it could be used to treat diseases that cause nervous system cells to die, such as ALS and retinal degeneration.
The investigators found that putting these iPSC-derived neural progenitors into the eyes of rodents with retinal degeneration led to protection of the cells in the eye that support vision.

When the team transplanted the same cells into the spinal cords of rodents with ALS, they found the cells helped protect the spinal cord cells that control movement. They also found that these cells were safe and did not cause tumors or other problems when transplanted into the animals for several months.
“We saw that the cells survived and integrated into the spinal cord,” said co-first author Alexandra Moser, PhD, a postdoctoral fellow in the Svendsen Laboratory. “They also largely formed astrocytes, which are protective and supportive cells, and we found they continued to produce GDNF. Most importantly, they didn’t form tumors.”
“We have successfully shown that we can develop human iPSCs that stably produce GDNF as a promising future cell and gene therapy,” said Laperle.
While the research results showed promise, more preclinical studies are needed to determine the optimal treatment level, noted Moser. The team is currently looking at ways to improve the expansion of these cells and the scalability of that process.
The paper will also be part of a special issue of Stem Cell Reports on clinical translation of iPSC products, which is scheduled to publish in July 2023.

A new study by researchers at Columbia University Mailman School of Public Health shows that water arsenic levels are linked to higher urinary arsenic among the U.S. population for users of both private wells and public water systems. The findings are published in the journal Environmental Research.
Long-term exposure to arsenic even at low and moderate levels can increase the risk of cancer and other types of chronic disease. While drinking water along with diet is a major source of arsenic for the general population, the contribution of arsenic in drinking water to total arsenic exposure has been unclear in U.S. populations, especially at less than high levels in public water supplies.
The researchers evaluated the association between arsenic in private wells and public water supplies using urinary arsenic biomarkers within U.S. populations. “To date, no nationwide study had evaluated the link between drinking water arsenic with arsenic biomarkers in urine to assess how drinking water contributes to arsenic exposure for both regulated community water systems (CWS) and unregulated private wells,” said Maya Spaur, a PhD candidate in environmental health sciences at Columbia Mailman School of Public Health.
The U.S. Department of Health and Human Services Agency for Toxic Substances and Disease Registry includes arsenic as a potent carcinogen and toxicant associated with numerous adverse health outcomes, ranking it number one on their substance priority list. The U.S. Environmental Protection Agency (EPA) regulates arsenic in public drinking water supplies and sets the maximum contaminant level (MCL) allowable in public water systems. However, differences in CWS arsenic concentrations persist across the U.S.
In 2006, the EPA reduced allowable maximum contaminant levels to10 µg/L, from 50 µg/L. However, based solely on risk to health, the EPA set an MCL goal (MCLG) of 0 µg/L. In addition to community water systems, arsenic exposure from drinking water is also a major concern for approximately 40 million U.S. residents reliant on private well water. However private wells are not subject to EPA’s MCL or other federal regulations.
To conduct the study the researchers evaluated 11,088 participants from the 2003-2014 National Health and Nutrition Examination Survey (NHANES). For each participant, the researchers assigned private well and CWS arsenic levels according to county of residence using estimates previously derived by the U.S. Environmental Protection Agency and U.S. Geological Survey. Participants also completed an in-person interview, dietary recall, and physical examination.
The average recalibrated urinary dimethylarsinate (rDMA), the main metabolite of arsenic excreted in urine was 2.52 µg/L among private well users and 2.64 µg/L among CWS users. Urinary rDMA was highest among participants in the West and South, and among Mexican American, other Hispanic, and non-Hispanic other participants. Urinary rDMA levels were 25 percent and 20 percent higher comparing the highest to the lowest third of the population distribution of CWS and private well arsenic, respectively.
“We found that higher private well and public water arsenic levels were linked to higher urinary arsenic among NHANES participants,” noted Spaur. “We further observed very similar relationships between water arsenic and urinary arsenic for both regulated public water supplies and unregulated private wells, but did see differences by region with the strongest associations in the South and West, and among Mexican American participants. Our findings show that water arsenic, including in public water, is a major contributor to total arsenic as measured in urine. Additional efforts are needed to target regions and communities that continue to experience higher exposure.”
“Evaluating the link between drinking water arsenic and arsenic levels within U.S. populations is critical for informing drinking water regulatory policies going forward and for identifying communities that need additional financial, technical, and regulatory assistance to reduce the exposure to their residents,” said Anne E. Nigra, assistant professor of environmental health sciences at Columbia Mailman School of Public Health, and senior author.
Co-authors are Melissa Lombard and Joseph Ayotte, U.S. Geological Survey, New England Water Science Center; Benjamin Bostick and Steven Chillrud, Lamont-Doherty Earth Observatory of Columbia University; and Ana Navas-Acienand Anne Nigra, Columbia Public Health.
The study was supported by NIEHS grants P42ES010349 and P30ES009089, and F31ES034284, and by NIH/National Institute of Dental & Craniofacial Research grant DP5OD031849.

The president is expected to pick Dr. Monica M. Bertagnolli, who last year became the director of the National Cancer Institute.WASHINGTON — President Biden plans to nominate Dr. Monica M. Bertagnolli, an oncologist who has run the National Cancer Institute for the past six months — and a cancer patient herself — to be the next director of the National Institutes of Health, an administration official said.If confirmed by the Senate, Dr. Bertagnolli would be only the second woman to serve as the medical research agency’s director on a permanent basis since its origins in the late 1800s. She is the first female director of the National Cancer Institute, which is part of the National Institutes of Health.The White House is expected to announced her selection in the coming days, the administration official said. A White House spokeswoman declined to comment, saying a decision on the new director was not yet final. The Wall Street Journal earlier reported on her emergence as Mr. Biden’s pick.Dr. Bertagnolli became the director of the National Cancer Institute, or N.C.I., in October. Two months later, she announced that she had received a diagnosis of early breast cancer and would begin treatment at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, where she had worked as a surgical oncologist before joining the federal government. She said her prognosis was good.“I’m in a waiting period right now, and there are things we don’t know,” she said then. “But thanks to research funded by N.C.I., answers about the treatment that’s best for me will come in time.”If confirmed, Dr. Bertagnolli would lead one of the world’s premier medical research agencies, a collection of 27 separate institutes and centers focusing on a wide array of medical matters, including cancer, infectious disease, heart and lung ailments, mental health and drug abuse. A branch of the federal Health and Human Services Department, the National Institutes of Health has an annual budget of more than $47 billion, much of it dispersed around the world to finance basic medical research.Dr. Bertagnolli would replace Dr. Lawrence A. Tabak, who has served in an acting capacity since Dr. Francis S. Collins stepped down at the end of 2021 after more than 12 years as director.Only one woman — Dr. Bernadine P. Healy, who was appointed by President George H.W. Bush — has served as the agency’s director, although Dr. Ruth Kirschstein, a longtime federal scientist and N.I.H. administrator, served as acting director.Before joining the National Cancer Institute, Dr. Bertagnolli was a professor of surgery specializing in surgical oncology at Harvard Medical School. Her past research has focused on the gene mutation that spurs the development of gastrointestinal cancer and on the role that inflammation plays in the growth of cancer.Ellen V. Sigal, the founder and chairwoman of Friends of Cancer Research, a research and advocacy group, said she would be thrilled if the president selected Dr. Bertagnolli.“She has every perspective that one would want in an N.I.H. leader,” Ms. Sigal said. “She has basic science. She has clinical experience. She has proven leadership capacity — and now is a patient.”

In a study published in Nature Communications, a team led by Krembil Brain Institute Senior Scientists, Drs. Lorraine Kalia and Suneil Kalia, and University of Toronto (U of T) Professor, Dr. Philip M. Kim, identified a protein-protein interaction that contributes to Parkinson’s disease.
In the disease, a protein called ?-synuclein (a-syn) accumulates in the brain and leads to cell death. Much research is currently focused on clearing a-syn with antibodies or using small molecules to prevent a-syn from aggregating. In this study, the researchers took an alternate approach by looking for protein-protein interactions that may be promoting the accumulation of a-syn in Parkinson’s disease.
Protein-protein interactions govern virtually all the inner workings of the cell, including breaking down disease-causing proteins. Inhibiting certain interactions has emerged as a promising approach to treat diseases such as stroke and cancer.
“Identifying a particular interaction that contributes to a disease and then finding ways to disrupt it, can be a painstaking and incredibly slow process,” explains Dr. Lorraine Kalia, who is also a staff neurologist at UHN and a scientist at U of T’s Tanz Centre for Research in Neurodegenerative Diseases, in the Temerty Faculty of Medicine.
“We all started out a bit skeptical that we would have something useful at the end, and so the fact that we do have something that warrants further work is much more than we anticipated.”
According to Dr. Kim, the team took the reverse approach to expedite the discovery of potential therapies. “We developed a platform to screen molecules called peptide motifs — short strings of amino acids that can disrupt protein-protein interactions — for their ability to protect cells from a-syn. Once we identified candidate peptides, we determined which protein-protein interactions they target.”
Through this approach, the team identified a peptide that reduced a-syn levels in cells by disrupting the interaction between a-syn and a protein subunit of the cellular machinery called ‘endosomal sorting complex required for transport III’ (ESCRT-III).

“ESCRT-III is a component of a pathway that cells use to break down proteins, called the endolysosomal pathway,” explains Dr. Lorraine Kalia. “We discovered that a-syn interacts with a protein within ESCRT-III — CHMP2B — to inhibit this pathway, thereby preventing its own destruction.”
“We were impressed that the platform worked,” she adds. “But I think what was more interesting is that, by doing this kind of screening, we were able to find an interaction that was really not previously characterized, and we also found a pathway that’s not yet been targeted for therapeutics.”
According to Dr. Suneil Kalia, once the group identified this interaction, they confirmed that they could use their peptide to disrupt it, preventing a-syn from evading the cell’s natural clearance pathways.
“We tested the peptide in multiple experimental models of Parkinson’s disease, and we consistently found that it restored endolysosomal function, promoted a-syn clearance and prevented cell death,” he said.
These findings indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as other conditions that involve a buildup of a-syn, such as dementia with Lewy bodies.

The next steps for this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach for delivering potential therapeutics to the brain.
“This research is still in its early stages — more work is definitely needed to translate this peptide into a viable therapeutic,” cautions Dr. Lorraine Kalia. “Nonetheless, our findings are very exciting because they suggest a new avenue for developing treatments for Parkinson’s disease and other neurodegenerative conditions.”
This study also highlights the value of multidisciplinary collaborations in health research.
“We simply could not have conducted this study in a silo,” says Dr. Suneil Kalia. “The endolysosomal pathway is underexplored, so it was not an obvious place to look for potential disease-related protein-protein interactions. Dr. Kim’s screening platform was critical for pointing us in the right direction.”
“It is extraordinary to see this platform — which we initially used to find potential therapeutics for cancer — yielding advances in brain research. The pathways that cells use to stay healthy are fundamentally very similar across tissues, so the insights that we gain about one organ system or disease could have important implications in other contexts,” says Dr. Kim.
“This is our first collaboration with Dr. Kim and it has been a productive one with a lot of synergy,” says Dr. Lorraine Kalia. “Seeking out technologies that are being used in other fields and applying them to our own field, we hope this will accelerate Parkinson’s research.”
She adds: “It’s really brand new science and brand new targets that haven’t been a focus for drug development for Parkinson’s. We hope this changes the landscape for treatment of this disease, which is so in need of new therapies.”

New research out of the University of Cincinnati examines the impact that maternal stress during pregnancy has on the neurodevelopment of babies.
The study was published in the journal Molecular Psychiatry.
Prenatal maternal stress life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but a chemical reaction in the body in which a small molecule known as a methyl group gets added to DNA, called DNA methylation, likely plays a role, according to researchers. These findings could provide new insights into how the fetal environment potentially influences not only neurodevelopment, but metabolism and immunologic functions as well.
More than 5,500 people took part in the study with that population broken down into 12 separate cohorts, according to Anna Ruehlmann, a postdoctoral fellow in the Department of Environmental and Public Health Sciences in the UC College of Medicine and lead author of the research.
“Our study is the first to look at such a large sample size and examine the entire epigenome, so it’s not just looking at the stress control genes as in previous studies, it’s looking at all the epigenomic sites available right now that you can study,” she says.
The research examines five separate categories of stress that expectant moms face during pregnancy. They are financial stress, conflict with a partner, conflict with a family member or friend, abuse (including physical, emotional and mental) and death of a friend or relative, plus a cumulative score that combines all the categories.
“We found that when mom experienced a cumulative amount of stress during pregnancy, there was, in fact, an association with DNA methylation in umbilical cord blood, which is a kind of epigenetic modification in the baby that’s developing in the womb,” Ruehlmann says. “An epigenetic modification is something that doesn’t change the sequence of the DNA, however the DNA is modified which is something that’s dynamic and can change in response to environmental exposures. Therefore, it’s something that can be turned on or off later in the child’s life or something that can maybe not do anything, it’s still unknown. It’s thought to be a mechanism of gene expression control.”
Ruehlmann says another unknown is how this process impacts children once they are born.
“We found five specific locations of DNA methylation with three different maternal stressors during pregnancy,” she says. “One was cumulative stress and the stressor specific domains of con?ict with family/friends, abuse (physical, sexual and emotional) and death of a close friend/relative that were associated with DNA methylation in the developing fetus. These were occurring in genes that have shown to be involved in neurodevelopment. The next steps are to do some functional analyses to see how these genes really work and how the DNA methylation affects their expression.”
Ruehlmann describes the process as being a huge puzzle.
“Epigenetic modifications are a very dynamic process, there are a lot of changes that can happen in response to environmental factors,” she says. “What you’re seeing biologically at the beginning of fetal development you might not see the outcome of until later on during a child’s development. It’s fascinating as a biologist to begin to uncover some of the biological clues to how neurodevelopment is affected during fetal development. There are a lot of pieces to the puzzle that have yet to be connected. It’s very exciting.”
The study’s corresponding author is Kelly Brunst from the UC Department of Environmental and Public Health Sciences. The work in this study was supported by grants T32ES010957 (Ruehlmann) and R00ES024116 and P30ES006096 (Brunst).