A new Science Immunology study highlights the limitations of preclinical models for human antibody-based drugs, and demonstrates how a humanized mouse model may improve study outcomes.
Preclinical modeling of human IgG–based drugs is enhanced through humanized Fcγ receptor and FcRn expression in a murine knockin model.
Current drugs for pancreatic cancer lose effectiveness within months because the tumor becomes resistant. Now, a group from Spain’s National Cancer Research Centre (CNIO) has been able to avoid the development of resistance in animal models with a combined triple therapy. Mariano Barbacid, head of the Experimental Oncology Group at the CNIO, has designed a therapy that successfully eliminates pancreatic tumors in mice completely and durably, with no significant side effects.
The study is published in the journal Proceedings of the National Academy of Sciences, with Carmen Guerra as co-lead author and Vasiliki Liaki and Sara Barrambana as first authors.
“These studies open the road to designing novel combination therapies that may improve the survival of PDAC patients [pancreatic ductal adenocarcinoma—the most common type of pancreatic cancer],” the authors state. “These results set the course for developing new clinical trials.”
A new study found that an enzyme involved in protein translation is essential for circulating immune cells, called monocytes, to mature into tissue-resident macrophages, a specialized population of immune cells that maintain organ health by clearing dead cells and debris. Without this enzyme, monocytes enter tissues but fail to fully differentiate, leading to impaired tissue maintenance and persistent immune cell infiltration that causes inflammation instead of repair.
The research, published in Nature, showed that deoxyhypusine synthase (DHPS) is required for both the differentiation and long-term survival of macrophages across multiple organs, including the lung, liver, brain, kidney, heart and peritoneal cavity.
Using a series of mouse models, the investigators demonstrated that DHPS controls a core, tissue-agnostic program that enables macrophages to adhere to their local environment, interact with surrounding cells and carry out the essential functions that maintain tissue balance and organ health.
The researchers traced these defects to the polyamine–hypusine pathway. Analyses of gene activity, protein production and protein-making machinery revealed that DHPS is required for efficient translation of a subset of genes involved in cell adhesion (the ability to stick to their surroundings and to other cells so they can stay in the correct place and function properly), signaling, and tissue interaction. Without DHPS, macrophages failed to express key proteins needed to anchor themselves within tissues and respond appropriately to local cues.
Imaging studies showed that DHPS-deficient macrophages had abnormal shape and positioning within tissues, while functional assays demonstrated defects in the clearance of dead cells and tissue maintenance. In the lung, this impairment led to accumulation of surfactant material, a substance in the lungs that keeps air sacs open, and immune cell infiltration, while in the liver, acute macrophage depletion followed by failed restoration resulted in vascular disruption and tissue damage. sciencenewshighlights ScienceMission.
New in eNeuro from Dutta Gupta et al: Some older male rats prefer familiarity over new social situations, which can be reversed via transcranial magnetic stimulation without affecting hippocampus-mediated spatial memory.
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Social cognition, central to emotional and cognitive well-being, is particularly vulnerable to aging, where impairments can lead to isolation and functional decline. Despite compelling evidence that altered social behavior is associated with cognitive decline and dementia risk, experimental strategies for testing causative links remain scarce. To address this gap, we aimed to establish a rat model for research on social neurocognitive aging. We conducted a large-scale behavioral study in 169 male young (6 months) and aged (24−25 months) Long-Evans rats. In order to explore potential relationships among aging outcomes, we first documented individual differences in a widely validated water maze test of hippocampal learning and memory. Sociability and social novelty were then evaluated in the same subjects using the three-chamber social interaction test. Aging induced a selective shift in social novelty preference, marked by a striking familiarity bias in a substantial subpopulation of old rats, while sociability remained entirely normal. Changes in social novelty preference were completely independent of individual differences in spatial memory, and unrelated to anxiety or sensorimotor function. Notably, neuromodulation via TMS enhanced social novelty preference selectively in aged rats that exhibited a social introversion phenotype before treatment, consistent with the possibility that this aging condition reflects a distinct and modifiable neural network state. Together, the results establish a valuable preclinical framework for developing a comprehensive neurobiology of social cognition in aging.
Significance statement Social behavior is a critical yet underexplored component of cognitive aging. While both human and animal studies report age-related narrowing of social networks, the behavioral and neurobiological underpinnings remain unclear. Using a well-powered rat model, here we demonstrate preserved sociability in aging alongside marked individual differences in social novelty preference. A subset of aged rats preferred familiar over novel conspecifics, resembling patterns observed in older humans and non-human primates. Social phenotypes were independent of hippocampal-dependent memory, suggesting a dissociation between these aging outcomes. This dissociation was further validated using transcranial magnetic stimulation, supporting the notion of distinct underlying neurobiological mechanisms. Collectively, the findings lay a powerful foundation for advancing the translational neurobiology of social behavior in cognitive aging and reserve.
What if the universe wasn’t the beginning? Long before the Big Bang, before the first stars ignited, and before time even had a direction, there were entities already lurking in the void.
Tonight, we’re diving into 20 beings that existed before the universe itself. From cosmic architects who engineered life in the stars to \.
AI may learn better when it’s allowed to talk to itself. Researchers showed that internal “mumbling,” combined with short-term memory, helps AI adapt to new tasks, switch goals, and handle complex challenges more easily. This approach boosts learning efficiency while using far less training data. It could pave the way for more flexible, human-like AI systems.
“Two things can happen: Either the planet gets very, very close to the binary, suffering tidal disruption or being engulfed by one of the stars, or its orbit gets significantly perturbed by the binary to be eventually ejected from the system,” said Dr. Mohammad Farhat.
Why is it so rare to find exoplanets orbiting two stars, also called circumbinary planets (CBPs)? This is what a recent study published in The Astrophysical Journal Letters hopes to address as a team of researchers investigated the celestial processes responsible for the formation and evolution of CBPs. This study has the potential to help scientists better understand solar system and planetary formation and evolution, which could narrow the search for life beyond Earth.
For the study, the researchers used a combination of computer models and Einstein’s theory of relativity to simulate the formation and evolution of CBPs. For example, the researchers explored the interaction between the CBP and its binary star, resulting in one of three outcomes: stable orbit, ejection, or consumption by the binary star. The reason Einstein’s theory of relativity was used as part of the study was because it calls for objects to have their orbit perturbed the closer they orbit to a larger object, like a star.
A common example that’s used for the theory is of a trampoline with objects falling inward when a large body is in the middle of it. Essentially, stars have “instability zones” where planets get consumed if they orbit too close. In the case of CBPs, the astronomers found that of the 14 known CBPs out of more than 6,000 confirmed exoplanets, 12 orbit just beyond the instability zone and none of the 14 have orbits less than seven days. The researchers concluded that a common phenomenon in astronomy called the three-body problem is responsible for the lack of CBPs.
In Science last year, researchers presented a method to safely and preferentially generate CAR T cells directly inside the body using targeted lipid nanoparticles that deliver mRNA directly to T cells.
The approach showed rapid and sustained immune reprogramming in preclinical models, highlighting its promise for treating cancer and autoimmune diseases.
Learn more on WorldCancerDay.
Lipid nanoparticles are designed to generate therapeutic T cells inside living animal models.
Vivek Peche and Stephen Gottschalk Authors Info & Affiliations
Science
Platelets are cell fragments that plug leaks in blood vessels, preventing bleeding. However, they also form clots that impede blood flow (thrombosis) and increase inflammation.
Activated platelets, which can bind to each other, and hyporesponsive platelets, which do not form clots, are detected in patients with acute severe infections, such as COVID-19 and sepsis. How to uncouple the protective and harmful proinflammatory functions of platelets is a therapeutic dilemma.
In Science, researchers report the formation of platelet-derived integrin-and tetraspanin-enriched tethers (PITTs) in patients with severe infections.
PITTs, which are enriched in specific platelet proteins, remain anchored to the blood vessel wall (endothelium) and promote neutrophil recruitment, inflammation, and tissue damage, whereas the main platelet body shears off and reenters circulation in a hyporesponsive state. PITTs may contribute to blood clotting, immune dysregulation, and bleeding complications that characterize severe infections.
Learn more in a new Science Perspective.
Platelet-derived structures in blood vessel walls increase inflammation and bleeding risk.
