Category: 7. Science

Summary: Scientists have uncovered how stem cells in the olfactory system continually regenerate neurons responsible for our sense of smell. Using live zebrafish imaging, cell tracking, and single-cell RNA sequencing, researchers identified a bistable toggle switch that drives progenitor cells to commit to specific fates and self-organize into “cellular neighborhoods.”

These findings explain how fluctuating, noisy signals can reliably produce new neurons throughout life. The work opens the door to applying these mechanisms in broader contexts, potentially advancing treatments for neurodevelopmental and neurodegenerative diseases.

Key Facts

• Toggle Switch: A bistable signaling mechanism controls stem cell fate in the olfactory system.
• Sustained Regeneration: Human olfactory neurons regenerate every few months across the lifespan.
• Therapeutic Potential: Findings may guide future approaches for brain repair and neurodegenerative disease treatments.

Source: University of Alabama Birmingham

Cellular differentiation of stem cells into specialized cells requires many steps, including division, to create more cells; fate determination, which is a commitment to a specific lineage or developmental path; and migration, to integrate the cell into its final location.

Previous in vitro work has shown that stem cells can spontaneously self-organize into groups of specialized cell types, yet little is known about how that happens in living animals — where densely populated microenvironments have high degrees of noise in cell-to-cell signaling and variations in gene expression.

In their study and a featured cover image in a special issue of Stem Cell Reports on Neural Stem Cells, researchers at the University of Alabama at Birmingham and the University of Illinois Chicago describe signaling mechanisms that determine one such example of vertebrate development — the transition from olfactory stem cells into highly regenerative olfactory neurons that are responsible for the sense of smell.

Applying multiple techniques including high-resolution imaging of live zebrafish embryos, quantitative tracking of cell fate and single-cell RNA sequencing, researchers identified a unique bistable toggle switch that assigns divergent cell fates to progenitor cells and drives their assembly into cellular “neighborhoods.”

In doing so, they showed how signaling that guides continuous neural development is integrated at multiple scales — single cells, small clusters of cells and between entire organs.

The study describes “a previously unknown paradigm of cellular neighborhood assembly through which the olfactory epithelium integrates fluctuating, stochastic signals to streamline fate commitment, differentiation and integration into the olfactory neuronal rosette,” wrote lead author Sriivatsan Govinda Rajan, Ph.D., and corresponding author Ankur Saxena, Ph.D., UAB Department of Cell, Developmental and Integrative Biology.

“These findings reveal how stochastic signaling networks spatiotemporally regulate a balance between progenitors and derivatives, driving sustained neurogenesis in an intricate organ system.”

“Remarkably, the human nose turns over its neurons every couple of months or so throughout our lifetimes,” Saxena said.

“Given this unusual neuroregeneration, we wanted to answer a fundamental question: How do stem cells funnel fluctuating signals to make new neurons over and over again?

“Now, we’re building on our molecular ‘answers’ from the zebrafish model system by asking if the identified molecular pathways can be applied in other contexts to shape the nervous system across vertebrates.

“Long-term, our hope is to discover new therapeutic avenues for patients with neurodevelopmental or neurodegenerative disorders.”

Co-authors with Rajan and Saxena in the study, “Progenitor neighborhoods function as transient niches to sustain olfactory neurogenesis,” are Lynne M. Nacke, UAB Department of Cell, Developmental and Integrative Biology; and Joseph N. Lombardo, Farid Manuchehrfar, Kaelan Wong, Pinal Kanabar, Elizabeth A. Somodji, Jocelyn Garcia, Mark Maienschein-Cline and Jie Liang, University of Illinois Chicago.

At UAB, Cell, Developmental and Integrative Biology is a department in the Marnix E. Heersink School of Medicine.

More information about the Saxena Lab’s work can be found at www.saxenalab.com. Rajan is now at Memorial Sloan Kettering Cancer Center, New York City, New York.

About this genetics and neuroregeneration research news

Author: Jeffrey Hansen
Source: University of Alabama at Birmingham
Contact: Jeffrey Hansen – University of Alabama at Birmingham
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Progenitor neighborhoods function as transient niches to sustain olfactory neurogenesis” by Sriivatsan Govinda Rajan et al. Stem Cell Reports

Abstract

Progenitor neighborhoods function as transient niches to sustain olfactory neurogenesis

Olfactory neurogenesis occurs throughout the lives of vertebrates, including in humans, and relies on the continuous differentiation and integration of neurons into a complex network.

How progenitor cells convert fluctuations in cell-cell signaling into streamlined fate decisions over both space and time is poorly understood.

Here, we track multicellular dynamics in the zebrafish olfactory epithelium, undertake targeted perturbations, and find that neurogenesis is driven by mutual antagonism between Notch signaling and insulinoma-associated 1a (Insm1a) that is responsive to inter-organ retinoic acid signaling.

Single-cell analysis reveals that olfactory neurons emerge from transient groups of cells termed cellular neighborhoods.

Stochastic modeling shows that neighborhood self-assembly is maintained by a tightly regulated bistable toggle switch. Differentiating cells migrate apically in response to brain-derived neurotrophic factor (BDNF) to take up residence as mature sensory neurons.

Cumulatively, these findings reveal how stochastic signaling networks spatiotemporally regulate a balance between progenitors and derivatives, driving sustained neurogenesis in an intricate organ system.

Aug. 29 (UPI) — An interdisciplinary team of specialists from Argentina’s National Scientific and Technical Research Council, or CONICET, discovered most of the skeleton — including the skull and jaws — of a large hypercarnivorous crocodile that lived in southern Argentina about 70 million years ago during the Late Cretaceous period.

Hypercarnivorous animals are those whose diet consists of more than 70% meat, and that include eagles, vultures, toothed whales, spiders and scorpions.

The discovery site, described Wednesday in the scientific journal PLOS One, is situated about 19 miles south of the town of El Calafate in Patagonia.

Researchers named the new species Kostensuchus atrox, combining “Kosten” — the Aonikenk/Tehuelche word for Patagonian wind — and “suchus” — from the Greek Souchos, the crocodile-headed Egyptian god.

“This new species is distinguished from all previously known species by traits such as the large size of its teeth and skull, the robustness of its jaw and the large cavities that housed the muscles responsible for its bite. These traits lead us to interpret it as a top predator in the ecosystem,” said Diego Pol, a CONICET researcher at the Bernardino Rivadavia Argentine Museum of Natural Sciences.

The animal was not a dinosaur, though it was a predator. It belongs to an extinct family of crocodiles known as peirosaurs, which evolved in South America and Africa during the Cretaceous Period.

Kostensuchus lived in humid, lush environments. It had a robust body and short legs positioned vertically beneath its torso, which made it more agile than modern caimans and crocodiles.

Its head measured about 20 inches — large for its overall size, earning it the nickname the “bulldog” of crocodiles — and its snout carried more than 50 teeth, some longer than 2 inches, with serrated edges for cutting flesh. Its jaws, powered by strong muscles, delivered a quick and extremely powerful bite.

“Another predator we discovered in these rocks is the dinosaur Maip macrothorax – a carnivorous predator that was among the last dinosaurs before extinction and a close relative of the Megaraptor from Neuquén. It is very likely that Kostensuchus and Maip competed for food, similar to the clashes that occur today in Africa between hyenas and lions,” said paleontologist Fernando Novas, a CONICET researcher at the Félix de Azara Natural History Foundation and lead author of the study.

The study expands the known diversity of vertebrates in Patagonia and marks the southernmost record of peirosaurids. It also reinforces evidence that, toward the end of the Cretaceous, a lineage of large, robust animals lived in both South America and Madagascar.

The project involved researchers from Argentina, Brazil and Japan, with support from National Geographic and Brazilian science agencies — the Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro and the National Council for Scientific and Technological Development.

CONICET said the discovery is a key piece in reconstructing the Patagonian ecosystem before the end of the dinosaur era.

In the search for life in the Universe, molecular oxygen (O₂) combined with a reducing species, such as methane (CH₄), is considered a promising disequilibrium biosignature.

In cases where it would be difficult or impossible to detect O₂ (e.g., mid-IR or low O₂ levels), it has been suggested that ozone (O₃), the photochemical product of O₂, could be used as a proxy for determining the abundance of O₂. As the O₂-O₃ relationship is nonlinear, the goal of this series of papers is to explore how it would change for different host stars and atmospheric compositions and learning how to use O3 to infer O₂.

We used photochemistry and climate modeling to further explore the O₂-O₃ relationship by modeling Earth-like planets with the present atmospheric level (PAL) of O₂ between 0.01% to 150% along with high and low CH₄ abundances of 1000% and 10% PAL, respectively. Methane is of interest not only because it is a biosignature, but also the source of hydrogen atoms for hydrogen oxide (HOx) which destroys O₃ through catalytic cycles and acts as a catalyst for the smog mechanism of O₃ formation in the lower atmosphere.

We find varying CH₄ causes changes to the O₂-O₃ relationship in ways that are highly dependent on both host star and O₂ abundance. A striking result for high CH₄ models in high O₂ atmospheres around hotter hosts is that enough CH4 is efficiently converted into H₂O to significantly impact stratospheric temperatures, and therefore the formation/destruction rates of O₃.

Changes in HOx also influenced the HOx catalytic cycle and smog O3, causing variations in harmful UV reaching the surface as well as changes in the 9.6~μm O₃ feature in emission spectra. This demonstrates the need to explore the O₂-O₃ relationship in order to use O₃ as a reliable proxy for O₂ in future observations.

Thea Kozakis, João M. Mendonça, Lars A. Buchhave, Luisa M. Lara

Comments: In production with A&A
Subjects: Earth and Planetary Astrophysics (astro-ph.EP)
Cite as: arXiv:2508.19062 [astro-ph.EP] (or arXiv:2508.19062v1 [astro-ph.EP] for this version)
https://doi.org/10.48550/arXiv.2508.19062
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Related DOI:
https://doi.org/10.1051/0004-6361/202556015
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From: Thea Kozakis
[v1] Tue, 26 Aug 2025 14:21:28 UTC (682 KB)
https://arxiv.org/abs/2508.19062

Astrobiology

Wide separation gas giant planets present a challenge to current planet formation theories, and the detection and characterisation of these systems enables us to constrain their formation pathways.

The WIde Separation Planets In Time (WISPIT) survey aims to detect and characterise wide separation planetary-mass companions over a range of ages from <5 to 20 Myr around solar-type host stars at distances of 75-500 (median: 140) parsecs.

The WISPIT survey carries out two 5 minute H-band exposures with the VLT/SPHERE instrument and IRDIS camera, separated by at least six months to identify co-moving companions via proper motion analysis. These two H-band observations in combination with a follow-up Ks-band observation were used to determine the colour-magnitude of the co-moving companions and to derive their masses by comparing to AMES-COND and AMES-DUSTY evolutionary tracks.

We report the discovery of WISPIT 1b and WISPIT 1c, two gas giant exoplanets that are co-moving with the stellar binary WISPIT 1, which itself consists of a K4 star and M5.5 star in a multi-decadal orbit. The planets are at projected separations of 338 au and 840 au and have masses of 10 Mj and 4 Mj respectively.

We identified two common proper motion planetary companions to a (previously unknown) stellar binary with a Sun-like primary. These targets are ideal for follow up characterisation with both ground and space-based telescopes.

Monitoring of the orbit with the GRAVITY interferometer will place constraints on their eccentricity, and spectroscopic characterisation will identify the composition and metallicity, providing information on their formation pathways.

Detail of the WISPIT 1 system. The top panel shows the SPHERE/IRDIS H-band image taken on 2022 November 19, processed with unsharp masking to suppress the stellar halo. The stellar binary WISPIT 1 (behind the coronagraph) is located in the upper left, with its companions highlighted with coloured boxes. Zoomed-in images of the unmasked observation centred on companions WISPIT 1b and WISPIT 1c, are shown in the lower left and lower right panels, respectively. — astro-ph.EP

Richelle F. van Capelleveen, Matthew A. Kenworthy, Christian Ginski, Eric E. Mamajek, Alexander J. Bohn, Rico Landman, Tomas Stolker, Yapeng Zhang, Nienke van der Marel, Ignas Snellen

Comments: Accepted for publication in Astronomy & Astrophysics section “10. Planets, planetary systems, and small bodies” on August 25, 2025
Subjects: Earth and Planetary Astrophysics (astro-ph.EP)
Cite as: arXiv:2508.18456 [astro-ph.EP](or arXiv:2508.18456v1 [astro-ph.EP] for this version)
https://doi.org/10.48550/arXiv.2508.18456
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Submission history
From: Richelle Van Capelleveen
[v1] Mon, 25 Aug 2025 20:04:02 UTC (3,867 KB)
https://arxiv.org/abs/2508.18456

Astrobiology, exoplanet,

A new synthesis method makes guava compounds widely available. It holds promise against deadly liver cancer.

Many modern medicines owe their origins to natural sources.

One well-known example is willow tree bark, often referred to as “nature’s aspirin.” It contains a compound called salicin, which the human body converts into salicylic acid, a substance that reduces pain and lowers fever.

A team led by William Chain, an associate professor in the University of Delaware’s Department of Chemistry and Biochemistry, has uncovered a promising approach to battling liver-related cancers, one of the leading causes of cancer deaths worldwide. Their research focuses on a molecule derived from a tropical fruit that may play a key role in developing new treatments.

Creating guava-based cancer fighters

Through a technique known as natural product total synthesis, Chain and his research group have established a laboratory pathway that uses readily available chemicals to produce molecules naturally found in guava plants. These molecules have been shown to combat aggressive liver cancers. The team’s results were published in Angewandte Chemie, a major international chemistry journal.

This breakthrough gives scientists an efficient and inexpensive method for generating large quantities of these natural compounds. By making them more accessible, the approach could pave the way for cancer treatments that are both more effective and more affordable.

“The majority of clinically approved medicines are either made from a natural product or are based on one,” Chain said. “But there aren’t enough natural resources to make enough treatments. Now chemists will be able to take our manuscripts and basically follow our ‘recipe’ and they can make it themselves.”

Collaboration and new pathways

The discovery invites collaboration with scientists around the world.

“We are the first ones to pave that road, and other people can repave it any which way. Find the shortcuts if they have to. But since we entered into that unknown territory, I think we helped shed light on this unknown pathway that can get us there. And I think that’s the cool part,” said Liam O’Grady, doctoral student in Chain’s lab and the article’s first author.

The potential impact is enormous. The number of liver and bile duct cancer cases has grown dramatically in recent years, with one in 125 men and women globally projected to be diagnosed with hepatocellular cancer over the course of their lives.

In the United States, chemotherapies for liver cancers are a multi-billion-dollar health burden and the current five-year survival rates for late-stage liver cancers are under 15%. In 2025, in the US alone, more than 42,000 people will be diagnosed and over 30,000 will lose their battle.

The team is working with the National Cancer Institute on the next steps for the process and whether the guava molecule may be effective in fighting other types of cancers.

Reference: “Enantioselective Total Synthesis of (–)-Psiguadial A” by Liam P. O’Grady, Marcel Achtenhagen, Michael F. Wisthoff, Robert S. Lewis, Katarina Pfeifer, Weifeng Zheng, Maxwell I. Martin, Glenn P. A. Yap and William J. Chain, 20 May 2025, Angewandte Chemie.
DOI: 10.1002/ange.202506537

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When you think about Earth’s building blocks, your mind probably doesn’t jump to a giant space butterfly 3,400 light-years away. But scientists studying one of the galaxy’s most dramatic nebulae – the Butterfly Nebula – say it might offer real answers about how rocky planets like ours came to be.

Thanks to the James Webb Space Telescope (JWST), researchers got the clearest look yet inside this strange, fiery structure. What they found were signs of dust – the kind that helped form Earth itself.

Webb spots building blocks of planets

Cosmic dust consists of minute mineral and organic debris suspended in space. It contains ingredients that probably took part in the beginning of life. Scientists weren’t entirely certain how it develops until now.

The Webb Telescope directed its keen eyes toward the dense center of the Butterfly Nebula, an incredible wing-like cloud of gas and dust in the constellation Scorpius, far beyond Earth. Instead of seeing just one type of dust, scientists found two.

“We were able to see both cool gemstones formed in calm, long-lasting zones and fiery grime created in violent, fast-moving parts of space, all within a single object,” said lead researcher Dr. Mikako Matsuura of Cardiff University.

Most dust in space is messy and disorganized, like soot. But some forms perfect crystals – much more structured, like tiny gems. The nebula contains both, all in one place. This suggests that different kinds of cosmic environments can create very different types of dust, even right next to each other.

“This discovery is a big step forward in understanding how the basic materials of planets, come together,” said Dr. Matsuura.

A star hiding in plain sight

The Butterfly Nebula’s bright, complex glow comes from a white-hot central star – one of the hottest of its kind, blazing at around 220,000 Kelvin (over 395,000°F).

But the star itself has been hard to spot. It’s buried inside a thick, dusty ring of gas shaped like a doughnut, called a torus. That doughnut blocks visible light, making it impossible to see with regular telescopes.

Webb’s Mid-Infrared Instrument (MIRI) employs a camera and a spectrograph that are capable of seeing through the dust. Using this technology, the researchers discovered the obscured star by identifying a glowing cloud of dust surrounding it, radiating in infrared wavelengths.

This dusty torus is made of crystalline silicates like quartz, plus irregular grains about a millionth of a meter across – surprisingly large for cosmic dust. Their size and shape suggest they’ve been growing steadily for a long time.

Fiery jets carve a cosmic butterfly

Past the torus, things get more chaotic. The nebula’s shape is bipolar, meaning it has two giant lobes stretching in opposite directions like wings. A pair of high-speed jets shoot out from the center, traced by elements like iron and nickel.

The new observations also uncovered layered shells of different atoms. Elements that need more energy to form cluster closer to the hot star, while others settle farther out. This paints a picture of a very organized – yet wild – environment.

Another surprise came in the form of polycyclic aromatic hydrocarbons (PAHs). These carbon-based molecules are built like tiny rings and are found on Earth in things like car exhaust, smoke from campfires, and even burnt toast.

The PAHs showed up in a place no one expected – inside an oxygen-rich planetary nebula. Usually, these kinds of molecules form in carbon-rich environments. Their presence here hints at a unique type of chemical reaction happening as fast winds from the central star slam into surrounding gas.

The team suspects this may be the first evidence of PAHs forming under these conditions.

Nebula chemistry reshapes rocky worlds

Planetary nebulae – despite the name – are the final stages of medium-sized stars like our Sun. They form when those stars puff off their outer layers before cooling down into white dwarfs.

That’s where many of the raw materials for future stars and planets are made. These nebulae might last only around 20,000 years – a blink in cosmic time – but during that period, they shape the chemistry of the galaxy.

The Butterfly Nebula is one of the best-studied examples, previously imaged by the Hubble Space Telescope. But the James Webb Space Telescope goes deeper, letting scientists explore not just the shape of the nebula, but its internal chemistry.

Using Webb’s detailed imaging along with radio data from the Atacama Large Millimeter/submillimeter Array, researchers found nearly 200 spectral lines – signals from different atoms and molecules. These signals showed how different chemicals are arranged in layers – revealing complex, nested structures.

Butterfly Nebula reveals planet recipes

The Butterfly Nebula’s beauty is just the surface. Underneath its glow lies a complicated process that turns dying stars into factories for dust and molecules – the very kind that can help form planets.

“For years, scientists have debated how cosmic dust forms in space. But now, with the help of the powerful James Webb Space Telescope, we may finally have a clearer picture,” said Dr. Matsuura.

With each new discovery, the question of how rocky worlds like Earth form becomes a little less mysterious – and a lot more exciting.

The full study was published in the journal Monthly Notices of the Royal Astronomical Society.

Image Credit: ESA/Webb, NASA & CSA, M. Matsuura, ALMA (ESO/NAOJ/NRAO), N. Hirano, M. Zamani (ESA/Webb)

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Disruption of KMT2D is associated with autism and other neurodevelopmental delay (NDD) phenotypes

We assemble genotype and phenotype data for 9 affected individuals from 9 unrelated families with predicted deleterious variants in KMT2D through literature and two web-based databases (DECIPHER and ClinVar) (Table S1). This includes 5 individuals with de novo (n = 4) and transmitted (n = 1) truncating variants, 1 individual with missense variant, and three with unknown variants (Fig. 1A).

The probands were diagnosed with autism (100%, 9/9). Intelligence disability (100%, 8/8), dysmorphic facial features (100%, 7/7), cardiac anomaly (57.14%, 4/7), Speech delay (50%, 3/6), and hypotonia (50%, 3/6) were commonly co-occurred. In addition, clinodactyly of the fifth finger (42.86%, 3/7), motor delay (33.3%, 2/6), anxiety (33.3%, 2/6), joint laxity (33.3%, 2/6), hearing loss (28.57%, 2/7), feeding difficulties (28.57%, 2/7), hyperactivity (16.67%, 1/6), coordination difficulty (16.67%, 1/6), and sleep problems (16.67%, 1/6) are also observed in subsets of the patients (Fig. 1B and Table S2). In summary, a wide range of ASD or NDD phenotypes are present in probands with KMT2D mutation.

Knockout of zebrafish kmt2d leads to developmental delay and autism-like behaviors

To examine whether KMT2D plays an evolutionarily conserved role, we utilized zebrafish models. We targeted the gene using the CRISPR/Cas9 system and generated a -92 + 6 bp deletion allele for kmt2d, which introduces frame shifts and early truncations in the corresponding proteins (Fig. 2A). Additionally, we conducted sanger sequencing, agarose gel electrophoresis and RT-qPCR to confirm the knockout effect of kmt2d mutant (Fig. 2B, C; Figs. S1, S4). Specifically, we conducted heterozygous-by-heterozygous crosses for the −92 + 6 bp deletion alleles and screened for phenotypes, with particular emphasis on the organs and systems affected in patients with KS. The kmt2d^−/− embryos exhibiting morphological abnormalities, including tail bending, yolk malformation, pericardial edema (Fig. 2D), and reduced body length at different developmental stages (Fig. 2F). RT-qPCR analysis confirmed that kmt2d mRNA expression was significantly reduced at three points in embryos with KS phenotypes (Fig. 2E). Our results indicated that the zebrafish kmt2d knockout line has been successfully established and can be utilized for further experiments.

A–C Diagram of zebrafish kmt2d gene and mutation induced by CRISPR/Cas9, gray boxes indicate exons. A target site was on Exon 28 resulting in a 92-base deletion and 6-base insertion. B Sanger sequence. C results of agarose gel electrophoresis. D kmt2d^−/− embryos exhibiting morphological abnormalities at the age of 24 h, 36 h and 72 h. E The expression levels of the Kmt2d gene decreased at three developmental point for embryos exhibiting KS phenotypes (Fifteen embryos per biological replicate were collected for zebrafish RT-qPCR, n = 3). F Body length was reduced in the kmt2d knockout zebrafish (n = 9). G Schematic diagram of the social preference behaviours experiment and motion trajectory chart for zebrafish. H Sniffing time exploring social region (n = 6 for wt, n = 7 for kmt2d^-/+). I The distance traveled in the mating tank, which suggested that the kmt2d^-/+ zebrafish had normal motor skill (n = 6 for wt, n = 7 for kmt2d^−/+). Error bars represent as mean ± SD. *P  <  0.05, **P  <  0.01, ***P  <  0.001, ns: P > 0.05, Mann-Whitney U test.

To investigate whether kmt2d haploinsufficiency leads to autistic-like behaviors in zebrafish as it does in human, we monitored the social behavior of kmt2d^+/− male adult zebrafish (12 weeks of age), in which a single kmt2d allele is inactivated. Zebrafish are gregarious animals with a strong inclination toward social activity. Their social preference behavior served as indicators of their social tendencies. In our research, we examined how kmt2d^+/− zebrafish interacted socially. In the social preference test, the kmt2d^+/+ zebrafish consistently moved through the designated social zone throughout the trial, while the kmt2d^+/− zebrafish exhibited aimless swimming patterns. The kmt2d^+/− zebrafish exhibited notable differences in behavior compared to their kmt2d^+/+ counterparts. Specifically, they spent significantly less time in the social zone (Fig. 2G, H). Despite maintaining typical motor skills (Fig. 2I), these kmt2d^+/− zebrafish displayed a propensity for large circular movements, a repetitive behavior commonly observed in zebrafish and similar to behaviors seen in individuals with autism (Fig. 2G).

Kmt2d deficiency mice showed defects in social behaviors and had repetitive behavior

Using published single-cell RNA sequencing datasets¹⁶ (CNP0003837), we found that Kmt2d is widely expressed in different subregions of the hippocampus and in various types of neurons (Fig. S2A, B), and further confirmed the expression of KMT2D in the hippocampus via immunofluorescence experiments (Fig. S2C). To elucidate the relationship between the function of KMT2D in the hippocampus and autism-like behaviors, we selectively knocked down the Kmt2d gene in the hippocampal region of mice and examined its impact on their social behavior. We firstly screened for effective RNA interference (RNAi) fragments targeting Kmt2d in mouse HT22 cells (Figs. S3A–C; S5B, C). Then, adeno-associated virus (AAV) vectors carrying Kmt2d-shRNA (AAV-RNAi) or control-shRNA (AAV-nc) were injected into the hippocampus, respectively. After a four-week post-injection period, we analyzed sections of mouse brain tissue under a fluorescence microscope and observed positive GFP expression specifically in the hippocampal region (Fig. 3A). The results of RT-qPCR demonstrated that the expression level of the kmt2d gene was significantly reduced in the AAV-RNAi group compared to the AAV-nc control group (Fig. 3B). Given that KMT2D functions as a histone methyltransferase responsible for catalyzing the formation of H3K4me3, it is not surprising that the H3K4me3 levels were also decreased in the hippocampus of mice with kmt2d knockdown (Figs. 3C, D; S5A). These results indicate that we have successfully established a mouse model with hippocampal-specific knockdown of kmt2d.

A The adeno-associated virus (AAV) vectors carrying Kmt2d-shRNA (AAV-RNAi) or control-shRNA was delivered to the hippocampal. B The results of RT-qPCR showed a significantly reduced of kmt2d in the AAV-RNAi group compared to that of AAV-nc group (n = 3). C, D The level of the H3K4me3 protein. The band density was quantified and expressed as the relative gray value (compared with the control) by arbitrarily setting the control value as 1 (n = 3). E Schematic diagram of the three-box social experiment. F The distance traveled in different areas within the open field for the mice (n = 6). G Motion trajectory chart for the control (AAV-nc) and knockdown (AAV-RNAi) mice in an Open Field Assay. H Number of marbles buried (n = 6). I, J During a social interaction session, Kmt2d deficiency mice didn’t have social preferences. I sniffing time exploring S1 and E (n = 6). J motion trajectory chart for the control (AAV-nc) and knockdown (AAV-RNAi) mice. K, L The same as (I, J) but for social novelty test. K sniffing time exploring S1 and S2. (n = 6). L motion trajectory chart. Error bars represent as mean ± SD. *P  <  0.05, **P  <  0.01, ***P  <  0.001, ns: P > 0.05, Mann-Whitney U test. A Created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

We assessed social behaviors in adult mice using the three-chamber sociability and social novelty tests (Fig. 3E). Control mice (AAV-nc) typically preferred social stimuli and spent more time with novel mice. In contrast, Kmt2d deficiency mice (AAV-RNAi) showed no preference for social stimuli or novel mice (Fig. 3I–L). Motor skills were normal in Kmt2d deficiency mice (Fig. 3F, G). Additionally, Kmt2d deficiency mice exhibited increased repetitive behaviors, burying more marbles than controls in the Marble Burying Test (Fig. 3H). Thus, Kmt2d deficiency mice displayed abnormal social behaviors and increased repetitive behaviors.

Knockdown of Kmt2d decreased excitatory and increased inhibitory synaptic transmission

To elucidate the neural mechanisms underlying the observed phenotypes, we further examined how the Kmt2d gene in the rat hippocampus influences the excitatory-inhibitory (E/I) balance—a key pathophysiological mechanism implicated in autism¹⁷. Rat hippocampal slice cultures are widely used in neurophysiological studies due to their larger hippocampal structure compared to mice, which facilitates higher success rates for slice culture and easier acquisition of stable synaptic activity signals. This allows for more accurate assessment of the impact of Kmt2d knockdown on synaptic function. For these experiments we used slice cultures from 8-to 10-day-old rats. We had screened for effective RNA interference fragments targeting Kmt2d in rat B104 cells (Fig. S3D, E) first. Then, Kmt2d knockdown was performed by an AAV vector containing Kmt2d-shRNA-eGFP infusion.

Based on published single-cell data, we found that the expression level of kmt2d do not significantly differ among different subregions of the hippocampus (Fig. S2A). Therefore, we hypothesize that knockdown of Kmt2d may alter synaptic function in both the CA1 and DG regions. We performed paired recordings from a transfected cells and a neighboring control cell in CA1 and DG, with synaptic responses evoked by electrical stimulation of the Schaffer collateral pathway (Fig. 4A). Our results revealed the following: First, analysis of IPSCs in kmt2d knockdown neurons from the CA1 region revealed a significant increase in amplitude compared to control neurons (Fig. 4C). Second, knockdown of kmt2d decreased the amplitude of AMPAR -mediated EPSCs in CA1 neurons but did not significantly affect NMDAR-mediated EPSCs (Fig. 4E). Finally, we observed similar changes in IPSCs and EPSCs in the DG region, consistent with the findings in the CA1 region (Fig. 4D, F). These data indicate that knockdown of KMT2D leads to functional defects in synaptic transmission, resulting in an imbalance between excitation and inhibition.

A Schematic diagram of hippocamcal cultured slice and dual whole-cell patch clamp. B Paired recordings from Kmt2d-shRNA-eGFP infection (bright cell) and control cell. C, D The amplitude of IPSCs in infected cells is increased compared to control cells in CA1 and DG regions, respectively (n = 10 for CA1 region; n = 9 for DG region). E, G The amplitude of AMPA receptor-mediated EPSCs in infected cells is decreased compared to control cells in CA1 and DG regions, respectively (n = 10 for CA1 region; n = 11 for DG region). F, H The amplitude of NMDA receptor-mediated EPSCs in infected cells remained unchanged compared to control cells in CA1 and DG regions, respectively (n = 9 for CA1 region; n = 11 for DG region). Error bars represent as mean ± SD. *P  <  0.05, **P  <  0.01, Mann-Whitney U test. A Created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

KMT2D regulates downstream target genes related to synaptic response

To further explore the molecular mechanisms by which KMT2D regulates autistic-like behaviors, we used RNA-seq to compare the gene expression profiles from whole 3-dpf zebrafish exhibiting KS phenotypes (Fig. 5A). A volcano plot graphically illustrates the distribution of differentially expressed genes (DEGs), revealing that 892 genes were downregulated and 617 genes were upregulated transcriptionally in the mutant zebrafish model (Fig. 5B; Supplementary Data 2). Analyses of Gene Ontology (GO) analysis showed that the DEGs were significantly enriched in glutamatergic and GABAergic pathways (Fig. 5C; Supplementary Data 2). To delve deeper into the regulatory mechanisms of KMT2D on synaptic function, we observed that multiple genes (shank2, cnksr1, csmd2 and srgap3) in the glutamatergic signaling pathway were downregulated, whereas genes (camk4, gabarabp, gabarapl2 and npas4a) in the GABAergic signaling pathway were upregulated (Fig. 5D). These findings were further corroborated by subsequent qPCR validation (Fig. 5E, F).

A RNA-seq analysis of zebrafish and mice samples. B Volcano plot showing differentially expressed genes (DEGs) in the km2d^+/+ and kmt2d^−/− zebrafish. C GO analysis of DEGs in the km2d^+/+ and kmt2d^−/− zebrafish. D–F Differentially expressed genes associated with glutamatergic and GABAergic synapse in the km2d^+/+ and kmt2d^−/− zebrafish. D Heatmap of 4 upregulated genes associated with GABAergic synapse, and 6 downregulated genes associated glutamatergic synapse. C RT-qPCR of shank2b (n = 3); D RT-qPCR of gabarapb (n = 3). G Volcano plot showing DEGs in the Km2d-KD and control mice hippocampus. H GO analysis of DEGs in the Km2d-KD and control mice hippocampus. I–K Differentially expressed genes associated with glutamatergic and GABAergic synapse in the Km2d-KD and control mice. I Heatmap of 6 upregulated genes associated with GABAergic synapse, and 6 downregulated genes associated glutamatergic synapse. C RT-qPCR of Cnksr1 (n = 3); D RT-qPCR of Fgf7 (n = 3). Error bars represent as mean ± SD. *P  <  0.05, **P  <  0.01, Mann-Whitney U test. Mice of Fig. 5, created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

When we compared the gene expression profiles of kmt2d^+/+ and kmt2d^−/− zebrafish, we made consistent observations of those made in hippocampus of Kmt2d-KD mice. A total of 996 DEGs were identified, including 469 downregulated genes and 527 upregulated genes (Fig. 5G; Supplementary Data 4). DEGs are significantly enriched in pathways related to glutamatergic and GABAergic function (Fig. 5H; Supplementary Data 5). In Kmt2d-KD mice, multiple genes associated with the glutamatergic signaling pathway, such as shank2, cnksr1, csmd2 and srgap3 are significantly downregulated, while several genes related to the GABAergic signaling pathway, including fgf7, gata3, syt1 and plcl1 are significantly upregulated (Fig. 5I–K). Interestingly, several genes in the glutamatergic signaling pathway, such as shank2, cnksr1, csmd2, srgap3, rap1gab and sipal1l, showed consistent changes in both Kmt2d-KD mice and kmt2d-KO zebrafish models (Fig. 5D, I). This finding suggests that the change of glutamatergic synapse is conserved across these two distinct species models. Totally, RNA-seq analysis revealed that under conditions of low kmt2d expression, differentially expressed genes were associated with glutamatergic and GABAergic synapses, supporting the dysregulation of E-I balance in the hippocampus.

The KMT2D network links the glutamatergic and GABAergic synaptic responses in ASD

A better understanding of the connections between KMT2D downstream genes and ASD-associated genes will help to more effectively link KMT2D to autism-like behaviors. By surveying 996 genes that were differentially expressed in the hypothalamus of Kmt2d-KD and control mice, we found that 61 genes were associated with ASD, 223 were related to glutamatergic synaptic responses, and 47 were related to GABAergic synaptic responses (Fig. 6A, B; Supplementary Data 6). As shown in Fig. 6C, the disrupted glutamatergic synaptic responses was one of the major causes of Kmt2d-deficiency-associated ASD (Fig. 6C; Supplementary Data 6).

A Venn-diagram showing the overlap genes between four different gene sets: DEGs: the differentially expressed genes detected in Kmt2d-KD mice RNA-seq. Glutamatergic genes: the DEGs associated with glutamatergic synaptic response. GABAergic genes: the DEGs associated with GABAergic synaptic response. ASD genes: the genes related with ASD based on SFARI. B The ratio of DEGs associated with ASD, glutamatergic and GABAergic synaptic signaling pathway. C Conduct visualization of DEGs related to the glutamatergic and GABAergic signaling pathways using the cluGO software. D The network representing protein interaction relationship between DEGs in ASD, glutamatergic and GABAergic signaling pathways based on Kmt2d-KD mice RNA-seq.

To further illustrate the connection among KMT2D-regulated genes, we studied a network of 118 DEGs that were involved in ASD, glutamatergic and GABAergic synaptic response, using the STRING database (Fig. 6D; Supplementary Data 7). The resulting network suggested that KMT2D regulated GABAergic synaptic response via ZFPM1, whose abnormal expressions and/or mutations have been associated with ASD and other neurological disorders^18,19. We found that 16 genes, including Shank2, Syt1, Ar, Tek, P2rx7, Styk1, and Rheb were ASD genes that were involved in the glutamatergic synaptic response. The network also illustrated 4 ASD genes that were associated with the GABAergic synaptic response, including Mink1, Cacna1i, Adora2a and Hivep3. Specifically, Mink1, Cacna1i, Adora2a was found to be a common gene shared by the glutamatergic synaptic response. Overall, our network further illustrates that Kmt2d deficiency increases the risk of ASD by disrupting the glutamatergic and GABAergic synaptic responses.

Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer (GC) with unique epidemiological and pathogenic characteristics. Despite its clinical significance, large-scale proteomic studies on GSRCC remain scarce, limiting our molecular understanding of the disease. Advanced mass spectrometry (MS)-based proteomics is crucial for identifying key biomarkers and drug targets, thereby enabling more effective therapeutic strategies.

In a recent study published in Genes & Diseases, researchers from several institutions, including Tianjin University, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Fudan University, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Chinese Academy of Medical Sciences and Peking Union Medical College, and University of Houston, characterizes the proteomic features and molecular mechanisms of GSRCC to date.

Initially, the research team analyzed clinical data from over 10,000 patients with GC between January 2010 and December 2019. An in-depth proteomic analysis was conducted on tumor tissues from 112 GSRCC patients, each with over 70% signet ring cell content. Using advanced MS, the team identified 7322 proteins, establishing the largest tissue-specific peptide spectral library for GSRCC. Additionally, through unsupervised clustering, the team identified four novel proteomic subtypes of GSRCC: Metabolism (S-Mb), Microenvironment Dysregulation (S-Me), Migration (S-M) and Proliferation (S-PF).

Two key prognostic biomarkers were identified and validated in an independent cohort of 75 patients: PRDX2, a protein associated with favorable prognosis; and DDX27, linked to poor survival outcomes. Furthermore, proteomic profiling of 79 biomarker-negative GSRCC cases revealed marked tumor heterogeneity. Notably, unsupervised clustering identified three distinct proteomic clusters, with cluster 2 linked to the poorest prognosis.

Focusing on HER2-negative, EBV-negative, and pMMR GSRCC cases (LMT [Lack of Medical Treatment]-GSRCC), the study identified four potential drug targets: eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), eukaryotic translation initiation factor 6 (EIF6), and nuclear factor kappa B subunit 2 (NFKB2). Remarkably, high expression of these proteins was associated with poor prognosis, underscoring their relevance as promising therapeutic candidates.

Interestingly, molecular docking and cytotoxicity testing singled out neratinib-a drug approved for breast cancer treatment-as the most promising candidate. Furthermore, in vitro and in vivo studies demonstrated neratinib’s potent ability to inhibit tumor growth, cell migration, and invasion, while promoting cancer cell apoptosis, all with minimal side effects.

In conclusion, this is the first study to focus specifically on the LMT-GSRCC population, uncovering potential biomarkers and drug targets through proteomic analysis. The findings from this study not only provide a foundation for developing novel targeted therapies but also personalized treatment strategies for GSRCC.