The researchers, whose findings appear in Nature Cell Biology, discovered in experiments with mouse models of pancreatic cancer and melanoma that the stress protein, known as ATF4, enables fibroblasts to support tumor growth by promoting the formation of tumor-serving blood vessels. Deleting ATF4 in fibroblasts severely impaired new tumor-supportive vessel formation as well as tumor growth, without causing significant harm to the mice, the researchers found.

“Our results suggest that inhibiting ATF4 could work against many types of cancer, and we’re now actively pursuing that strategy,” said study senior author Constantinos Koumenis, PhD, the Richard H. Chamberlain Professor of Research Oncology in the department of Radiation Oncology at Penn. “Every tumor we’ve looked at upregulates ATF4.”

The study’s first author, who performed most of the experiments, was Ioannis Verginadis, PhD, a senior research investigator and adjunct assistant professor in Koumenis’s laboratory.

ATF4 is produced in cells as part of a broad response to stresses such as oxygen- or nutrient-deprivation. It works as a master switch for the activities of hundreds of genes that help cells survive these stresses. As Koumenis’s laboratory and others have shown in recent years, many tumor types rely on this ATF4-associated stress response to survive despite the severe stresses they create for themselves by their rapid growth.

The researchers began the new study by engineering mice whose ATF4 gene could be deleted body-wide at any time. They found that if they deleted ATF4 before or even after tumors began growing in the mice, the growth of the tumors and their ability to spread to distant organs were greatly impaired. The scientists then used a powerful and relatively new technique called single-cell RNA sequencing to examine the impact of ATF4 deletion in all the cell types within the tumor — and observed a strikingly large effect on a population of tumor-supporting cells called cancer-associated fibroblasts (CAFs).

Fibroblasts are support cells that exist in virtually all organs, producing the key structural protein collagen, promoting new blood vessel formation, and generally assisting with tissue repair and maintenance. Many tumor types co-opt nearby fibroblasts, switching them to CAF mode in which they principally support the tumor. However, the researchers observed that in their ATF4-deficient mice, CAFs often lacked the usual markers of activation, and were defective in producing collagen and secreting molecules that promote new vessel growth. As a result, levels of collagen and tumor-supplying blood vessels were greatly reduced within the mouse tumors, causing large die-offs of tumor cells.

When the scientists deleted ATF4 only in fibroblasts, they saw a tumor-slowing effect almost as strong as that observed with full-body ATF4 deletion. And when the researchers added normal, ATF4-containing fibroblasts to ATF4-deficient mice, the growth-slowing effect of ATF4 deletion was largely reversed.

“These findings indicate that ATF4’s support for tumors is mediated to a great extent by CAFs,” Verginadis said.

Underscoring the likely relevance of their results to human cancers, the researchers found that in tumor tissue from human pancreatic cancer and melanoma patients there was a significant correlation between markers of ATF4 activity and markers of collagen production. Moreover, in the melanoma cases, higher collagen production correlated with worse prognoses.

The researchers are hopeful that targeting ATF4 won’t have unacceptable side effects, since the mice in which the gene was deleted in adulthood showed only modest and temporary weight loss and other minor abnormalities.

“On the whole, ATF4 appears to be an attractive cancer target,” Koumenis said. “A drug that inhibits it would block its pro-tumor effect not only in tumor cells but also in cancer-associated fibroblasts, so it should be a double-whammy for the tumor. But we’re still a few years away from that.”

Koumenis’s laboratory is now working to develop inhibitors of ATF4 that could be tested in further animal studies and ultimately in human cancer patients.

The research was supported by the National Institutes of Health (P01 CA165997, 1R01CA268597, P01 CA217805, UL1TR001878)

Among those pieces of machinery, and one of the most complex, is something known as the nuclear pore complex (NPC). The NPC, which is made of more than 1,000 individual proteins, is an incredibly discriminating gatekeeper for the cell’s nucleus, the membrane-bound region inside a cell that holds that cell’s genetic material. Anything going in or out of the nucleus has to pass through the NPC on its way.

The NPC’s role as a gatekeeper of the nucleus means it is vital for the operations of the cell. Within the nucleus, DNA, the cell’s permanent genetic code, is copied into RNA. That RNA is then carried out of the nucleus so it can be used to manufacture the proteins the cell needs. The NPC ensures the nucleus gets the materials it needs for synthesizing RNA, while also protecting the DNA from the harsh environment outside the nucleus and enabling the RNA to leave the nucleus after it has been made.

“It’s a little like an airplane hangar where you can repair 747s, and the door opens to let the 747 come in, but there’s a person standing there who can keep a single marble from getting out while the doors are open,” says Caltech’s André Hoelz, professor of chemistry and biochemistry and a Faculty Scholar of the Howard Hughes Medical Institute. For more than two decades, Hoelz has been studying and deciphering the structure of the NPC in relation to its function. Over the years, he has steadily chipped away at its secrets, unraveling them piece by piece by piece by piece.

The implications of this research are potentially huge. Not only is the NPC central to the operations of the cell, it is also involved in many diseases. Mutations in the NPC are responsible for some incurable cancers, for neurodegenerative and autoimmune diseases such as amyotrophic lateral sclerosis (ALS) and acute necrotizing encephalopathy, and for heart conditions including atrial fibrillation and early sudden cardiac death. Additionally, many viruses, including the one responsible for COVID-19, target and shutdown the NPC during the course of their lifecycles.

Now, in a pair of papers published in the journal Science, Hoelz and his research team describe two important breakthroughs: the determination of the structure of the outer face of the NPC and the elucidation of the mechanism by which special proteins act like a molecular glue to hold the NPC together.

A very tiny 3D jigsaw puzzle

In their paper titled “Architecture of the cytoplasmic face of the nuclear pore,” Hoelz and his research team describe how they mapped the structure of the side of the NPC that faces outward from the nucleus and into the cells’ cytoplasm. To do this, they had to solve the equivalent of a very tiny 3-D jigsaw puzzle, using imaging techniques such as electron microscopy and X-ray crystallography on each puzzle piece.

Stefan Petrovic, a graduate student in biochemistry and molecular biophysics and one of the co-first authors of the papers, says the process began with Escherichia coli bacteria (a strain of bacteria commonly used in labs) that were genetically engineered to produce the proteins that make up the human NPC.

“If you walk into the lab, you can see this giant wall of flasks in which cultures are growing,” Petrovic says. “We express each individual protein in E. coli cells, break those cells open, and chemically purify each protein component.”

Once that purification — which can require as much as 1,500 liters of bacterial culture to get enough material for a single experiment — was complete, the research team began to painstakingly test how the pieces of the NPC fit together.

George Mobbs, a senior postdoctoral scholar research associate in chemistry and another co- first author of the paper, says the assembly happened in a “stepwise” fashion; rather than pouring all the proteins together into a test tube at the same time, the researchers tested pairs of proteins to see which ones would fit together, like two puzzle pieces. If a pair was found that fit together, the researchers would then test the two now-combined proteins against a third protein until they found one that fit with that pair, and then the resulting three-piece structure was tested against other proteins, and so on. Working their way through the proteins in this way eventually produced the final result of their paper: a 16-protein wedge that is repeated eight times, like slices of a pizza, to form the face of the NPC.

“We reported the first complete structure of the entire cytoplasmic face of the human NPC, along with rigorous validation, instead of reporting a series of incremental advances of fragments or portions based on partial, incomplete, or low-resolution observation,” says Si Nie, postdoctoral scholar research associate in chemistry and also a co-first author of the paper. “We decided to patiently wait until we had acquired all necessary data, reporting a humungous amount of new information.”

Their work complemented research conducted by Martin Beck of the Max Planck Institute of Biophysics in Frankfurt, Germany, whose team used cryo-electron tomography to generate a map that provided the contours of a puzzle into which the researchers had to place the pieces. To accelerate the completion of the puzzle of the human NPC structure, Hoelz and Beck exchanged data more than two years ago and then independently built structures of the entire NPC. “The substantially improved Beck map showed much more clearly where each piece of the NPC — for which we determined the atomic structures — had to be placed, akin to a wooden frame that defines the edge of a puzzle,” Hoelz says.

The experimentally determined structures of the NPC pieces from the Hoelz group served to validate the modeling by the Beck group. “We placed the structures into the map independently, using different approaches, but the final results completely agreed. It was very satisfying to see that,” Petrovic says.

“We built a framework on which a lot of experiments can now be done,” says Christopher Bley, a senior postdoctoral scholar research associate in chemistry and also co-first author. “We have this composite structure now, and it enables and informs future experiments on NPC function, or even diseases. There are a lot of mutations in the NPC that are associated with terrible diseases, and knowing where they are in the structure and how they come together can help design the next set of experiments to try and answer the questions of what these mutations are doing.”

“This elegant arrangement of spaghetti noodles”

In the other paper, titled “Architecture of the linker-scaffold in the nuclear pore,” the research team describes how it determined the entire structure of what is known as the NPC’s linker-scaffold — the collection of proteins that help hold the NPC together while also providing it with the flexibility it needs to open and close and to adjust itself to fit the molecules that pass through.

Hoelz likens the NPC to something built out of Lego bricks that fit together without locking together and are instead lashed together by rubber bands that keep them mostly in place while still allowing them to move around a bit.

“I call these unstructured glue pieces the ‘dark matter of the pore,'” Hoelz says. “This elegant arrangement of spaghetti noodles holds everything together.”

The process for characterizing the structure of the linker-scaffold was much the same as the process used to characterize the other parts of the NPC. The team manufactured and purified large amounts of the many types linker and scaffold proteins, used a variety of biochemical experiments and imaging techniques to examine individual interactions, and tested them piece by piece to see how they fit together in the intact NPC.

To check their work, they introduced mutations into the genes that code for each of those linker proteins in a living cell. Since they knew how those mutations would change the chemical properties and shape of a specific linker protein, making it defective, they could predict what would happen to the structure of the cell’s NPCs when those defective proteins were introduced. If the cell’s NPCs were functionally and structurally defective in the way they expected, they knew they had the correct arrangement of the linker proteins.

“A cell is much more complicated than the simple system we create in a test tube, so it is necessary to verify that results obtained from in vitro experiments hold up in vivo,” Petrovic says.

The assembly of the NPC’s outer face also helped solve a longtime mystery about the nuclear envelope, the double membrane system that surrounds the nucleus. Like the membrane of the cell within which the nucleus resides, the nuclear membrane is not perfectly smooth. Rather, it is studded with molecules called integral membrane proteins (IMPs) that serve in a variety of roles, including acting as receptors and helping to catalyze biochemical reactions.

Although IMPs can be found on both the inner and outer sides of the nuclear envelope, it had been unclear how they actually traveled from one side to the other. Indeed, because IMPs are stuck inside of the membrane, they cannot just glide through the central transport channel of the NPC as do free-floating molecules.

Once Hoelz’s team understood the structure of the NPC’s linker-scaffold, they realized that it allows for the formation of little “gutters” around its outside edge that allow the IMPs to slip past the NPC from one side of the nuclear envelope to the other while always staying embedded in the membrane itself.

“It explains a lot of things that have been enigmatic in the field. I am very happy to see that the central transport channel indeed has the ability to dilate and form lateral gates for these IMPs, as we had originally proposed more than a decade ago,” Hoelz says.

Taken together, the findings of the two papers represent a leap forward in scientists’ understanding of how the human NPC is built and how it works. The team’s discoveries open the door for much more research. “Having determined its structure, we can now focus on working out the molecular bases for the NPC’s functions, such as how mRNA gets exported and the underlying causes for the many NPC-associated diseases with the goal of developing novel therapies,” Hoelz says.

The papers describing the work appear in the June 10 issue of the journal Science.

Funding for the research was provided by the National Institutes of Health, the Howard Hughes Medical Institute, and the Heritage Medical Research Institute.

T cells are the immune system’s SWAT team. Their job is to constantly patrol the blood, lymphatic system, tissues, and organs. If they come across cells that are contaminated with or damaged by pathogens, they eliminate them. They can also recognize and destroy cancer cells. The problem, though, is that the tumor cells find ways of escaping this line of defense. Researchers around the world are working to prevent these evasive maneuvers and harness T cells for targeted immunotherapies against cancer.

The labs led by Dr. Armin Rehm and Dr. Uta Höpken at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin have now identified a mechanism that tumor cells use to dodge the body’s immune response. “In many cases, tumor cells read the EBAG9 gene especially often. The cells then produce a protein that protects them. But EBAG9 also influences the cells of the immune system because T cells produce it too. In T cells, EBAG9 inhibits the secretion of enzymes that act as poison to kill tumor cells,” says Rehm. Writing in the journal JCI Insight, the researchers describe how they released this brake in mice: “We shut down the EBAG9 gene,” says co-lead author Dr. Anthea Wirges, who works in Rehm’s research group. “This meant we could stop EBAG9 being produced in the T cells and strengthen the immune response to cancer for the long term.”

EBAG9 disarms immune cells

Scientists already know that cancer cells can outwit immune cells. This knowledge led to the development of checkpoint inhibitors, a type of immunotherapy that is already in clinical use. Checkpoint inhibitors make it hard for the cancer cells to trick T cells into thinking they’re harmless. “But EBAG9 gives cancer cells another line of defense against our immune system,” says Rehm. “It disarms the immune cells and stops them from secreting substances that would harm the cancer cells.”

Rehm and Höpken have long suspected that EBAG9 inhibits T cells. In 2009, Rehm’s ream developed a mouse model in which the researchers switched off the EBAG9 gene. “The mice’s immune system worked better without EBAG9 and they were able fight infections much more effectively,” says Rehm. Höpken’s team then crossed the EBAG9-free mice with another genetically modified mouse model that spontaneously developed leukemia. “We observed these doubly modified mice over a long period of time,” says Höpken. “Their tumors developed much more slowly than in the mice with EBAG9.”

Cancer and infections trigger different immune responses

Wirges checked the effects of the EBAG9 gene on the T cells using single-cell RNA sequencing and bioinformatic methods. As well as confirming that EBAG9 inhibits the T cell response, the data also showed that the immune response to cancer differs from the one triggered by infections.

“Knowledge about how the immune system develops a ‘memory’ comes from infection models. It can’t be transferred 1:1 to tumors,” says Rehm. T cells recognize diseased or infected cells by the signaling molecules on their surface. When they detect these harmful structures, they differentiate into cytotoxic T cells and memory T cells. The cytotoxic T cells secrete proteins that punch holes in the target cell’s membrane so that they can penetrate it and kill it by poisoning. Infected tissue also produces inflammatory signaling molecules, such as cytokines, that summon more T cells and cause them to mature into memory T cells. The memory cells record the immune response so that the immune system doesn’t have to start from scratch every time the T cells detect a disease.

The idea: Create CAR T cells without an immune brake

Tumors don’t cause inflammation in their early stages. Previously, scientists assumed that this was because T cells can’t identify tumor cells very well. “Because they’re produced by the body, tumor cells have very few surface molecules that are identifiable as foreign,” says Höpken. But it seems as if these minimal differences are enough for the T cells to spot the tumor cells: When the researchers switched off EBAG9, the reaction was astonishing. “The uninhibited T cells eliminate tumor cells very early and very radically,” notes Rehm. This also creates lasting protection against tumor cells. “The stronger the initial T cell reaction, the better the subsequent T cell memory,” says Rehm.

“Based on these findings, we now want to develop CAR T cells without EBAG9 as an immunotherapy for leukemia,” says Wirges. CAR stands for chimeric antigen receptor — an artificial receptor that detects tumor cells and is integrated into the patient’s own T cells. When patients have a CAR T-cell infusion, it equips their body with cells capable of fighting the cancer. The MDC researchers expect the CAR T cells to be even more effective without EBAG9. Although it will be a while before the cells reach the clinical trial stage, it could well be worth the wait: “We aren’t just hoping that this therapy will result in more efficient treatments for leukemia and lymphoma. We’re hoping that it will cure them,” says Rehm.

The University of Alabama at Birmingham Cancer Data analysis portal, or UALCAN, was developed and released to public use in 2017 as a user-friendly portal for pan-cancer omics data analysis, including transcriptomics, epigenetics and proteomics. UALCAN has had nearly 920,000 site visits from researchers in more than 100 countries, and it has been cited more than 2,750 times.

“UALCAN is an effort to distribute comprehensive cancer data to researchers and clinicians in a user-friendly format to make discoveries and find needles in the haystack,” said Sooryanarayana Varambally, Ph.D., professor in the UAB Department of Pathology Division of Molecular and Cellular Pathology and director of UAB’s Translational Oncologic Pathology Research program. “Cancer detection, diagnosis, treatment, cure and research need a global team effort, and making sense of the huge amount of data involved needs a way to analyze and interpret these data.”

Cancer is a complex disease, and its initiation, progression and metastasis, the spread to distant organs, involves dynamic molecular changes in each type of cancer. Individual cancer patients show variations apart from some of the common genomic events.

In the new study, Varambally worked with longtime collaborator Chad Creighton, Ph.D., Baylor College of Medicine, Houston, Texas. Creighton led the proteomic study, published in Nature Communications, “Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways.” This extends two early proteomics studies published in 2019 and 2021.

Previously the team performed RNA transcripts analysis, providing the data to researchers through UALCAN, to determine which pathways the myriad forms of cancer use to aid growth, spread and aggressiveness. With this recent study, the team performed and incorporated large-scale proteomics analysis. The data and results provide new ideas for further research and possible therapeutic interventions.

A proteome is the complement of proteins expressed in a cell or tissue, and these can be measured quantitatively through recent technological advances in mass-spectrometry. In cells, DNA makes mRNA, and mRNA makes protein, processes known as the central dogma of molecular biology. Proteins are major functional moieties of cells, crucial in cell metabolism, structure, growth, signaling and movement.

The cancer types represented in the UALCAN proteomic dataset include breast, colorectal, gastric, glioblastoma, head and neck, liver, lung adenocarcinoma, lung squamous, ovarian, pancreatic, pediatric brain, prostate, renal, and uterine cancers. The number of tumors in each cancer type in the study ranged from 76 to 230, with an average of 143. Intriguingly, the pan-cancer, proteome-based subtypes the current study found cut across tumor lineages.

The compendium proteomic dataset came from 17 individual studies. Corresponding multi-omics data were available for most of these tumors, including mRNA levels, DNA somatic small mutations and insertions/deletions, and DNA somatic copy number alterations.

In general, the researchers found the protein expression of genes across tumors broadly correlated with corresponding mRNA levels or copy number alterations. However, there were some notable exceptions.

They identified 11 distinct proteome-based pan-cancer subtypes — named s1 through s11 — that can provide insights into the deregulated pathways and processes in tumors that make them cancerous. Each subtype spanned multiple tissue-based cancer types, though subtype s11 was specific to brain tumors, spanning glioblastomas and pediatric brain tumors.

Each subtype expressed specific gene categories, some seen before in a previous, less comprehensive proteomic study. Three subtypes showed new gene categories: subtype s7 with “axon guidance” and “frizzled binding” genes, subtype s10 with “DNA repair” and “chromatin organization” genes, and subtype s11 with “synapse,” “dendrite” and “axon” genes.

At the DNA level, the study detailed differences among the proteome-based subtypes in overall copy number alterations of genes, and somatic mutations in subtypes associated with higher pathway activity, as inferred by proteome or transcriptome data.

“Our study results provide a framework for understanding the molecular landscape of cancers at the proteome level to integrate and compare the data with other molecular correlates of cancers,” Varambally said. “The associated datasets and gene-level associations represent a resource for the research community, including helping to identify gene candidates for functional studies and further develop candidates as diagnostic markers or therapeutic targets for specific subset of cancers.

“Furthermore, this study reinforces the notion that cancers should be comprehensively surveyed at the protein level, though expression profiling on tumors has historically been mostly limited to the RNA transcript level. Many of the analyses in this ever-evolving cancer data analysis platform are based on user or expert requests, and the team is indebted to the support and encouragement from the researchers who use this platform to make discoveries that make a difference in cancer research.”

Some of the large datasets for the UAB site are generated by consortiums like The Cancer Genome Atlas, or TCGA, and the Clinical Proteomic Tumor Analysis Consortium, or CPTAC, of the National Cancer Institute.

Precision targeting of cancer requires the identification of individual or subclass-specific genomic and molecular alterations. To help cancer researchers perform various data analyses for better understanding of these large datasets, Darshan Shimoga Chandrashekar, Ph.D., led the development of the UALCAN portal under the mentorship of Varambally. Updates to this continuously evolving portal were recently published in Neoplasia.

The UALCAN initiative and its continuous development involve contributions from a team of experts including bioinformaticians, computer scientists, statisticians, cancer biologists, pathologists and oncologists. “It is a team science approach to enable the global cancer research team to tackle cancer,” Varambally said.

Support came from National Institutes of Health grants CA125123 and CA118948 and United States Department of Defense grant W81XWH-19-1-0588.

Co-first authors of this study are Yiqun Zhang and Fengju Chen, Baylor College of Medicine, and Chandrashekar, UAB Department of Pathology Division of Molecular and Cellular Pathology.

Pathology is a department in the Marnix E. Heersink School of Medicine at UAB. Varambally is a senior scientist in the O’Neal Comprehensive Cancer Center and the Informatics Institute at UAB and is co-director of Cancer Biology Theme of Graduate Biomedical Sciences at UAB. He holds an adjunct position at the Michigan Center for Translational Pathology, the University of Michigan, Ann Arbor.

Their study, published today in Science Advances, shows that the inner core changed direction in the six-year period from 1969-74, according to the analysis of seismic data. The scientists say their model of inner core movement also explains the variation in the length of day, which has been shown to oscillate persistently for the past several decades.

“From our findings, we can see the Earth’s surface shifts compared to its inner core, as people have asserted for 20 years,” said John E. Vidale, co-author of the study and Dean’s Professor of Earth Sciences at USC Dornsife College of Letters, Arts and Sciences. “However, our latest observations show that the inner core spun slightly slower from 1969-71 and then moved the other direction from 1971-74. We also note that the length of day grew and shrank as would be predicted.

“The coincidence of those two observations makes oscillation the likely interpretation.”

Analysis of atomic tests pinpoints rotation rate and direction

Our understanding of the inner core has expanded dramatically in the past 30 years. The inner core — a hot, dense ball of solid iron the size of Pluto — has been shown to move and/or change over decades. It’s also impossible to observe directly, meaning researchers struggle through indirect measurements to explain the pattern, speed and cause of the movement and changes.

Research published in 1996 was the first to propose the inner core rotates faster than the rest of the planet — also known as super-rotation — at roughly 1 degree per year. Subsequent findings from Vidale reinforced the idea that the inner core super-rotates, albeit at a slower rate.

Utilizing data from the Large Aperture Seismic Array (LASA), a U.S. Air Force facility in Montana, researcher Wei Wang and Vidale found the inner core rotated slower than previously predicted, approximately 0.1 degrees per year. The study analyzed waves generated from Soviet underground nuclear bomb tests from 1971-74 in the Arctic archipelago Novaya Zemlya using a novel beamforming technique developed by Vidale.

The new findings emerged when Wang and Vidale applied the same methodology to a pair of earlier atomic tests beneath Amchitka Island at the tip of the Alaskan archipelago — Milrow in 1969 and Cannikin in 1971. Measuring the compressional waves resulting from the nuclear explosions, they discovered the inner core had reversed direction, sub-rotating at least a tenth of a degree per year.

This latest study marked the first time the well-known six-year oscillation had been indicated through direct seismological observation.

“The idea the inner core oscillates was a model that was out there, but the community has been split on whether it was viable,” Vidale says. “We went into this expecting to see the same rotation direction and rate in the earlier pair of atomic tests, but instead we saw the opposite. We were quite surprised to find that it was moving in the other direction.”

Future research to dig deeper into why inner core formed

Vidale and Wang both noted future research would depend on finding sufficiently precise observations to compare against these results. By using seismological data from atomic tests in previous studies, they have been able to pinpoint the exact location and time of the very simple seismic event, says Wang. However, the Montana LASA closed in 1978 and the era of U.S. underground atomic testing is over, meaning that the researchers would need to rely on comparatively imprecise earthquake data, even with recent advances in instrumentation.

The study does support the speculation that the inner core oscillates based on variations in the length of day — plus or minus 0.2 seconds over six years — and geomagnetic fields, both of which match the theory in both amplitude and phase. Vidale says the findings provide a compelling theory for many questions posed by the research community.

“The inner core is not fixed — it’s moving under our feet, and it seems to going back and forth a couple of kilometers every six years,” Vidale said. “One of the questions we tried to answer is, does the inner core progressively move or is it mostly locked compared to everything else in the long term? We’re trying to understand how the inner core formed and how it moves over time — this is an important step in better understanding this process.”

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Materials provided by University of Southern California. Original written by Paul McQuiston. Note: Content may be edited for style and length.

In the study, published June 10 in Science Immunology, the team focused on a class of antibodies called IgG, which help rid the body of infectious bacteria and viruses. Little was known about how IgG antibodies that are naturally induced by gut bacteria influence infant gut immunity. So, the investigators used a mouse model to determine how these IgG antibodies are transferred from a mother’s blood to her breast milk and how they protect young mice from Citrobacter rodentium (equivalent to pathogenic E. coli in humans) that causes potentially dangerous intestinal infections.

“We found that these IgG antibodies were protective against gut infection in the babies and that we could enhance this protection,” said senior author Dr. Melody Zeng, an assistant professor of immunology in pediatrics within the Department of Pediatrics and a member of the Gale and Ira Drukier Institute for Children’s Research at Weill Cornell Medicine.

Just as antibodies against the SARS-CoV-2 virus are detected in the breast milk of women who had been vaccinated with mRNA vaccines for COVID-19, the researchers sought to confer extra protection against intestinal infections in infants by inducing IgG antibodies that could be transferred this way. They developed a vaccine using a component found in gut bacteria, then immunized female mice with it before they became pregnant.

“The same concept, in which vaccination enhances mothers’ IgG antibody levels and transfers this immunity to her babies, could protect human babies,” Dr. Zeng said. “This strategy could especially benefit premature babies, since they tend to be at much higher risk from diarrheal diseases.”

Such infections pose significant dangers for young children in general. Diarrheal illnesses are the second leading cause of death among children under five, according to the World Health Organization.

In their experiments, the researchers, including co-first authors Dr. Katherine Sanidad and Dr. Mohammed Amir, both postdoctoral associates in the Zeng lab, first demonstrated that when passed to infant mice through breast milk, IgG prevented disease-causing bacteria from attaching themselves to the lining of infants’ intestines, an early step in infection.

They also studied how IgG interacted with another set of microbes — beneficial bacteria that live in the gut — to facilitate healthy development of gut bacteria in infants. Scientists are finding that these microbes contribute to the development and function of the immune system. For instance, helpful bacteria train the immune system to recognize their pathogenic relatives.

This study uncovered long-term effects of these protective IgG antibodies too. Mice that never received IgG from their mothers developed abnormal microbial communities within their guts, which led to changes to their immune systems. Specifically, the researchers found an increase in gut immune cells that produce IL-17, a proinflammatory cytokine that is linked to inflammatory diseases. As adults, the IgG-deprived mice were more susceptible to abnormal inflammation associated with inflammatory bowel disorder.

“Our findings really underscore the benefits of breastfeeding, both immediately and for the long-term development of the immune system in the offspring,” Dr. Zeng said.

Dr. Melody Zeng is a consultant for Guidepoint.

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In a study published in Genetics in Medicine, researchers analysed genetic data collected on over 200,000 UK men aged 40-70 from UK Biobank, a biomedical database and research resource containing anonymised genetic, lifestyle and health information from half a million UK participants. They found 356 men who carried either an extra X chromosome or an extra Y chromosome.

Sex chromosomes determine our biological sex. Men typically have one X and one Y chromosome, while women have two Xs. However, some men also have an extra X or Y chromosome — XXY or XYY.

Without a genetic test, it may not be immediately obvious. Men with extra X chromosomes are sometimes identified during investigations of delayed puberty and infertility; however, most are unaware that they have this condition. Men with an extra Y chromosome tend to be taller as boys and adults, but otherwise they have no distinctive physical features.

In today’s study, the researchers identified 213 men with an extra X chromosome and 143 men with an extra Y chromosome. As the participants in UK Biobank tend to be ‘healthier’ than the general population, this suggests that around one in 500 men may carry an extra X or Y chromosome.

Only a small minority of these men had a diagnosis of sex chromosome abnormality on their medical records or by self-report: fewer than one in four (23%) men with XXY and only one of the 143 XYY men (0.7%) had a known diagnosis.

By linking genetic data to routine health records, the team found that men with XXY have much higher chances of reproductive problems, including a three-fold higher risk of delayed puberty and a four-fold higher risk of being childless. These men also had significantly lower blood concentrations of testosterone, the natural male hormone. Men with XYY appeared to have a normal reproductive function.

Men with either XXY or XYY had higher risks of several other health conditions. They were three times more likely to have type 2 diabetes, six times more likely to develop venous thrombosis, three times as likely to experience pulmonary embolism, and four times more likely to suffer from chronic obstructive pulmonary disease (COPD).

The researchers say that it isn’t clear why an extra chromosome should increase the risk or why the risks were so similar irrespective of which sex chromosome was duplicated.

Yajie Zhao, a PhD student at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the study’s first author, said: “Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this. This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases — diseases that may be preventable.”

Professor Ken Ong, also from the MRC Epidemiology Unit at Cambridge and joint senior author, added: “Genetic testing can detect chromosomal abnormalities fairly easily, so it might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern.

“We’d need more research to assess whether there is additional value in wider screening for unusual chromosomes in the general population, but this could potentially lead to early interventions to help them avoid the related diseases.”

Professor Anna Murray, at the University of Exeter, said: “Our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past.”

Previous studies have found that around one in 1,000 females have an additional X chromosome, which can result in delayed language development and accelerated growth until puberty, as well as lower IQ levels compared to their peers.

The research was funded by the Medical Research Council.

Tracking the adaptations to wet conditions

Plant species differ greatly in their ability to survive periods of flooding or waterlogging. “In the case of potatoes, the roots die after two days due to a lack of oxygen. Rice plants are much more resistant, able to survive their entire lives in waterlogged paddy fields,” Hartman explains. The Arabidopsis thaliana, a model organism for plant research, can be used to study the genes and proteins that make up this adaptation. “Plants notice that they are surrounded by water because the gas ethylene, which all plant cells produce, can no longer escape into the air,” Hartman continues. The researchers showed this in previous studies at Utrecht University. Receptors throughout the plant subsequently respond to increased concentrations of the hormone.

Simulate flooding with oxygen deprivation

The team simulated flooding by placing Arabidopsis seedlings in a bell jar without light or oxygen. When the seedlings were previously exposed to ethylene gas, the root tip cells survived longer. The treated plants stopped root growth and switched energy production in the cells to oxygen-free metabolic processes. In addition, the ethylene caused the cells to be better protected against harmful oxygen radicals that accumulate in oxygen-deprived plants. This was revealed by analyses of gene activity and protein composition of the cells.

“Taken together, these rearrangements that ethylene triggers improve plant survival during and after flooding,” Hartman summarizes. “As we better understand these signaling pathways, we can learn to make crops more resilient to flooding to combat climate change.”

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In a new research study published in Global Change Biology, lead author Michael Crossley, assistant professor and agricultural entomologist at the University of Delaware, and his collaborators examined trends in breeding monarchs across their entire range, and found there are local regions of decline, but also regions of increase. When considering the entire species range, there was no overall decline, and in fact, even a slight increase in abundance.

“The whole reason that we did this research is because monarch colonies have been declining,” said Crossley. “Up until now, there were real fears that the monarch is in trouble.”

The study’s results suggest that population growth in summer is compensating for losses during the winter. Additionally, findings indicate that changing environmental variables have offsetting effects on deaths and reproduction.

North America’s three largest countries have more in common than playing the 2026 hosts of soccer’s biggest spectacle — the FIFA World Cup. The perception of the monarchs’ decline had prompted the U.S. Fish and Wildlife Service to determine if the species warrants a higher level of protection. Canada’s equivalent agency is strongly considering listing monarchs as an endangered species because of the declines in Mexico.

As the researchers analyzed the data, patterns emerged and were location specific. Portions of the U.S. Northeast and parts of the Midwest revealed population declines. The U.S. Southeast and Northwest were unchanged or increasing, yielding a slightly positive overall trend across the species range. Monarchs in Florida appear to be doing exceptionally well.

“Our question was, ‘Are monarchs declining across their breeding range?’ The key take home message was yes, monarchs are declining in some places, but increasing in other locations,” said Crossley, who conducts research and teaches in the UD Department of Entomology and Wildlife Ecology. “There is no consistent, long-term trend.”

So how is that possible? Near agricultural fields that use glyphosate, which is used in products such as Roundup, sites typically had fewer monarchs. This occurrence was especially evident in the upper Midwest — the corn and soy belt. The researchers also found positive effects of temperature, which is generally increasing faster in northern latitudes, which seems to be counterbalancing glyphosate effects.

“These two effects seem to cancel each other out, especially in the upper Midwest,” said Crossley.

Crossley contends that the different trends in these locations are related to the environment.

“For example, there are populations now that will overwinter in California, Florida or even southern Georgia because it’s become more feasible with increasing winter temperatures,” Crossley said. “We may see fewer migrants because monarchs are doing well, staying in Florida and not joining the migration.”

Since accelerating climate change may bring growing threats, Crossley cautioned against complacency.

The dataset that the researchers used was made possible by the North American Butterfly Association and thousands of citizen scientists — volunteers and butterfly enthusiasts — who collected butterfly counts for the past 25 years at more than 400 sites around the continent.

Another conclusion of the study is that other butterfly species are facing greater peril than monarchs. The authors argue that some of these butterflies — like Poweshiek skipperling (in the upper Midwest), Florida leafwing (in extreme southern Florida) and Hermes copper (in extreme southern California) — deserve more attention. Though monarchs are the most popular among the general public, they are far from the only type of butterfly. The North American Butterfly Association observes more than 450 species. Though it’s facing overall population declines, the monarch is doing comparatively well; 320 species face steeper population losses.

“It seems like breeding monarchs in North America are not in trouble despite winter colony declines,” said Crossley. “This could lead to several explanations about why a disconnect exists between numbers in the breeding range and numbers in overwintering sites.”

The grueling journey

The findings show that monarchs are breeding in strong numbers. Then the insects trek to places like Mexico to overwinter, but these colonies are generally shrinking in size. So, what is hindering the journey southward to the winter colonies? Study co-author Andy Davis of the University of Georgia has investigated parasites of monarchs and found that a protozoan parasite, Ophryocystis elektroscirrha (OE), is on the rise, and could affect the success of the fall migration. As Davis described, making that journey with parasites in tow is equivalent to running a marathon with the flu. And monarchs’ total mileage, which falls between 1,200 and 2,800 miles, far eclipses human’s 26.2-mile mark for a marathon.

“A lot of monarchs are not going to make that southward journey if they are infected,” said Crossley. “One way to reconcile the disconnect [between breeding numbers and overwinter numbers] is to say, well, maybe monarchs have an incredible ability to rebound every spring and summer from relatively small overwintering sizes. And the decline is occurring during this southward migration.”

Besides parasites, other factors are affecting monarchs’ migration. Climate change is making the journey south hotter and drier, making the extended trip more arduous for these small creatures. Additionally, many butterflies use certain valleys as their flyways, which are unfortunately along highways. Cars and trucks are simply running into the iconic insects, something Crossley points out could potentially be amended.

“For other types of species, officials reduce speed limits or reroute traffic during certain times of year, so these animals can cross the road,” said Crossley.

Finally, when you’re on a long trip, you always stop and grab a bite to eat, right? Monarchs feed on nectar. Loss of habitat and nectar resources mean more butterflies lack the energy to fly south. The average person can take action on their own and plant native, fall-blooming goldenrods, asters and perennial sunflowers to fuel the monarchs.

“We certainly can’t go wrong by making more insect habitats. Whether humans or animals, we could all use more,” Crossley said. “We can do that with native plants right in our own backyards.”

The paper was co-authored by the University of Georgia’s Davis and William Snyder; Timothy Meehan, of the National Audubon Society; Matthew Moran, of Hendrix College; and Jeffrey Glassberg, of Rice University and the North American Butterfly Association.