eLife: latest articles

Newly trained navigation and verbal memory skills in humans elicit changes in task-related networks but not brain structure

adekstrom@arizona.edu (Andrew McAvan) — Tue, 28 Oct 2025 00:00:00 +0000

Training cognitive skills, such as remembering a list of words or navigating a new city, has important implications for everyday life. Yet, understanding what brain changes in humans underlies the acquisition of complex cognitive skills remains unresolved. Here, we developed and validated intensive multiweek interventions in which participants were randomly assigned training in either navigation or verbal memory. Healthy young participants (N=75) underwent structural and functional imaging prior to and following the training. Based on pre-registered and exploratory analyses, we did not find any evidence for changes to gross hippocampal or hippocampal subfield volume, cortical brain volume, or microstructural properties of major white matter tracts due to the training. In contrast, network-based analyses suggested changes in task-related informational connectivity, which occurred primarily between cortical areas and mostly involved putative cognitive control networks. These results suggest that cognitive interventions target more transient configurations in network connectivity rather than more durable structural changes.

Cell membrane glycan contents are biochemical factors that constitute a kinetic barrier to viral particle uptake in a protein-nonspecific manner

KAIZUKA.Yoshihisa@nims.go.jp (Rika Machida) — Tue, 28 Oct 2025 00:00:00 +0000

Various types of glycoproteins have been suggested to inhibit viral infection of cells via steric repulsion. However, it is difficult to evaluate such physical actions genetically, simply because they are nonspecific and can be caused by any molecule. Therefore, we investigated a method to compare this nonspecific action among cells with diverse membrane protein profiles. We found that a wide range of glycoproteins individually had a strong inhibitory effect on infection, while on the other hand, the total amount of glycans was negatively correlated with the infection level in each cell. Thus, the infection-inhibitory effect of glycoproteins was molecularly nonspecific but was additively enhanced according to the amount of glycans on the cell surface. In this correlation, glycans function as a fundamental factor. Further investigating the mechanism by which glycans function as a factor in infection control, we conclude that the repulsion between proteins created by branched glycans forms a kinetic energy barrier against packing the virus into the region of protein interstitial space. As a result, the formation of the adhesive interface between the virus and the cell membrane, which is necessary for infection, is inhibited. This study attempted to link the cell’s nonspecific physical properties with intracellular biochemicals. A similar approach may be applied to quantify other nonspecific biological phenomena.

Deep3DSIM: Super-resolution imaging of thick tissue using 3D structured illumination with adaptive optics

ian.dobbie@jhu.edu (Ana Rita Faria) — Tue, 28 Oct 2025 00:00:00 +0000

Three-dimensional structured illumination microscopy (3D-SIM) doubles the resolution of fluorescence imaging in all directions and enables optical sectioning with increased image contrast. However, 3D-SIM has not been widely applied to imaging deep in thick tissues due to its sensitivity to sample-induced aberrations, making the method difficult to apply beyond 10 µm in depth. Furthermore, 3D-SIM has not been available in an upright configuration, limiting its use for live imaging while manipulating the specimen, for example, with electrophysiology. Here, we have overcome these barriers by developing a novel upright 3D-SIM system (termed Deep3DSIM) that incorporates adaptive optics for aberration correction and remote focusing, reducing artefacts, improving contrast, restoring resolution, and eliminating the need to move the specimen or the objective lens in volume imaging. These advantages are equally applicable to inverted 3D-SIM systems. We demonstrate high-quality 3D-SIM imaging in various samples, including imaging more than 130 µm into the Drosophila brain.

Gene regulatory dynamics during craniofacial development in a carnivorous marsupial

lecook@lbl.gov (Andrew J Pask) — Tue, 28 Oct 2025 00:00:00 +0000

Marsupials and placental mammals exhibit significant differences in reproductive and life history strategies. Marsupials are born highly underdeveloped after an extremely short period of gestation, leading to prioritized development of structures critical for post-birth survival in the pouch. Critically, they must undergo accelerated development of the orofacial region compared to placentals. Previously, we described the accelerated development of the orofacial region in the carnivorous Australian marsupial, the fat-tailed dunnart Sminthopsis crassicaudata, that has one of the shortest gestations of any mammal. By combining genome comparisons of the mouse and dunnart with functional data for the enhancer-associated chromatin modifications, H3K4me3 and H3K27ac, we investigated divergence of craniofacial regulatory landscapes between these species. This is the first description of genome-wide face regulatory elements in a marsupial, with 60,626 putative enhancers and 12,295 putative promoters described. We also generated craniofacial RNA-seq data for the dunnart to investigate expression dynamics of genes near predicted active regulatory elements. While genes involved in regulating facial development were largely conserved in mouse and dunnart, the regulatory landscape varied significantly. Additionally, a subset of dunnart-specific enhancers was associated with genes highly expressed only in dunnart relating to cranial neural crest proliferation, embryonic myogenesis, and epidermis development. Comparative RNA-seq analyses of facial tissue revealed dunnart-specific expression of genes involved in the development of the mechanosensory system. Accelerated development of the dunnart sensory system likely relates to the sensory cues received by the nasal–oral region during the postnatal journey to the pouch. Together, these data suggest that accelerated face development in the dunnart may be driven by dunnart-specific enhancer activity. Our study highlights the power of marsupial–placental comparative genomics for understanding the role of enhancers in driving temporal shifts in development.

Nocebo effects are stronger and more persistent than placebo effects in healthy individuals

Katharina.Schmidt@uk-essen.de (Angelika Kunkel) — Tue, 28 Oct 2025 00:00:00 +0000

Placebo and nocebo effects illustrate the profound influence of cognitive-affective processes on symptom perception and treatment outcomes, with the potential to significantly alter responses to medical interventions. Despite their clinical relevance, the question of how placebo and nocebo effects differ in strength and duration remains largely unexplored. Using a within-subject design in 104 healthy individuals, we investigated and directly compared the magnitude and persistence of placebo and nocebo effects on experimental pain. Effects were assessed immediately after their induction through verbal instructions and conditioning and at a 1-week follow-up. The study was preregistered in the German Clinical Trials Register (registration number: DRKS00029228). Significant placebo and nocebo effects were detected on days 1 and 8, but nocebo effects were stronger on both test days. Sustained effects after 1 week were primarily predicted by individuals’ experienced effects on day 1. Our findings underscore the enduring nature of placebo and nocebo effects in pain, with nocebo responses demonstrating consistently greater strength, which is consistent with an evolutionarily advantageous ‘better-safe-than-sorry’ strategy. These insights emphasise the significant impact of nocebo effects and stress the need to prioritise efforts to mitigate them in clinical practice.

Changes in neural progenitor lineage composition during astrocytic differentiation of human iPSCs

webberc4@cardiff.ac.uk (Caleb Webber) — Tue, 28 Oct 2025 00:00:00 +0000

The regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their application in disease modelling and cell-based therapies. Due to the lack of subtype-defining markers for astrocytes in different regions of the brain, the regional identity of in vitro-derived astrocytes is often declared by the dominant positional characteristics of their antecedent neural progenitors, patterned to a fate of interest, with the assumption that the positional trait is preserved by the derived astrocytes via linear descent. Using a human induced pluripotent stem cell line designed for tracing derivatives of LMX1A⁺ cells combined with a ventral midbrain induction paradigm, we show that astrocytes originating from LMX1A⁺ progenitors can only be generated if these progenitors are purified prior to the astrocyte differentiation process, or their progenies are gradually lost to progenies of LMX1A^- progenitors. This finding indicates that the lineage composition of iPSC-derived astrocytes may not accurately recapitulate the founder progenitor population. Using deep single-cell RNA sequencing, we identified distinct transcriptomic signatures in astrocytes derived from the LMX1A⁺ progenitor cells. Our study highlights the need for rigorous characterization of pluripotent stem cell-derived regional astrocytes and provides a resource for assessing LMX1A⁺ ventral midbrain progenitor-derived human astrocytes.

Neuronal migration depends on blood flow in the adult mammalian brain

sawamoto@med.nagoya-cu.ac.jp (Akari Saito) — Tue, 28 Oct 2025 00:00:00 +0000

In animal tissues, several cell types migrate along blood vessels, raising the possibility that blood flow influences cell migration. Here, we show that blood flow promotes the migration of new olfactory-bulb neurons in the adult mammalian brain. Neuronal migration is facilitated by blood flow, leading to accumulation of new neurons near blood vessels with abundant blood flow. Blood flow inhibition attenuates blood vessel-guided neuronal migration, suggesting that blood contains factors beneficial to neuronal migration. We found that ghrelin, which is increased in blood by hunger, directly influences neuronal migration. Ghrelin signaling promotes somal translocation by activating actin cytoskeleton contraction at the rear of the cell soma. New neurons mature in the olfactory bulb and contribute to the olfactory function for sensing odorants from food. Finally, we show that neuronal migration is increased by calorie restriction, and that ghrelin signaling is involved in the process. This study suggests that blood flow promotes neuronal migration through blood-derived ghrelin signaling in the adult brain, which could be one of the mechanisms that improves the olfactory function for food-seeking behavior during starvation.

Critique of impure reason: Unveiling the reasoning behaviour of medical large language models

shamus@qmed.asia (Shamus Zi Yang Sim) — Tue, 28 Oct 2025 00:00:00 +0000

Despite the current ubiquity of large language models (LLMs) across the medical domain, there is a surprising lack of studies which address their reasoning behaviour. We emphasise the importance of understanding reasoning behaviour as opposed to high-level prediction accuracies, since it is equivalent to explainable AI (XAI) in this context. In particular, achieving XAI in medical LLMs used in the clinical domain will have a significant impact across the healthcare sector. Therefore, in this work, we adapt the existing concept of reasoning behaviour and articulate its interpretation within the specific context of medical LLMs. We survey and categorise current state-of-the-art approaches for modelling and evaluating reasoning in medical LLMs. Additionally, we propose theoretical frameworks which can empower medical professionals or machine learning engineers to gain insight into the low-level reasoning operations of these previously obscure models. We also outline key open challenges facing the development of large reasoning models. The subsequent increased transparency and trust in medical machine learning models by clinicians as well as patients will accelerate the integration, application as well as further development of medical AI for the healthcare system as a whole.

The holocephalan ratfish endoskeleton shares trabecular and areolar mineralization patterns, but not tesserae, with elasmobranchs little skate and catshark

b.frank@usask.ca (B Frank Eames) — Mon, 27 Oct 2025 00:00:00 +0000

Specific character traits of mineralized endoskeletal tissues need to be clearly defined and comprehensively examined among extant chondrichthyans (elasmobranchs, such as sharks and skates, and holocephalans, such as chimaeras) to understand their evolution. For example, tiles of mineralized polygonal structures called tesserae occur at cartilage surfaces in chondrichthyans, but recent studies showing trabecular mineralization at elasmobranch cartilage surfaces suggest that tesserae are not as common as previously thought. Also, while areolar mineralized tissue in elasmobranchs is generally considered a unique, shared chondrichthyan feature, some chondrichthyan species demonstrate bone-like tissues in both a specific region of tesserae termed the cap zone and continuous (not tiled) mineralized neural arches. To clarify the distribution of specific endoskeletal features among extant chondrichthyans, adult skeletal tissues in a holocephalan chimaera (spotted ratfish) and two elasmobranchs (small-spotted catshark and little skate) were characterized using synchrotron radiation and desktop micro-CT imaging, and histological and immunofluorescent assays. Endoskeletal mineralization in the ratfish, catshark, and little skate varied both quantitively in tissue mineral density (TMD) and qualitatively in the morphology and localization of mineralized structures and tissues. For example, TMD of several skeletal elements was significantly lower in ratfish, compared to catshark and little skate. Trabecular and areolar mineralization were shared among these extant chondrichthyan species, but tesserae and bone-like tissues were not. Interestingly, three separate analyses argued that the adult chimaera endoskeleton has features of the embryonic little skate endoskeleton. Generally, this study proposes specific terminology for character states of the extant chondrichthyan endoskeleton and infers those states in ancestral chondrichthyans with reference to fossil data.

Brown adipose tissue and skeletal muscle coordinately contribute to thermogenesis in mice

hsakaue@tokushima-u.ac.jp (Hiroshi Sakaue) — Mon, 27 Oct 2025 00:00:00 +0000

Endotherms increase the rate of metabolism in metabolic organs as one strategy to cope with a decline in the temperature of the external environment. However, an additional major contributor to maintenance of body temperature in a cold environment is contraction-based thermogenesis in skeletal muscle. Here, we show that impairment of hind limb muscle contraction by cast immobilization induced a loss of function of skeletal muscle and activated brown adipose tissue (BAT) thermogenesis as a compensatory mechanism. BAT utilizes free branched-chain amino acids (BCAAs) derived from skeletal muscle as an energy substrate for thermogenesis, and interleukin-6 released by skeletal muscle stimulates BCAAs production in muscle for support of BAT thermogenesis. Additionally, this thermoregulatory system between BAT and skeletal muscle may also play an important role in response to cold temperatures or acute stress. Our findings suggest that BAT and skeletal muscle cooperate to maintain body temperature in endotherms.

Tonotopy is not preserved in a descending stage of auditory cortex

yzhou@tmmu.edu.cn (Chunqing Zhang) — Mon, 27 Oct 2025 00:00:00 +0000

Previous studies based on layer specificity suggest that ascending signals from the thalamus to the sensory neocortex preserve spatially organized information, but it remains unknown whether sensory information descending from sensory neocortex to the thalamus also maintains such spatial organization pattern. By focusing on projection specificity, we mapped the tone response properties of two groups of cortical neurons in the primary auditory cortex (A1), based on the relationship between their specific connections to other regions and their function in ascending (thalamocortical recipient [TR] neurons) or descending (corticothalamic [CT] neurons) auditory information. A clear tonotopic gradient was observed among TR neurons, but not CT neurons. Additionally, CT neurons exhibited markedly higher heterogeneity in their frequency tuning and had broader bandwidth than TR neurons. These results reveal that the information flow descending from A1 to the thalamus via CT neurons is not arranged tonotopically, suggesting that the descending information flow possibly contributes to higher-order feedback processing of diverse auditory inputs.

Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity

sarahjiesun@gmail.com (Luis B Barreiro) — Fri, 24 Oct 2025 00:00:00 +0000

The epigenetic adaptation of innate immune cells to inflammatory stimuli, or trained immunity, represents an evolutionarily conserved feature of host defense. Recent advances have revealed that such adaptations can occur at the level of hematopoietic stem and progenitor cells, resulting in long-lasting epigenetic reprogramming of the immune system. However, a comprehensive mechanistic understanding of these processes remains incomplete, limiting our capacity to predict or therapeutically manipulate the adaptive capacity of hematopoiesis. In this review, we survey the current literature to support a model of hematopoietic memory whose stimulus-specific nuances are shaped by specific cytokine environments and driven by the combinatorial activity of key transcription factors. Comparative analyses underscore the evolutionary conservation and essential biological roles of these factors, suggesting that trained immunity may reflect the strategic repurposing of ancient transcriptional programs for the purpose of enhancing host defense.

Single-cell transcriptome sequencing for opening the blood-brain barrier through specific mode electroacupuncture stimulation

linxianming1966@163.com (Congcong Ma) — Fri, 24 Oct 2025 00:00:00 +0000

The blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats. Here, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the Sprague-Dawley rat cerebral cortex. We identified 23 cell subsets and eight types of cells in the brain by cell annotation. scRNA-seq revealed transcriptional changes in the cerebral cortex under EA. Our findings offer valuable insights into the molecular and cellular modifications in the brain resulting from EA intervention and serve as a resource for drug delivery across healthy and diseased states. Innovative approaches to enhance BBB opening will lead to more effective therapeutic plans and enhanced drug delivery.

Spatiotemporal brain complexity quantifies consciousness outside of perturbation paradigms

martin.breyton@univ-amu.fr (Giovanni Rabuffo) — Thu, 23 Oct 2025 00:00:00 +0000

Signatures of consciousness are found in spectral and temporal properties of neuronal activity. Among these, spatiotemporal complexity after a perturbation has recently emerged as a robust metric to infer levels of consciousness. Perturbation paradigms remain, however, difficult to perform routinely. To discover alternative paradigms and metrics, we systematically explore brain stimulation and resting-state activity in a whole-brain model. We find that perturbational complexity only occurs when the brain model operates within a specific dynamical regime, in which spontaneous activity produces a large degree of functional network reorganizations referred to as being fluid. The regime of high brain fluidity is characterized by a small battery of metrics drawn from dynamical systems theory and predicts the impact of consciousness-altering drugs (Xenon, Propofol, and Ketamine). We validate the predictions in a cohort of 15 subjects at various stages of consciousness and demonstrate their agreement with previously reported perturbational complexity, but in a more accessible paradigm. Beyond the facilitation in clinical use, the metrics highlight complexity properties of brain dynamics in support of the emergence of consciousness.

Toward stable replication of genomic information in pools of RNA molecules

gerland@tum.de (Ludwig Burger) — Thu, 23 Oct 2025 00:00:00 +0000

The transition from prebiotic chemistry to living systems requires the emergence of a scheme for enzyme-free genetic replication. Here, we analyze a recently proposed prebiotic replication scenario, the so-called Virtual Circular Genome (VCG) [Zhou et al., RNA 27, 1-11 (2021)]: Replication takes place in a pool of oligomers, where each oligomer contains a subsequence of a circular genome, such that the oligomers encode the full genome collectively. While the sequence of the circular genome may be reconstructed based on long oligomers, monomers and short oligomers merely act as replication feedstock. We observe a competition between the predominantly error-free ligation of a feedstock molecule to a long oligomer and the predominantly erroneous ligation of two long oligomers. Increasing the length of long oligomers and reducing their concentration decreases the fraction of erroneous ligations, enabling high-fidelity replication in the VCG. Alternatively, the formation of erroneous products can be suppressed if each ligation involves at least one monomer, while ligations between two long oligomers are effectively prevented. This kinetic discrimination (favoring monomer incorporation over oligomer–oligomer ligation) may be an intrinsic property of the activation chemistry, or can be externally imposed by selectively activating only monomers in the pool. Surprisingly, under these conditions, shorter oligomers are extended by monomers more quickly than long oligomers, a phenomenon that has already been observed experimentally [Ding et al., JACS 145, 7504-7515 (2023)]. Our work provides a theoretical explanation for this behavior and predicts its dependence on system parameters such as the concentration of long oligomers. Taken together, the VCG constitutes a promising scenario of prebiotic information replication: It could mitigate challenges in non-enzymatic copying via template-directed polymerization, such as short lengths of copied products and high error rates.

Molecular dynamics of the matrisome across sea anemone life history

suat.oezbek@cos.uni-heidelberg.de (Aissam Ikmi) — Thu, 23 Oct 2025 00:00:00 +0000

The evolutionary expansion of extracellular matrix (ECM) molecules has been crucial for the establishment of cell adhesion and the transition from unicellular to multicellular life. Members of the early diverging metazoan phylum Cnidaria offer an exceptionally rich perspective into the metazoan core adhesome and its original function in developmental and morphogenetic processes. Here, we present the ensemble of ECM proteins and associated factors for the starlet sea anemone Nematostella vectensis based on in silico prediction and quantitative proteomic analysis of decellularized mesoglea from different life stages. The integration of the matrisome with single-cell transcriptome atlases shows that gastrodermal cells are the primary producers of Nematostella’s complex ECM, confirming the homology of the cnidarian inner cell layer with bilaterian mesoderm. The transition from larva to polyp is marked by an upregulation of metalloproteases and basement membrane components including all members of an unusually diversified SVEP1/Polydom family, suggesting massive epithelial remodeling. The enrichment of Wnt/PCP pathway factors during this process further indicates directed cell rearrangements as a key contributor to the polyp’s morphogenesis. Mesoglea maturation in adult polyps involves wound response proteins indicating shared molecular patterns in growth and regeneration. Our study identifies conserved matrisomal networks that coordinate transitions in Nematostella’s life history.

IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders

John.Schoggins@UTSouthwestern.edu (Anthony M De Maria) — Wed, 22 Oct 2025 00:00:00 +0000

Mammalian mRNAs possess an N7-methylguanosine (m7G) cap and 2'O methylation of the initiating nucleotide at their 5' end, whereas certain viral RNAs lack these characteristic features. The human antiviral restriction factor IFIT1 recognizes and binds to specific viral RNAs that lack the 5' features of host mRNAs, resulting in targeted suppression of viral RNA translation. This interaction imposes significant host-driven evolutionary pressures on viruses, and many viruses have evolved mechanisms to evade the antiviral action of human IFIT1. However, little is known about the virus-driven pressures that may have shaped the antiviral activity of IFIT1 genes across mammals. Here, we take an evolution-guided approach to show that the IFIT1 gene is rapidly evolving in multiple mammalian clades, with positive selection acting upon several residues in distinct regions of the protein. In functional assays with 39 IFIT1s spanning diverse mammals, we demonstrate that IFIT1 exhibits a range of antiviral phenotypes, with many orthologs lacking antiviral activity against viruses that are strongly suppressed by other IFIT1s. We further show that IFIT1s from human and a bat, the black flying fox, inhibit Venezuelan equine encephalitis virus (VEEV) and strongly bind to Cap0 RNAs. Unexpectedly, chimpanzee IFIT1, which differs from human IFIT1 by only eight amino acids, does not inhibit VEEV infection and exhibits minimal Cap0 RNA-binding. In mutagenesis studies, we determine that amino acids 364 and 366, the latter of which is rapidly evolving, are sufficient to confer the differential anti-VEEV activity between human and chimpanzee IFIT1. These data suggest that virus-host genetic conflicts have influenced the antiviral specificity of IFIT1 across diverse mammalian orders.

Chromatin activity of IκBα mediates the exit from naïve pluripotency

lespinosa@researchmar.net (Alberto Villanueva) — Wed, 22 Oct 2025 00:00:00 +0000

Maintenance of pluripotency is a multifactorial process in which NF-κB is a negative regulator. Our previous work identified a chromatin role for IκBα, the master regulator of NF-κB signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that IκBα accumulates specifically in the chromatin fraction of mouse pluripotent stem cells. IκBα depletion does not affect NF-kB-dependent transcription, but causes a profound epigenetic rewiring in pluripotent stem cells, including alterations in H3K27me3, a histone mark catalyzed by Polycomb repression complex 2. Chromatin changes induced by IκBα depletion affect a subset of pluripotency genes and are associated with altered gene transcription. At the cellular level, IκBα-deficient embryonic stem cells are arrested in a naive pluripotency state when cultured in serum/LIF conditions and fail to exit pluripotency under differentiation conditions. By constructing separation-of-function mutants, we show that the effects of IκBα in regulating stem cell pluripotency are NF-κB-independent, but mainly rely on its chromatin-related function. Taken together, our results reveal a novel mechanism by which IκBα participates in the regulation of the pluripotent state of mouse embryonic stem cells and shed light on the interplay between inflammatory signals and the regulation of pluripotency.

Longitudinal assessment of DREADD expression and efficacy in the monkey brain

nagai.yuji@qst.go.jp (Haruhiko Iwaoki) — Wed, 22 Oct 2025 00:00:00 +0000

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [¹¹C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [¹¹C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after 2 years. Significant chemogenetic control of neural activity and behavior persisted for about 2 years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.

Blood pressure variability compromises vascular function in middle-aged mice

JFILOSA@augusta.edu (Jessica A Filosa) — Wed, 22 Oct 2025 00:00:00 +0000

Blood pressure variability (BPV) has emerged as a significant risk factor for cognitive decline and dementia, independent of alterations in average blood pressure (BP). However, the impact of large BP fluctuations on neurovascular function remains poorly understood. In this study, we developed a novel murine model of BPV in middle-aged mice using intermittent angiotensin II infusions. Radio telemetry confirmed that 24 hr BP averages in BPV mice remained comparable to controls, demonstrating BPV in the absence of hypertension. Chronic (20–25 days) BPV resulted in a blunted bradycardic response and cognitive deficits. Two-photon imaging revealed heightened pressure-evoked constrictions (myogenic response) in parenchymal arterioles of BPV mice. While sensory stimulus-evoked dilations (neurovascular coupling) were amplified at higher BP levels in control mice, this pressure-dependent effect was abolished in BPV mice. Our findings indicate that chronic BP fluctuations impair vascular function within the neurovascular complex and contribute to cognitive decline, emphasizing BPV as a critical factor in brain health.

Sequential temporal anticipation characterized by neural power modulation and in recurrent neural networks

XiangbinTeng@cuhk.edu.hk (Ru-Yuan Zhang) — Wed, 22 Oct 2025 00:00:00 +0000

Relevant prospective moments arise intermittently, while most of the time is filled with irrelevant events, or noise, that constantly bombard our sensory systems. Thus, anticipating a few key moments necessitates disregarding what lies between the present and the future – the noise. Here, through examining how the brain and recurrent neural networks (RNNs) anticipate a sequence of prospective moments without relying on any external timing cues, we provided a reinterpretation of temporal anticipation. We first designed a ‘premembering’ task, where we marked three temporal locations in white noise and asked human listeners to detect a tone at one of these points. Using power modulation analyses, we investigated the memory-guided anticipatory processes in trials involving only flat noise. Our research revealed a unique neural-power modulation pattern for sequential temporal anticipation: neural power within the alpha-beta band range fluctuates over time, accurately identifying the marked locations on a sub-second scale and correlating with tone detection performance. To understand the functional roles of these neural modulations, we utilized RNNs optimized for the behavioral task. The hidden dynamics of the RNNs mirrored the neural modulations, and additional analyses and perturbations on the RNNs indicated that the neural power modulations in the alpha-beta band resulted from selective suppression of irrelevant noise periods and heightened sensitivity to anticipated temporal locations. Our behavioral, neural, and modeling findings collectively indicate that sequential temporal anticipation involves a process of dynamic gain control: anticipating a few significant moments involves actively disregarding irrelevant events that frequently occur.

Stabilisation of HIF signalling in the mouse epicardium extends embryonic potential and neonatal heart regeneration

joaquim.nunes_vieira@kcl.ac.uk (Adam B Lokman) — Wed, 22 Oct 2025 00:00:00 +0000

In humans, new-born infants can regenerate their heart during early life. This is modelled in the mouse, where regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential; however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explored a role for hypoxia and HIF signalling on the regulation of epicardial activity in the developing mouse heart and in modulating the response to injury. Hypoxic regions were found in the epicardium from mid-gestation, associating with HIF-1α and HIF-2α, and expression of the epicardial master regulator Wilms’ tumour 1 (WT1). Epicardial deletion of Hif1α reduced WT1 levels, leading to impaired coronary vasculature. Targeting of the HIF degradation enzyme PHD, through pharmacological inhibition with a clinically approved drug or epicardial-specific genetic deletion of Egln1, stabilised HIF and promoted WT1 activity ex vivo. Finally, a combination of genetic and pharmacological stabilisation of HIF during neonatal heart injury led to prolonged epicardial activation, preservation of myocardium, augmented infarct resolution and preserved function beyond the 7-day regenerative window. These findings suggest modulation of HIF signalling extends epicardial activation to maintain myocardial survival beyond the neonatal regenerative window and may represent a viable strategy for treating ischaemic heart disease.

3D directional tuning in the orofacial sensorimotor cortex during natural feeding and drinking

vhosack@uw.edu (Fritzie Arce-McShane) — Tue, 21 Oct 2025 00:00:00 +0000

Directional tongue movements are crucial for feeding and speech, ensuring proper food positioning for chewing and swallowing, as well as accurate sound production. While directional tuning in the arm region of the sensorimotor cortex during reaching tasks is well studied, little is known about how three-dimensional (3D) tongue direction is encoded in the orofacial sensorimotor cortex (OSMCx) during natural behaviors. Understanding this neural representation has important implications for rehabilitating individuals with orolingual dysfunctions. This study examines the directional tuning and population dynamics in OSMCx during naturalistic feeding and drinking, and how these are affected by sensory loss. Using biplanar video-radiography, we tracked implanted tongue markers in behaving rhesus macaques (Macaca mulatta) and simultaneously recorded 3D positional data with spiking activity from chronically implanted microelectrode arrays in primary motor (MIo) and somatosensory (SIo) areas of the orofacial cortex. In some sessions, tasks were preceded by bilateral nerve block injections to the sensory branches of the trigeminal nerve. Modulation to 3D tongue direction during feeding and drinking was found in most MIo and SIo neurons. Directional information at both individual and population levels was higher in feeding and was more robust in MIo. Following sensory loss, alterations in tongue kinematics were accompanied by changes in directional information in MIo and SIo, manifesting as modifications in both individual neuron tuning characteristics and the broader dynamics of population-level neural activity. This study advances our understanding of single-neuron and population activity in OSMCx and their potential contributions to the sensorimotor control of complex naturalistic tongue movements. By extending current knowledge of orofacial control to 3D tongue movements, our findings demonstrate the specificity and adaptability of population activity in MIo and SIo in response to different behavioral contexts, providing important insights for understanding neural mechanisms underlying skilled tongue control.

Twist is the key to the gating of mechanosensitive ion channel NOMPC

c.song@pku.edu.cn (Chen Song) — Tue, 21 Oct 2025 00:00:00 +0000

NOMPC, a tethered mechanosensitive ion channel belonging to the transient receptor potential (TRP) family, converts mechanical stimuli into ionic electric signals that excite neuronal cells (Yan et al., 2013). Previous investigations have demonstrated that a pushing force applied to the linker helix domain or the compression of NOMPC’s ankyrin repeat (AR) domain can trigger channel opening (Wang et al., 2021). In this study, we explored the direct mechanical causes of NOMPC channel opening as well as the torsional properties of the AR domain, using all-atom molecular dynamics simulations. Our results indicate that a torque directed toward the extracellular side, exerted on the amphipathic TRP domain, is the primary factor driving channel opening. The coupling between compression and twisting of the AR domain ensures that both types of deformation can induce channel opening. Therefore, we propose a twist-to-open model, facilitated by the compression-twist coupling property of the AR domain, to provide further insight into the gating mechanism of the NOMPC channel.

Asymmetric cortical projections to striatal direct and indirect pathways distinctly control actions

xjin@bio.ecnu.edu.cn (Edward M Callaway) — Tue, 21 Oct 2025 00:00:00 +0000

The striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs also target D1-SPNs, while only one-third do so vice versa. Optogenetic stimulation of striatal D1- vs. D2-SPN-projecting cortical neurons differently regulate locomotion, reinforcement learning, and sequence behavior, implying the functional dichotomy of pathway-specific corticostriatal subcircuits. These results reveal the partially segregated yet asymmetrically overlapping cortical projections on striatal D1- vs. D2-SPNs, and that the pathway-specific corticostriatal subcircuits distinctly control behavior. It has important implications in a wide range of neurological and psychiatric diseases affecting cortico-basal ganglia circuitry.

TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer

celine.gongora@inserm.fr (Adam Aissanou) — Tue, 21 Oct 2025 00:00:00 +0000

In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Among them, AZD2858 disrupted TopBP1 assembly induced by the clinically relevant topoisomerase I inhibitor SN-38, thereby inhibiting the ATR/Chk1 signaling pathway. We found that AZD2858 exerted its effects by disrupting TopBP1 self-interaction and binding to ATR in mammalian cells, and by increasing its chromatin recruitment in cell-free Xenopus laevis egg extracts. Moreover, AZD2858 prevented S-phase checkpoint induction by SN-38, leading to increased DNA damage and apoptosis in a colorectal cancer cell line. Lastly, AZD2858 showed a synergistic effect in combination with the FOLFIRI chemotherapy regimen in a spheroid model of colorectal cancer.

Exploring neurodevelopment via spatiotemporal collation of anatomical networks with NeuroSC

wmohler@uchc.edu (Daniel A Colón-Ramos) — Tue, 21 Oct 2025 00:00:00 +0000

Volume electron microscopy (vEM) datasets such as those generated for connectome studies allow nanoscale quantifications and comparisons of the cell biological features underpinning circuit architectures. Quantifying cell biological relationships in the connectome yields rich, multidimensional datasets that benefit from data science approaches, including dimensionality reduction and integrated graphical representations of neuronal relationships. We developed NeuroSC (also known as NeuroSCAN, https://neurosc.net/) an open source online platform that bridges sophisticated graph analytics from data science approaches with the underlying cell biological features in the connectome. We analyze a series of published C. elegans brain neuropils and demonstrate how these integrated representations of neuronal relationships facilitate comparisons across connectomes, catalyzing new insights into the structure-function relationships of the circuits and their changes during development. NeuroSC is designed for intuitive examination and comparisons across connectomes, enabling synthesis of knowledge from high-level abstractions of neuronal relationships derived from data science techniques to the detailed identification of the cell biological features underpinning these abstractions.

The capsule and genetic background, rather than specific individual loci, strongly influence in vitro pneumococcal growth kinetics

chrispin.chaguza@gmail.com (Amelieke JH Cremers) — Tue, 21 Oct 2025 00:00:00 +0000

Bacterial growth characteristics intrinsic to each strain can impact and influence gene expression, antibiotic susceptibility, and disease pathogenesis. However, little is known about specific genomic variations that influence these bacterial growth features. Here, we investigate the impact of Streptococcus pneumoniae genetics on its in vitro growth features to shed light on genes that may be important targets in the development of vaccines and therapeutics. We use statistical models to estimate growth features and demonstrate that they varied significantly across capsular serotypes and lineages, were strongly correlated with phylogeny, and showed high heritability, highlighting a strong genetic basis. Despite this, genome-wide association studies revealed no specific genomic loci statistically associated with the growth features independently of the genetic background, including those in the locus responsible for capsular polysaccharide synthesis. Our findings suggest that the serotype and lineage, as well as a combination of genomic loci, influence intrinsic pneumococcal growth kinetics, which may have implications for pneumococcal disease pathogenesis.

Resident memory macrophages and trained innate immunity at barrier tissues

jeyanat@mcmaster.ca (Alisha Kang) — Mon, 20 Oct 2025 00:00:00 +0000

Innate immune memory, or trained innate immunity (TII), represents a form of immunological adaptation in which innate immune cells, including myeloid and lymphoid cells, retain a trained state following prior exposure to immunological stimuli. This long-lasting modification either enhances or reduces the innate immune response to subsequent heterologous infections or inflammatory insults. While TII often provides protective benefits, including enhanced protection against pathogens and tumors, it can contribute to maladaptive inflammation in certain conditions. Epigenetic changes and metabolic reprogramming are key drivers of innate immune memory, but it is important to distinguish between transient acute changes and persistent modifications that define bona fide innate immune memory. Innate immune memory can be induced centrally, through systemic events that train hematopoietic progenitors in the bone marrow, or locally, via tissue-resident cells such as macrophages. The presence of trained tissue-resident immune cells offers significant advantages, but their responses may not always result in universally enhanced protection. This review explores recent advances in the understanding of tissue-resident memory macrophages and TII at barrier tissue sites, including the lung, skin, gut, and peritoneum, highlighting the implications for vaccine and immunotherapeutic strategies. Ongoing research promises to accelerate progress in this field and inform new clinical and vaccinology approaches.

Protein language model identifies disordered, conserved motifs implicated in phase separation

binz@mit.edu (Bin Zhang) — Mon, 20 Oct 2025 00:00:00 +0000

Intrinsically disordered regions (IDRs) play a critical role in phase separation and are essential for the formation of membraneless organelles (MLOs). Mutations within IDRs can disrupt their multivalent interaction networks, altering phase behavior and contributing to various diseases. Therefore, examining the evolutionary constraints of IDRs provides valuable insights into the relationship between protein sequences and phase separation. In this study, we utilized the ESM2 protein language model to map the residue-level mutational tolerance landscapes of IDRs. Our findings reveal that IDRs, particularly those actively participating in phase separation, contain conserved amino acids. This conservation is evident through mutational constraints predicted by ESM2 and supported by direct analyses of multiple sequence alignments. These conserved, disordered amino acids include residues traditionally identified as ‘stickers’ as well as ‘spacers’ and frequently form continuous sequence motifs. The strong conservation, combined with their potential role in phase separation, suggests that these motifs may act as functional units under evolutionary selection to support stable MLO formation. Our findings underscore the insights into phase separation’s molecular grammar made possible through evolutionary analysis enabled by protein language models.

Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain

michael.ohh@utoronto.ca (Cassandra C Taber) — Mon, 20 Oct 2025 00:00:00 +0000

Mutations in EGLN1, the gene encoding for hypoxia-inducible factor (HIF) prolyl-4-hydroxylase 2 (PHD2), cause erythrocytosis and in rare cases the development of neuroendocrine tumors. In the presence of oxygen, PHD2 hydroxylates one or both conserved prolines in the oxygen-dependent degradation domain (ODD) of HIFα subunits, sufficiently marking HIFα for binding and ubiquitylation via the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase and subsequent degradation by the 26S proteasome. However, prolyl-hydroxylation in the C-terminal ODD appears to be the predominant and sufficient event in triggering the oxygen-dependent destruction of HIFα, rendering the biological significance of N-terminal ODD proline unclear. Here, we examined seven disease-associated EGLN1 mutations scattered across the catalytic core and showed definitively that all PHD2 mutants have a structural and/or catalytic activity defect as measured by time-resolved nuclear magnetic resonance. Notably, we identified one of the PHD2 mutants, P317R, to retain comparably wild-type capacity to hydroxylate the predominant proline in the C-terminal ODD but had uniquely compromised ability to hydroxylate the N-terminal ODD proline. These findings support the notion that deregulation of HIF ultimately underlies PHD2-driven erythrocytosis and challenge the currently held uncertainty that the N-terminal ODD prolyl-hydroxylation event is dispensable in normal hypoxic signaling pathway.

Probing the role of synaptic adhesion molecule RTN4RL2 in setting up cochlear connectivity

yunfeng.hua@shsmu.edu.cn (Anneliese Schrott-Fischer) — Mon, 20 Oct 2025 00:00:00 +0000

Sound encoding depends on the precise and reliable neurotransmission at the afferent synapses between the sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs). The molecular mechanisms contributing to the formation, as well as interplay between the pre- and postsynaptic components, remain largely unclear. Here, we tested the role of the synaptic adhesion molecule and Nogo/RTN4 receptor homolog RTN4RL2 (also referred to as NgR2) in the development and function of afferent IHC–SGN synapses. Upon deletion of RTN4RL2 in mice (RTN4RL2 KO), presynaptic IHC active zones showed enlarged synaptic ribbons and a depolarized shift in the activation of Ca_V1.3 Ca²⁺ channels. The postsynaptic densities (PSDs) of SGNs were smaller and deficient of GluA2–4 AMPA receptor subunits despite maintained Gria2 mRNA expression in SGNs. Next to synaptically engaged PSDs, we observed ‘orphan’ PSDs located away from IHCs, likely belonging to a subset of SGN peripheral neurites that do not contact the IHCs in RTN4RL2 KO cochleae, as found by volume electron microscopy reconstruction of SGN neurites. Auditory brainstem responses of RTN4RL2 KO mice showed increased sound thresholds indicating impaired hearing. Together, these findings suggest that RTN4RL2 contributes to the proper formation and function of auditory afferent synapses and is critical for normal hearing.

The unique synaptic circuitry of specialized olfactory glomeruli in Drosophila melanogaster

jrybak@ice.mpg.de (Bill S Hansson) — Mon, 20 Oct 2025 00:00:00 +0000

In the Drosophila olfactory system, most odorants are encoded in the antennal lobe in a combinatory way, activating several glomerular circuits. However, odorants of particular ecological role for the fly are encoded through activation of a single specialized olfactory pathway. Comparative analyses of densely reconstructed connectomes of one broadly tuned glomerulus (DL5) and one narrowly tuned glomerulus (DA2) gained detailed insight into the variations of synaptic circuitries of glomeruli with different computational tasks. Our approach combined laser branding of glomeruli of interest with volume-based focused ion beam-scanning electron microscopy to enable precise targeting and analysis of the two glomeruli. We discovered differences in their neuronal innervation, synaptic composition, and specific circuitry of their major cell types: olfactory sensory neurons (OSNs), uniglomerular projection neurons, and multiglomerular neurons. By comparing our data with a previously mapped narrowly tuned glomerulus (VA1v), we identified putative generic features of narrowly tuned glomerular circuits, including higher density of neuronal fibers and synapses, lower degree of OSN lateralization, stronger axo-axonic connections between OSNs, dendro-dendritic connections between many uPNs, and lower degree of presynaptic input on OSN axons. In addition, this work revealed that the dendrites of the single uPN in DL5 contain a substantial amount of autapses interconnecting distant regions of the dendritic tree. The comparative analysis of glomeruli allows us to formulate synaptic motifs implemented in olfactory circuits with different computational demands.

How hunger guides new brain cells to their destination

lnguyen@uliege.be (Fang-Shin Nian) — Mon, 20 Oct 2025 00:00:00 +0000

Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.

Alternative splicing across the tree of life

science.rdelafuente@hotmail.com (Andres Moya) — Fri, 17 Oct 2025 00:00:00 +0000

There is a growing understanding of how alternative splicing contributes to functional specialization and adaptation, especially in well-studied model organisms. However, its large-scale evolutionary dynamics remain poorly understood. Through a comparative analysis of alternative splicing across 1494 species spanning the entire tree of life, this study integrates numerous lines of prior evidence to provide a unified view of alternative splicing. We propose a novel genome-scale metric designed to support cross-species comparison. Our findings indicate that alternative splicing is highly variable across lineages. While unicellular eukaryotes and prokaryotes display minimal splicing, mammals and birds exhibit the highest levels of alternative splicing. Despite sharing a conserved intron-rich genomic architecture, mammals and birds show considerable interspecies divergence in splicing activity. In contrast, plants display moderate levels of alternative splicing but exhibit high variability of genomic composition. Furthermore, a strong negative correlation is observed between alternative splicing and the proportion of coding content in genes, with the highest levels of alternative splicing observed in genomes containing approximately 50% intergenic DNA.

scRNA+TCR-seq reveals the proportion and characteristics of dual TCR Treg cells in mouse lymphoid and non-lymphoid tissues

immunology@126.com (Jun Li) — Fri, 17 Oct 2025 00:00:00 +0000

The rearrangement of TCR germline V(D)J genes during T cell development, including allelic exclusion and tolerance selection, ensures the clonal selection theory, which states that ‘a lymphocyte expresses only one type of antigen receptor’. This forms the basis for T cell-specific responses. However, the existence of ‘dual TCR T cells’ has consistently been supported by specific experimental evidence. Detailed reports on the origin, proportion, tissue distribution, and CDR3 characteristics of ‘dual TCR Treg cells’ are currently lacking. In this study, we utilized scRNA+TCR-seq technology to achieve in-depth analysis of single and dual TCR T pairings, along with their mRNA expressions, from over 5000 T cells in each sample. Through comparative studies with shared databases, we provided a detailed analysis of the proportions and characteristics of dual TCR Tregs in mouse lymphoid and non-lymphoid tissues (such as inguinal lymph node, mesenteric lymph node, blood, and skin). Our findings revealed a high proportion of dual TCR Tregs across various mouse tissues, with their TCR pairing patterns, V(D)J usage, and mRNA expression showing both homogeneity and certain differences compared to single TCR Tregs, as well as heterogeneity across different tissue sites. This research provides new insights and technical approaches for studying the origins, characteristics, effects, and mechanisms of Treg cells in different tissue locations.

Remote automated delivery of mechanical stimuli coupled to brain recordings in behaving mice

ia2458@columbia.edu (Abednego Delinois) — Fri, 17 Oct 2025 00:00:00 +0000

The canonical framework for testing pain and mechanical sensitivity in rodents is manual delivery of stimuli to the paw. However, this approach is time-consuming, produces variability in results, requires significant training, and is ergonomically unfavorable to the experimenter. To circumvent limitations in manual delivery of stimuli, we have created a device called the automated reproducible mechanostimulator (ARM). Built using a series of linear stages, cameras, and stimulus holders, the ARM is more accurate at hitting the desired target, delivers stimuli faster, and decreases variability in delivery of von Frey hair filaments. We demonstrate that the ARM can be combined with traditional measurements of pain behavior and automated machine-learning-based pipelines. Importantly, the ARM enables remote testing of mice with experimenters outside the testing room. Using remote testing, we found that mice habituated more quickly when an experimenter was not present, and experimenter presence led to significant sex-dependent differences in paw withdrawal and pain-associated behaviors. Lastly, to demonstrate the utility of the ARM for neural circuit dissection of pain mechanisms, we combined the ARM with cellular-resolved microendoscopy in the amygdala, linking stimulus, behavior, and brain activity of amygdala neurons that encode negative pain states. Taken together, the ARM improves speed, accuracy, and robustness of mechanical pain assays and can be combined with automated pain detection systems and brain recordings to map central control of pain.

Adult neurogenesis reconciles flexibility and stability of olfactory perceptual memory

h-riecke@northwestern.edu (Bennet Sakelaris) — Fri, 17 Oct 2025 00:00:00 +0000

In brain regions featuring ongoing plasticity, the task of quickly encoding new information without overwriting old memories presents a significant challenge. In the rodent olfactory bulb, which is renowned for substantial structural plasticity driven by adult neurogenesis and persistent turnover of dendritic spines, we show that by synergistically combining both types of plasticity, this flexibility-stability dilemma can be overcome. To do so, we develop a computational model for structural plasticity in the olfactory bulb and show that it is the maturation process of adult-born neurons that enables the bulb to learn quickly and forget slowly. Particularly important are the transient enhancement of the plasticity, excitability, and susceptibility to apoptosis that characterizes young neurons. The model captures many experimental observations and makes a number of testable predictions. Overall, it identifies memory consolidation as an important role of adult neurogenesis in olfaction and exemplifies how the brain can maintain stable memories despite ongoing extensive neurogenesis and synaptic plasticity.

Cross-species insemination reveals mouse sperm ability to enter and cross the fish micropyle

mavella@sidra.org (Abbirami Sathappan) — Thu, 16 Oct 2025 00:00:00 +0000

Extracellular matrices surrounding eggs in fish (chorion) and mammals (zona pellucida [ZP]) regulate gamete recognition before fertilization, though their mechanisms differ. Mouse sperm bind and cross the ZP at any site, while fish sperm cross the chorion through a funnel-shaped opening, the micropyle. To explore these divergent processes, we established cross-species insemination assays, mixing zebrafish eggs with mouse sperm. While mouse sperm could not bind to the chorion, a subpopulation successfully located and crossed the fish micropyle. Confocal and electron microscopy revealed that sperm entered the micropyle and accumulated in the zebrafish inter-chorion space. However, transgenic mouse sperm with mCherry-labeled acrosomes failed to undergo acrosome exocytosis efficiently in the micropyle, with both acrosome-intact and reacted sperm found in the inter-chorion space. Sperm entry and crossing were dependent on hyperactive motility, as sperm from CatSperd^Null mice, which fail to undergo hyperactivation, did not interact with or cross the micropyle. These findings suggest a conserved mechanism for sperm entry into the micropyle, providing a novel platform to investigate cross-species gamete interactions and uncover novel steps in fertilization.

Interleukin 10 controls the balance between tolerance, pathogen elimination, and immunopathology in birds

david.hume@uq.edu.au (Androniki Psifidi) — Thu, 16 Oct 2025 00:00:00 +0000

Effective mucosal immunity in the intestine involves a fine balance between tolerance of the microbiome, recognition, and elimination of pathogens, and inflammatory tissue injury. The anti-inflammatory cytokine IL10 regulates these processes in the intestines of mice and humans; the anti-inflammatory activity of IL10 is also conserved in birds. To determine the function of IL10 in avian mucosal immunity, we generated germ line modifications of the chicken IL10 locus to abolish or reduce IL10 expression. In vitro analysis of macrophage response to lipopolysaccharide confirmed the loss of IL10 protein expression, the lack of dosage compensation in heterozygotes, and prevention of autocrine inhibition of nitric oxide production in homozygous IL10 knockout macrophages. IL10-deficiency significantly altered the composition of the caecal microbiome, but unlike IL10-deficient mice and humans, IL10-deficient chickens did not exhibit spontaneous colitis. Following experimental challenge with Salmonella enterica serovar Typhimurium or Campylobacter jejuni in IL10-deficient chickens, enhanced clearance of the pathogens was associated with elevated transcription of pro-inflammatory genes and increased infiltration of inflammatory cells into gut mucosa. In IL10-deficient chickens challenged with the parasite Eimeria tenella, pathogen clearance was accelerated but caecal lesions were more severe and weight gain was compromised. Neither the heterozygous IL10 knockout nor a homozygous IL10 enhancer mutation had a major effect on pathogen clearance or inflammation in any of the challenge models. Our findings highlight the intrinsic compromise in mucosal immune response and have important implications for the development of strategies to combat avian and zoonotic pathogens in poultry.

BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment

malieva@iib.uam.es (Anne Rios) — Wed, 15 Oct 2025 00:00:00 +0000

Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that often exceed the analytical capacity of traditional uni-parametric approaches, which can neglect single-cell heterogeneous in vivo behavior and limit insights into microenvironmental influences on cellular behavior. To overcome these limitations, we present BEHAV3D Tumor Profiler (BEHAV3D-TP), a computational framework that enables unbiased single-cell classification based on a range of morphological, environmental, and dynamic single-cell features. BEHAV3D-TP integrates with widely used 2D and 3D image processing pipelines, enabling researchers without advanced computational expertise to profile cancer and healthy cell dynamics in IVM data from mouse models. Here, we apply BEHAV3D-TP to study diffuse midline glioma (DMG), a highly aggressive pediatric brain tumor characterized by invasive progression. By extending BEHAV3D-TP to incorporate tumor microenvironment (TME) data from IVM or fixed correlative imaging, we demonstrate that distinct migratory behaviors of DMG cells are associated with specific TME components, including tumor-associated macrophages and vasculature. BEHAV3D-TP enhances the accessibility of computational tools for analyzing the complex behaviors of cancer cells and their interactions with the TME in IVM data.

Correction: Emergent periodicity in the collective synchronous flashing of fireflies

Wed, 15 Oct 2025 00:00:00 +0000

HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos

magdaz@caltech.edu (Estefania Sanchez-Vasquez) — Tue, 14 Oct 2025 00:00:00 +0000

Human fertility is suboptimal in part by error-prone divisions during early cleavage stages, which frequently result in chromosomal aneuploidy. Most human pre-implantation embryos are mosaics of euploid and aneuploid cells, yet those with a low proportion of aneuploid cells can develop to term at rates similar to fully euploid embryos. How embryos manage aneuploidy during early development remains poorly understood – yet this knowledge is crucial for improving fertility outcomes and reducing developmental defects. To investigate these mechanisms, we established a new mouse model of chromosome mosaicism to trace the fate of aneuploid cells during pre-implantation development. We previously used the Mps1 inhibitor reversine to induce aneuploidy. Here, we demonstrate that the more specific Mps1 inhibitor AZ3146 similarly disrupts chromosome segregation but supports higher developmental potential than reversine. AZ3146-treated embryos transiently upregulate hypoxia-inducible factor-1A (HIF1A) without triggering Trp53 activation. Given that pre-implantation embryos develop in a hypoxic environment in vivo, we further explored the role of oxygen tension. Hypoxia exposure in vitro reduced DNA damage in response to Mps1 inhibition and increased the proportion of euploid cells in mosaic epiblast. Conversely, HIF1A inhibition decreased the proportion of aneuploid cells. Together, these findings uncover a role for hypoxia signaling in modulating the response to chromosomal errors and suggest new strategies to improve the developmental potential of mosaic human embryos.

Homeostatic synaptic plasticity of miniature excitatory postsynaptic currents in mouse cortical cultures requires neuronal Rab3a

koesteag@ucmail.uc.edu (Andrew G Koesters) — Tue, 14 Oct 2025 00:00:00 +0000

Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of plasticity termed ‘homeostatic synaptic plasticity’. We previously showed that a presynaptic protein, the small GTPase Rab3a, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction (NMJ) in vivo, where an increase in postsynaptic receptors does not contribute. It is unknown whether this form of Rab3a-dependent homeostatic plasticity at the NMJ shares any characteristics with central synapses. We show here that homeostatic synaptic plasticity of mEPSCs is impaired in mouse cortical neuron cultures prepared from Rab3a^−/− and mutant mice expressing a single-point mutation of Rab3a, Rab3a Earlybird mice. To determine if Rab3a is involved in the well-established homeostatic increase in postsynaptic AMPA-type receptors (AMPARs), we performed a series of experiments in which electrophysiological recordings of mEPSCs and confocal imaging of synaptic AMPAR immunofluorescence were assessed within the same cultures. We found that the increase in postsynaptic AMPAR levels in wild-type cultures was more variable than that of mEPSC amplitudes, which might be explained by a presynaptic contribution, but we cannot rule out variability in the measurement. Finally, we demonstrate that Rab3a is acting in neurons because only selective loss of Rab3a in neurons, not glia, disrupted the homeostatic increase in mEPSC amplitudes. This is the first demonstration that a protein thought to function presynaptically is required for homeostatic synaptic plasticity of quantal size in central neurons.

Probing the staying power of chemogenetics

ikagan@dpz.eu (Igor Kagan) — Mon, 13 Oct 2025 00:00:00 +0000

A study that monitored the expression and function of designer receptors called DREADDs in macaque monkeys for a period of three years demonstrates that they are effective in long-term studies of nonhuman primates.

Synchronous ensembles of hippocampal CA1 pyramidal neurons during novel exploration

beijunglin@nycu.edu.tw (Bei-Jung Lin) — Mon, 13 Oct 2025 00:00:00 +0000

Synchronous neuronal ensembles play a pivotal role in the consolidation of long-term memory in the hippocampus. However, their organization during the acquisition of spatial memory remains less clear. In this study, we used neuronal population voltage imaging to investigate the synchronization patterns of mice CA1 pyramidal neuronal ensembles during the exploration of a new environment, a critical phase for spatial memory acquisition. We found synchronous ensembles comprising approximately 40% of CA1 pyramidal neurons, firing simultaneously in brief windows (~25ms) during immobility and locomotion in novel exploration. Notably, these synchronous ensembles were not associated with contralateral ripple oscillations but were instead phase-locked to theta waves recorded in the contralateral CA1 region. Moreover, the subthreshold membrane potentials of neurons exhibited coherent intracellular theta oscillations with a depolarizing peak at the moment of synchrony. Among newly formed place cells, pairs with more robust synchronization during locomotion displayed more distinct place-specific activities. These findings underscore the role of synchronous ensembles in coordinating place cells of different place fields.

Transcranial direct current stimulation modulates primate brain dynamics across states of consciousness

guylaine.hoffner@inserm.fr (Alain Destexhe) — Mon, 13 Oct 2025 00:00:00 +0000

The resting primate brain is traversed by spontaneous functional connectivity patterns that show striking differences between conscious and unconscious states. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulatory technique, can improve signs of consciousness in disorders of consciousness (DOCs); however, can it influence both conscious and unconscious dynamic functional connectivity? We investigated the modulatory effect of prefrontal cortex (PFC) tDCS on brain dynamics in awake and anesthetized non-human primates using functional MRI. In awake macaques receiving either anodal or cathodal tDCS, we found that cathodal stimulation robustly disrupted the repertoire of functional connectivity patterns, increased structure–function correlation (SFC), decreased Shannon entropy, and favored transitions toward anatomically based patterns. Under deep sedation, anodal tDCS significantly altered brain pattern distribution and reduced SFC. The prefrontal stimulation also modified dynamic connectivity arrangements typically associated with consciousness and unconsciousness. Our findings offer compelling evidence that PFC tDCS induces striking modifications in the fMRI-based dynamic organization of the brain across different states of consciousness. This study contributes to an enhanced understanding of tDCS neuromodulation mechanisms and has important clinical implications for DOCs.

Age and learning shapes sound representations in auditory cortex during adolescence

mizrahi.adi@mail.huji.ac.il (Adi Mizrahi) — Mon, 13 Oct 2025 00:00:00 +0000

Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20–42) and adult (postnatal day 60–82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period.

Shared functional organization between pulvinar-cortical and cortico-cortical connectivity and its structural and molecular imaging correlates

alberto.cacciola0@gmail.com (Alberto Cacciola) — Mon, 13 Oct 2025 00:00:00 +0000

The pulvinar, the largest thalamic nucleus, is a highly interconnected structure supporting perception, visuospatial attention, and emotional processing. Such a central role relies on a precise topographical organization reflected in anatomical connectivity and neurochemical markers. Traditionally subdivided into distinct subnuclei, recent work shows that these divisions only partially explain its organization, which is better captured by continuous gradients of cortical connections along dorso-ventral and medio-lateral axes. While well studied in primates, this gradient-based architecture remains less explored in humans. The present work combines high-quality, multimodal structural and functional imaging with a whole-brain, large-scale, PET atlas mapping 19 neurotransmitter systems. By applying diffusion embedding to tractography, functional connectivity, and receptor coexpression, we identify multiple gradients of structural connections, functional coactivation, and molecular binding patterns. These converge on a shared representation along the dorso-ventral and medio-lateral axes of the human pulvinar, aligning with connectivity transitions from lower-level to higher-order cortical regions. Moreover, this is paralleled by gradual changes in the expression of molecular markers associated with key neuromodulator systems, including serotoninergic, noradrenergic, dopaminergic, and opioid systems. Our findings advance the understanding of pulvinar anatomy and function, offering an exploratory framework to investigate the role of this structure in both health and disease.

KDM5 demethylases suppress R-loop-mediated ‘viral mimicry’ and DNA damage in breast cancer cells

classon.marie@gmail.com (Ahu Turkoz) — Mon, 13 Oct 2025 00:00:00 +0000

Tumors with low expression of interferon-stimulated genes (ISG) and antigen presentation (AP) genes respond relatively poorly to current immunotherapies. One of the early hallmarks of cancer is DNA hypomethylation in genomic repeat regions that can result in the expression of normally silenced endogenous ‘viral’ elements. Such epigenetic changes have the potential to augment anti-tumor immune responses as well as reduce tumor cell fitness through the generation of aberrant nucleic acid species (NAS) and consequent activation of NAS-sensing pathways. Therefore, tumor evolution should favor additional selective events that suppress NAS generation, possibly yielding specific therapeutic vulnerabilities. Here, we show that the lysine demethylase 5 (KDM5) family of epigenetic regulatory enzymes suppresses R-loop formation in genomic repeat regions specifically in cancer cells. We find that KDM5 inhibition in luminal breast cancer cells results in R-loop-mediated DNA damage, reduced cell fitness, and an increase in ISG and AP signatures as well as cell surface major histocompatibility complex (MHC) class I, mediated by RNA:DNA hybrid activation of the CGAS/STING pathway. KDM5 inhibition does not result in DNA damage or activation of the CGAS/STING pathway in normal breast epithelial cells, suggesting that KDM5 inhibitors may enable a wide therapeutic window in this setting, compared to STING agonists or type I interferons. These findings provide new insights into the interplay between epigenetic regulation of genomic repeats, R-loop formation, innate immunity, and cell fitness in the context of cancer evolution and therapeutic vulnerability.