Publisher Health

Recent developments in cancer research have highlighted the vital role of the immune system, particularly in the notable successes of cancer immunotherapy.
Now, a paradigm-shifting study led by researchers at the Icahn School of Medicine at Mount Sinai in New York in collaboration with the University of Helsinki and Massachusetts General Hospital sheds light on how variations in immune genetics influence lung cancer risk, potentially paving the way for enhanced prevention strategies and screening.
The findings were described in the February 22 online issue of Science.
The investigators utilized genetic epidemiology and multimodal genomic analyses of data from the UK Biobank, validating it in FinnGen. Their study focused on human leukocyte antigen (HLA) molecules — the most diverse genes in the human genome and at the core of immune recognition. These genes contain instructions to make proteins, which play a crucial role in presenting foreign antigens on cell surfaces. This process aids the immune system in identifying and eliminating threats such as cancer cells.
Surprisingly, the study found that individuals with heterozygosity (having different versions of a gene) at HLA-II, rather than HLA-I, experienced a decreased risk of lung cancer. This effect was particularly pronounced among smokers, a population already at higher risk for lung cancer due to exposure to carcinogens.
“Our findings challenge conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, plays a significant role in lung cancer risk, especially among smokers,” says co-senior author Diego Chowell, PhD, Assistant Professor of Oncological Sciences, and Immunology and Immunotherapy at Icahn Mount Sinai. “Further, when we added polygenic risk scores — which is a measure of genetic predisposition based on multiple genes — to the analysis, it increased the lifetime risk of lung cancer, specifically in smokers who have identical versions of the HLA-II genes.
The implications of this research extend beyond lung cancer, offering a new perspective on cancer risk assessment, the researchers say. The conventional thinking on the causes of cancer is that the disease is caused by random mutations arising during DNA replication, inherited mutations, and environmental factors. The research showed that the immune system is also part of the etiology of cancer, Dr. Chowell says. By considering immune genetics alongside hereditary and environmental factors, the investigators’ aim to develop more effective prevention strategies, potentially harnessing the immune system to combat cancer.

“These results highlight a previously overlooked aspect of cancer risk assessment,” says co-senior author Robert Samstein, MD, PhD, Assistant Professor of Radiation Oncology, and Immunology and Immunotherapy at Icahn Mount Sinai. “Our study marks a big step toward understanding the intricate interplay between the immune system and cancer risk. We hope that by identifying individuals with increased susceptibility based on their immune genetics, we can implement more targeted screening, prevention, and treatment strategies.”
Next, the research team plans to delve deeper into the mechanisms underlying HLA heterozygosity’s protective effects, with a focus on preclinical models of disease. Additionally, they aim to explore the role of non-classical CD4 T cells and HLA class II in cancer biology, opening the door for potential progress in the mitigation and treatment of cancer.
The paper is titled “An immunogenetic basis for lung cancer risk.”
The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are: Chirag Krishna, PhD (Pfizer); Anniina Tervi, PhD (University of Helsinki); Miriam Saffern (PhD candidate); Eric A. Wilson, PhD; Seong-Keun Yoo, PhD; Nina Mars, MD, PhD (University of Helsinki and The Broad Institute of Harvard and MIT); Vladimir Roudko, PhD; Byuri Angela Cho, PhD; Samuel Edward Jones, PhD (University of Helsinki); Natalie Vaninov (PhD candidate); Myvizhi Esai Selvan, PhD; Zeynep H Gu?mu?s, PhD; FinnGen Consortium; Tobias L. Lenz, PhD (University of Hamburg); Miriam Merad, MD, PhD; Paolo Boffetta, MD (Stony Brook University in New York and University of Bologna); Francisco Marti?nez-Jime?nez, PhD (Stony Brook University in New York and Vall d’Hebron Institute of Oncology, Barcelona); and Hanna M. Ollila, PhD (Massachusetts General Hospital, Harvard Medical School, The Broad Institute, and University of Helsinki).

Cedars-Sinai investigators have discovered why some injured kidneys heal while others develop scarring that can lead to kidney failure. Their findings, detailed in a paper published in the peer-reviewed journal Science, could lead to the development of noninvasive tests to detect kidney scarring and, eventually, new therapies to reverse the condition.
“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” said Sanjeev Kumar, MD, PhD, a nephrologist-scientist in the Board of Governors Regenerative Medicine Institute and the Department of Medicine at Cedars-Sinai and senior author of the study. “Injured cells activate a protein called SOX9 to regenerate themselves. When they have healed, the cells silence this protein. Cells that aren’t able to regenerate leave SOX9 active, and this leads to a type of scarring called fibrosis. But when we deactivate SOX9 in a timely fashion, the scarring literally goes away.”
The kidneys, two fist-sized organs that filter waste from the blood, can be injured by diabetes and high blood pressure, serious infections such as COVID-19, and overuse of antibiotics and non-steroidal anti-inflammatory pain medications, said Kumar, who is also part of the Department of Biomedical Sciences at Cedars-Sinai.
The SOX9 protein plays a major role in organ development but is not active in healthy adult kidneys. In previous work at another institution, Kumar and team found that when kidneys are injured, the surviving cells reactivate SOX9 as part of the healing process.
In this study, Kumar and fellow investigators studied kidney damage in laboratory mice. They labeled individual cells at the point of injury, then followed how the cells’ progeny evolved over time.
“At Day 10, some cells’ descendants were fully healed while others were not,” Kumar said. “The cell lineage that healed had switched off SOX9 expression, while the unhealed lineage, in a continuing attempt to fully regenerate, maintained SOX9 activity. It’s like a sensor that switches on when cells want to regenerate, and off when they are restored, and we are the first to identify this.”
Further, investigators discovered that cells that were unable to regenerate began recruiting proteins called Wnts, another key player in organ development. Over time, this accumulation of Wnts triggered scarring. And they found that deactivating SOX9 a week after injury promoted kidney recovery.

Investigators observed the same process in patient databases from collaborating institutions in Switzerland and Belgium.
“We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” Kumar said. “And in our collaborators’ database, we were able to distinguish that patients who had sustained SOX9 activation had lower kidney function and more scarring than those who did not. Human kidneys with cells that maintained SOX9 were also enriched with Wnts and showed increased fibrosis.”
These discoveries provide targets for drug development, as well as for noninvasive biomarker discovery permitting diagnosis of kidney fibrosis through the urine, Kumar said. Currently, the only available test for kidney fibrosis is a biopsy, which carries many risks.
“Elucidating the mechanisms of scarless healing versus fibrosis has eluded investigators for decades and has implications beyond the kidney, including for certain cancers,” said Paul Noble, MD, chair of the Department of Medicine and director of the Women’s Guild Lung Institute at Cedars-Sinai and a co-author of the study.
The findings could also lead to new treatment options for patients, said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and a co-author of the study.
“These findings help us understand for the first time how the kidney’s response to injury sometimes leads to fibrosis,” Svendsen said. “Future work along these lines could also advance our understanding of fibrosis in the heart, lungs and liver.”

Nearly 30 years ago, scientists discovered a unique class of anticancer molecules in a family of bryozoans, a phylum of marine invertebrates found in tropical waters.
The chemical structures of these molecules, which consist of a dense, highly complex knot of oxidized rings and nitrogen atoms, has attracted the interest of organic chemists worldwide, who aimed to recreate these structures from scratch in the laboratory. However, despite considerable effort, it has remained an elusive task. Until now, that is.
A team of Yale chemists, writing in the journal Science, has succeeded in synthesizing eight of the compounds for the first time using an approach that combines inventive chemical strategy with the latest technology in small molecule structure determination.
“These molecules have been an outstanding challenge in the field of synthetic chemistry,” said Seth Herzon, the Milton Harris ’29 Ph.D. Professor of Chemistry in Yale’s Faculty of Arts and Sciences and corresponding author of the new study. “A number of research groups have tried to recreate these molecules in the lab, but their structures are so dense, so intricately connected, that it hasn’t been possible. I’ve been reading about efforts to synthesize these compounds since I was a graduate student in the early 2000s.”
In nature, the molecules are found in some species of bryozoa — small, aquatic animals that feed by filtering prey from the water via tiny tentacles. Researchers worldwide consider bryozoans to be a potentially valuable source of new medications, and many molecules isolated from bryozoans have been studied as novel anticancer agents. However, the complexity of the molecules often limits their further development.
Herzon’s team looked at a particular species of bryozoa called Securiflustra securifrons.
“We worked on these molecules about a decade ago, and though we were not successful in recreating them at that time, we gleaned insight into their structure and chemical reactivity, which informed our thinking,” Herzon said.

The new approach involved three key strategic elements. First, Herzon and his team avoided constructing a reactive heterocyclic ring, known as an indole, until the end of the process. A heterocyclic ring contains two or more elements — and this specific ring is known to be reactive and create problems, Herzon said.
Second, the researchers used methods known as oxidative photocyclizations to construct some of the key bonds in the molecules. One of these photocyclizations involved the reaction of a heterocycle with molecular oxygen, which was first studied by Yale’s Harry Wasserman in the 1960s.
Lastly, Herzon and his team employed microcrystal electron diffraction (MicroED) analysis to help visualize the structure of the molecules. Herzon said conventional methods for structure determination were inadequate in this context.
The result of the new approach is eight new synthetic molecules with therapeutic potential — and the promise of more new chemistry to come.
“These molecules hit right at my love of complex synthetic challenges,” said Herzon, who is also a member of the Yale Cancer Center and holds joint appointments in pharmacology and therapeutic radiology at Yale School of Medicine. “On a molecular weight basis, they are modest relative to other molecules we’ve studied in my lab. But from the vantage point of chemical reactivity, they present some of the greatest challenges we’ve ever taken on.”
Co-first authors of the new study are Yale chemistry graduate students Brandon Alexander and Noah Bartfield. Co-authors are Vaani Gupta, a Yale chemistry graduate student; Brandon Mercado, a Yale X-ray crystallographer and lecturer in the Department of Chemistry; and Mark Del Campo of Rigaku Americas Corporation.
The National Science Foundation helped fund the research.

In the race to identify the hormones used to control bodily functions, he battled with his former partner. They later shared the glory.Roger Guillemin, a neuroscientist who was a co-discoverer of the unexpected hormones with which the brain controls many bodily functions, died on Wednesday at a senior living facility in San Diego. He was 100.His death was confirmed by his daughter Chantal.Dr. Guillemin’s career was marked by two spectacular competitions that ruffled the staid world of endocrinological research. The first was a 10-year tussle with his former partner, Andrew V. Schally, which ended in a draw when the two shared half of the Nobel Prize in Physiology or Medicine in 1977. (The other half went to the American medical physicist Rosalyn Yalow for unrelated research.)Dr. Guillemin, fourth from right, posed with other winners of the 1977 Nobel Prizes in Oslo, Norway. He shared half of the Nobel in medicine with his rival and former partner Andrew Schally, third from right. Rosalyn Yalow, who received the other half of that prize, stood next to Dr. Guillemin. PA Images, via Getty ImagesThe second competition began shortly afterward when Wylie Vale Jr., Dr. Guillemin’s longtime collaborator and protégé, set up a rival laboratory on the same campus at the Salk Institute for Biological Studies in San Diego, where both men worked, plunging Dr. Guillemin yet another period of intense scientific struggle.Roger Charles Louis Guillemin (pronounced, with a hard g, GEE-eh-mah) might have pursued a quiet career as a family doctor in the French city of Dijon, the Burgundy region’s capital, where he was born on Jan. 11, 1924, and where he went to public schools and then medical school. But a chance meeting with Hans Selye, an expert on the body’s reaction to stress, took him to Montreal, where he was introduced to medical research at Dr. Selye’s newly created Institute of Experimental Medicine and Surgery at the University of Montreal.There he became interested in a leading problem of the day — that of how the brain controls the pituitary gland, the maestro organ that cues production of the body’s other major glands.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

The A.G., Letitia James, called on the F.D.A. to redouble efforts to alert doctors about potential side effects of Singulair and to consider discouraging use of the drug in children.The New York attorney general on Thursday urged the Food and Drug Administration to “take immediate action” and renew alerts to doctors and patients about the dangerous effects of Singulair for children, saying that the current warnings about the drug’s psychiatric side effects were not sufficient.In a letter, the attorney general, Letitia James, also called on the federal agency to consider discouraging the prescription of Singulair, an asthma and allergy drug, to children.Thousands of patients and parents have complained to the F.D.A. about symptoms of anxiety, rage, hallucinations and other psychiatric problems that they linked to the drug, which is also known in its generic form as montelukast. Those reports, combined with an emotional F.D.A. hearing in 2019 and cases cited in medical literature, led the F.D.A. in 2020 to order its most stringent warning on instructions for the drug’s usage.But an examination by The New York Times found that people continued to report that they were not aware of the possible side effects, which include suicide or suicide attempts, when they took the medication or gave it to their children.Ms. James cited The Times’s article, and called on the F.D.A. “to implement new, more stringent safety regulations for the drug,” particularly for children.“Parents and guardians have the right to be fully informed of a medication’s potential side effects when making choices about their children’s health,” Ms. James said in a statement on Thursday. “The risks associated with taking Singulair are far too dire to come without a very clear warning.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

The clinics are routinely sued by patients for errors that destroy embryos, as happened in Alabama. An effort to define them legally as “unborn children” has raised the stakes. To the fertility patients whose embryos were destroyed at an Alabama clinic, the circumstances must have been shocking. Somehow, a patient in the hospital housing the clinic had wandered into a storage room, pulled the embryos from a tank of liquid nitrogen, and then dropped them on the floor — probably because the tank was kept at -360 degrees.The bizarre incident was at the center of lawsuits filed by three families that eventually reached the Alabama Supreme Court. On Friday, a panel of judges ruled that the embryos destroyed at the clinic should be considered children under state law, a decision that sent shock waves through the fertility industry and raised urgent questions about how treatments could possibly proceed in the state.Yet the accident in the Alabama clinic echoes a pattern of serious errors that happen all too frequently during fertility treatment, a rapidly growing industry with little government oversight, experts say. From January 2009 through April 2019, patients brought more than 130 lawsuits over destroyed embryos, including cases where embryos were lost, mishandled or stored in freezer tanks that broke down.Those errors have taken on new gravity as the anti-abortion movement aims to extend “personhood” to fetuses and embryos conceived through in vitro fertilization, arguing that they are “unborn children” and bringing cases to an increasingly polarized judiciary open to considering the idea.“When things go wrong with I.V.F., it opens a window for this kind of strategy,” said Sonia Suter, a law professor at George Washington University who has studied in vitro fertilization litigation. “To the extent that there is little regulation, it does provide an opportunity to promote the personhood agenda.”Denise Burke, senior counsel with the Alliance Defending Freedom, which opposes abortion rights, called the Alabama decision “a tremendous victory for life” that protected “unborn children created through assisted reproductive technology.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

The gut microbiome interacts with the loss of female sex hormones to exacerbate metabolic disease, including weight gain, fat in the liver and the expression of genes linked with inflammation, researchers found in a new rodent study.
The findings, published in the journal Gut Microbes, may shed light on why women are at significantly greater risk of metabolic diseases such as obesity and Type 2 diabetes after menopause, when ovarian production of female sex hormones diminishes.
“Collectively, the findings demonstrate that removal of the ovaries and female hormones led to increased permeability and inflammation of the gut and metabolic organs, and the high-fat diet exacerbated these conditions,” said Kelly S. Swanson, the director of the Division of Nutritional Sciences and the Kraft Heinz Endowed Professor in Human Nutrition at the University of Illinois Urbana-Champaign who is a corresponding author of the paper. “The results indicated that the gut microbiome responds to changes in female hormones and worsens metabolic dysfunction.”
“This is the first time it has been shown that the response of microbiome to the loss of ovarian hormone production can increase metabolic dysfunction,” said first author Tzu-Wen L. Cross, a professor ofnutrition science and the director of the Gnotobiotic Animal Facility at Purdue University. Cross was a doctoral student at the U. of I. when she began the research.
“The gut microbiome is sensitive to sex hormone changes and can further impact the risk of disease development.”
Cross said early microbiome research, beginning around 2005, looked at how the microbiome contributes to obesity development, but most of those studies focused on males.
“Metabolic dysfunction that is driven by the loss of ovarian-function in menopausal women — and how much the gut microbiome contributes to that — has not been studied. The etiology is clearly very complex, but those gut-microbiome related factors are certainly components that we speculated play a role,” she said.

The scientists created diet-induced obesity in female mice and simulated the loss of female sex hormones by removing the ovaries in half of the population to examine any metabolic and inflammatory changes, including those to enzymes in the gut. The diets for both groups of mice were identical except for the proportion of fat, which constituted 60% or 10% of calories for those in the high-fat and low-fat groups, respectively.
In the second leg of the study, fecal samples were harvested from mice with or without ovaries and implanted in germ-free mice to study the impact on weight gain and metabolic and inflammatory activity in the gut, liver and fat tissue.
“The mice that were recipients of the gut microbiome of ovariectomized mice gained more weight and fat mass, and they had greater expression of genes in the liver associated with inflammation, obesity, Type 2 diabetes, fatty liver disease and atherosclerosis compared with those in the control group,” Swanson said.
In assessing the severity of fatty tissue and triglyceride concentrations in the liver, the scientists found that the triglyceride levels were significantly higher and fatty deposits in the liver and groin were greater in the mice that consumed the high-fat diet compared with all other treatment groups, according to the study.
Those on the high-fat diet and those without ovaries had significantly larger fat cells, which are associated with cell death and the infiltration of macrophages — a type of white blood cell that destroys dead cells and microorganisms and secretes pro-inflammatory proteins. Along with elevated expression of the genes associated with inflammation and macrophage markers, these mice had lower expression of genes that are involved with glucose and lipid metabolism.
In the donor mice without ovaries that consumed the low-fat diet, the scientists found increased levels of beta-glucuronidase, an enzyme produced by the colon and some intestinal bacteria that breaks down and recycles steroidal metabolites such as estrogen and various toxins, including carcinogens.

The scientists also examined the expression of genes coding for tight-junction proteins, which affect cell membranes’ permeability. They found that the mice without ovaries and those fed the high-fat diet had lower levels of these proteins in the liver and colon, which suggested their gut barriers were more permeable, compromised by either their diet or the absence of female hormones.
In the livers of the recipient mice that received transplants from donors without ovaries, the scientists found elevated expression levels of the gene for arginase-1, which plays a critical role in the elimination of nitrogenous waste. High levels of this protein have been associated with cardiovascular problems such as hypertension and atherosclerosis, according to the study.
The paper was co-written by Erik R. Nelson, a professor of molecular and integrative physiology; animal sciences professor Brett R. Loman; and Matthew A. Wallig, a professor emeritus of pathobiology, all at the U. of I.
Additional co-authors were Aadra P. Bhatt, a professor in the Division of Gastroenterology and Hepatology; and Matthew R. Redinbo, a professor of biochemistry and biophysics, both at the University of North Carolina at Chapel Hill.
Co-authors also included bacteriology professor Federico E. Rey and senior scientist Eugenio I. Vivas, both at the University of Wisconsin-Madison; and Jan S. Suchodolski, associate director of research and head of microbiome sciences in veterinary medicine and biomedical sciences at Texas A&M University.
Additional co-authors were then-research assistant Abigayle M.R. Simpson at Purdue University, and then-graduate student Ching-Yen Lin and then-undergraduate student Natasha M. Hottmann, both at the U. of I.
The research was supported by the National Institutes of Health and the National Heart, Lung and Blood Institute.

Medical summarization, a process that uses artificial intelligence (AI) to condense complex patient information, is currently used in health care settings for tasks such as creating electronic health records and simplifying medical text for insurance claims processing. While the practice is intended to create efficiencies, it can be labor-intensive, according to Penn State researchers, who created a new method to streamline the way AI creates these summaries, efficiently producing more reliable results.
In their work, which was presented at the Proceedings of the 2023 Conference on Empirical Methods in Natural Language Processing in Singapore last December, the researchers introduced a framework to fine-tune the training of natural language processing (NLP) models that are used to create medical summaries.
“There is a faithfulness issue with the current NLP tools and machine learning algorithms used in medical summarization,” said Nan Zhang, a graduate student pursing a doctorate in informatics the College of Information Sciences and Technology (IST) and the first author on the paper. “To ensure records of doctor-patient interactions are reliable, a medical summarization model should remain 100% consistent with the reports and conversations they are documenting.”
Existing medical text summarization tools involve human supervision to prevent the generation of unreliable summaries that could lead to serious health care risks, according to Zhang. This “unfaithfulness” has been understudied despite its importance for ensuring safety and efficiency in healthcare reporting.
The researchers began by examining three datasets — online health question summarization, radiology report summarization and medical dialogue summarization — generated by existing AI models. They randomly selected between 100 and 200 summaries from each dataset and manually compared them to the doctors’ original medical reports, or source text, from which they were condensed. Summaries that did not accurately reflect the source text were placed into error categories.
“There are various types of errors that can occur with models that generate text,” Zhang said. “The model may miss a medical term or change it to something else. Summarization that is untrue or not consistent with source inputs can potentially cause harm to a patient.”
The data analysis revealed instances of summarization that were contradictory to the source text. For example, a doctor prescribed a medication to be taken three times a day, but the summary reported that the patient should not take said medication. The datasets also included what Zhang called “hallucinations,” resulting in summaries that contained extraneous information not supported by the source text.

The researchers set out to mitigate the unfaithfulness problem with their Faithfulness for Medical Summarization (FaMeSumm) framework. They began by using simple problem-solving techniques to construct sets of contrastive summaries — a set of faithful, error-free summaries and a set of unfaithful summaries containing errors. They also identified medical terms through external knowledge graphs or human annotations. Then, they fine-tuned existing pre-trained language models to the categorized data, modified objective functions to learn from the contrastive summaries and medical terms and made sure the models were trained to address each type of error instead of just mimicking specific words.
“Medical summarization models are trained to pay more attention to medical terms,” Zhang said. “But it’s important that those medical terms be summarized precisely as intended, which means including non-medical words like no, not or none. We don’t want the model to make modifications near or around those words, or the error is likely to be higher.”
FaMeSumm effectively and accurately summarized information from different kinds of training data. For example, if the provided training data comprised doctor notes, then the trained AI product was suited to generate summaries that facilitate doctors’ understanding of their notes. If the training data contained complex questions from patients, the trained AI product generated summaries that helped both patients and doctors understand the questions.
“Our method works on various kinds of datasets involving medical terms and for the mainstream, pre-trained language models we tested,” Zhang said. “It delivered a consistent improvement in faithfulness, which was confirmed by the medical doctors who checked our work.”
Fine-tuning large language models (LLMs) can be expensive and unnecessary, according to Zhang, so the experiments were conducted on five smaller mainstream language models.
“We did compare one of our fine-tuned models against GPT-3, which is an example of a large language model,” he said. “We found that our model reached significantly better performance in terms of faithfulness and showed the strong capability of our method, which is promising for its use on LLMs.”
This work contributes to the future of automated medical summarization, according to Zhang.

“Maybe, in the near future, AI will be trained to generate medical summaries as templates,” he said. “Doctors could simply doublecheck the output and make minor edits, which could significantly reduce the amount of time it takes to create the summaries.”
Prasenjit Mitra, professor in the College of IST and Zhang’s graduate adviser; Rui Zhang, assistant professor in the College of Engineering and Zhang’s graduate co-adviser; and Yusen Zhang, doctoral student in the College of Engineering — all from Penn State — and Wu Guo, with the Children’s Hospital Affiliated to Zhengzhou University in China, contributed to this research.
The Federal Ministry of Education and Research in Germany, under the LeibnizKILabor project, partially funded this research. Rui Zhang supported the travel funding.

Scientists at the University of Zurich have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration. Their research pinpointed a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Neurodegenerative diseases cause some of the neurons in our brains to die, resulting in different symptoms depending on the brain region affected. In amyotrophic lateral sclerosis (ALS), neurons in the motor cortex and spinal cord degenerate, leading to paralysis. In frontotemporal dementia (FTD), on the other hand, neurons located in the parts of the brain involved in cognition, language and personality are affected.
Both ALS and FTD are relentlessly progressive diseases and effective treatments are still lacking. As the population ages, the prevalence of age-related neurodegenerative diseases such as ALS and FTD is expected to increase.
Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of ALS and about half of FTD patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown.
Flexible, durable, reproducible: ideal cell culture model for ALS and FTD research
In their study, first author Marian Hruska-Plochan and corresponding author Magdalini Polymenidou of the Department of Quantitative Biomedicine at the University of Zurich developed a novel neural cell culture model that replicates the aberrant behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in the protein NPTX2, suggesting it as a potential therapeutic target for ALS and FTD.
To mimic neurodegeneration, Marian Hruska-Plochan developed a new cell culture model called “iNets,” derived from human induced pluripotent stem cells. These cells, originated from skin cells and reprogrammed to a very early, undifferentiated stage in the laboratory, serve as a source for developing many different, desired cell types. iNets are a network of interconnected neurons and their supporting cells growing in multiple layers in a dish.

The cultures lasted exceptionally long — up to a year — and were easily reproduced. “The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise,” says Hruska-Plochan. “And the flexibility of the model makes it suitable for a wide range of experimental methodologies.” As a case in point, the iNets cell cultures provided the ideal model to investigate the progression from TDP-43 dysfunction to neurodegeneration.
How protein dysfunction leads to neurodegeneration
Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology.
In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons. Therefore, drugs that reduce the amount of the protein NPTX2 have potential as a therapeutic strategy to halt neurodegeneration in ALS and FTD patients.
Magdalini Polymenidou sees great promise in this discovery: “We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease,” she said. “In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTD in the future,” she added.

We know that greenhouse gas emissions like carbon dioxide should increase rainfall. The emissions heat the atmosphere, causing a one-two punch: warmer oceans make it easier for water to evaporate, and warmer air can hold more water vapor, meaning more moisture is available to fall as rain. But for much of the 20th century, that increase in precipitation didn’t clearly show up in the data.
A new study led by researchers at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) finds that the expected increase in rain has been largely offset by the drying effect of aerosols — emissions like sulfur dioxide that are produced by burning fossil fuels, and commonly thought of as air pollution or smog. The research is published today in the journal Nature Communications.
“This is the first time that we can really understand what’s causing extreme rainfall to change within the continental U.S.,” said Mark Risser, a research scientist at Berkeley Lab and one of the lead authors for the study. He noted that until the 1970s, the expected increases to extreme rainfall were offset by aerosols. But the Clean Air Act caused a drastic reduction in air pollution in the United States. “The aerosol masking was turned off quite suddenly. That means rainfall might ramp up much more quickly than we would have otherwise predicted.”
Traditional climate models have struggled to confidently predict the human impact on rainfall at scales smaller than a continent — and that regional level is precisely where most climate change adaptations and mitigations take place. By using a new method and relying heavily on measurements from rain gauges from 1900 to 2020, researchers were able to more robustly determine how human activities have influenced rainfall in the United States.
“Prior to our study, the Intergovernmental Panel on Climate Change [IPCC] had concluded that the evidence was mixed and inconclusive for changes in U.S. precipitation due to global warming,” said Bill Collins, associate laboratory director for the Earth and Environmental Sciences Area at Berkeley Lab and co-lead author on the study. “We have now provided conclusive evidence for higher rainfall and also helped explain why past studies assessed by the IPCC reached conflicting conclusions.”
Specifically, the study isolates how greenhouse gas and aerosol emissions affect both average and extreme rainfall. Researchers confirmed that increased greenhouse gas emissions, which quickly disperse over the whole planet, cause an increase in rainfall. The impact from aerosols is more nuanced. Over the long term, aerosols cool the planet, which causes a drying effect. But they also have a faster, more local response. That fast impact depends on the season, with aerosols generally reducing rainfall in the winter and spring, and amplifying it in summer and fall over much of the United States.
“The seasonality piece is really important,” Risser said. “For rainfall, the nature of climate change depends on what season you’re talking about, since different kinds of weather systems create precipitation in different parts of the year.”
Some of the conflicting studies looking at precipitation trends of the last century can be explained by how the effect of aerosols offsets the effect of greenhouse gases, and how models and simulations factor in these two driving forces. The researchers noted that tracking aerosols and incorporating them more fully into models and simulations will be important for improving the predictions used for infrastructure design and water resource management.
The United States has already seen examples of recent increases in extreme precipitation, with several intense, record-setting storms in the past few years.
“Thanks to improvements in air quality, the aerosols that shielded us from the worst effects of global warming are declining worldwide,” Collins said. “Our work shows that the increases in extreme precipitation driven by elevated ocean temperatures will become increasingly obvious during this decade.”