eLife: latest articles

Lipid peroxidation and type I interferon coupling fuels pathogenic macrophage activation causing tuberculosis susceptibility

ikramnik@bu.edu (Alexander A Gimelbrant) — Thu, 02 Oct 2025 00:00:00 +0000

A quarter of the human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure (1) to properly sequester intracellular iron and (2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled superinduction of Ifnβ and sustained the type I interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within the granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of the Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

Balancing safety and efficiency in human decision-making

pranav.mahajan@ndcn.ox.ac.uk (Ben Seymour) — Thu, 02 Oct 2025 00:00:00 +0000

The safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a specific fear memory during exploratory decision-making. In a series of simulations, we show this promotes safe but efficient learning and is optimised by arbitrating Pavlovian avoidance of instrumental decision-making according to uncertainty. We provide a basic test of this model in a simple human approach-withdrawal experiment in virtual reality and show that this flexible avoidance model captures choice and reaction times. These results show that the Pavlovian fear system has a more sophisticated role in decision-making than previously thought, by shaping flexible exploratory behaviour in a computationally precise manner.

Age-related changes in ‘cortical’ 1/f dynamics are linked to cardiac activity

Fabian.Schmidt@plus.ac.at (Dominic P Klein) — Thu, 02 Oct 2025 00:00:00 +0000

The power of electrophysiologically measured cortical activity decays with an approximately 1 /f^X function. The slope of this decay (i.e. the spectral exponent, X) is modulated by various factors such as age, cognitive states or psychiatric/neurological disorders. Interestingly, a mostly parallel line of research has also uncovered similar effects for the spectral slope in the electrocardiogram (ECG). This raises the question of whether these bodywide changes in spectral slopes are (in-)dependent. Focusing on well-established age-related changes in spectral slopes, we analyzed a total of 1282 recordings of magnetoencephalography (MEG) resting state measurements with concurrent ECG in an age-diverse sample (18–88 years). Using a diverse array of analytical approaches, we demonstrate that the aperiodic signal recorded via surface electrodes/sensors originates from multiple physiological sources. Furthermore, our results suggest that common ‘artifact’ rejection approaches (i.e. ICA) may not be sufficient to separate cardiac from neural activity. In particular, significant parts of age-related changes in aperiodic activity normally interpreted to be of neural origin can be explained by cardiac activity. Moreover, our results suggest that changes (flattening/steepening) of the spectral slope with age are dependent on the recording site and investigated frequency range. Our results highlight the complexity of aperiodic activity while raising concerns when interpreting aperiodic activity as ‘cortical’ without considering physiological influences.

Understanding the global rise of artemisinin resistance: Insights from over 100,000 Plasmodium falciparum samples

cristina.ariani@gmail.com (Andrew J Balmer) — Thu, 02 Oct 2025 00:00:00 +0000

Artemisinin partial resistance (ART-R) in Plasmodium falciparum is a major challenge to malaria control globally. Over the last two decades, ART-R has spread widely across Southeast Asia, undermining public health strategies and hindering elimination. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically impact current efforts to control malaria in the region. Mitigating its spread requires detailed genomic surveillance of point mutations in the kelch13 gene, the primary known determinant of artemisinin resistance. Although extensive surveillance data on these markers is available, it is distributed across many literature studies and open databases. In this review, we aggregate spatiotemporal data for 112,933 P. falciparum samples collected between 1980 and 2023 into a single resource, providing the most comprehensive overview of kelch13 markers to date. We outline the history and current status of these mutations globally, with particular focus on their emergence in Southeast Asia and East/Northeast Africa. Concerningly, we find the recent increases in ART-R in Africa mirror patterns observed in Southeast Asia 10–15 years ago. We examine factors that may influence its spread, including fitness costs, treatment strategies, and local epidemiological dynamics, before discussing potential scenarios for how resistance may spread in Africa in coming years. This review provides a comprehensive account of how the situation of ART-R has unfolded globally so far, highlighting insights for researchers and public health bodies which aim to reduce its negative effects.

Endophilin A1 facilitates organization of the GABAergic postsynaptic machinery to maintain excitation-inhibition balance

jjliu@genetics.ac.cn (Deng Pan) — Thu, 02 Oct 2025 00:00:00 +0000

The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits, and the lack of typical postsynaptic dense structure, there are relatively few studies on the regulatory mechanisms for inhibitory synaptic structure and function, and insufficient understanding of the cellular and molecular abnormalities of inhibitory synapses in neurological and neuropsychiatric disorders. Here, we report a crucial role for endophilin A1 in inhibitory synapses. We show that endophilin A1 directly interacts with the inhibitory postsynaptic scaffold protein gephyrin in excitatory neurons and promotes organization of the inhibitory postsynaptic density and synaptic recruitment/stabilization of the γ-aminobutyric acid type A receptors via its plasma membrane association and actin polymerization-promoting activities. Loss of endophilin A1 by gene knockout in mouse hippocampal CA1 pyramidal cells weakens inhibitory synaptic transmission and causes imbalance in the excitatory/inhibitory function of neural circuits, leading to increased susceptibility to epilepsy. Our findings identify endophilin A1 as an iPSD component and provide new insights into the organization and stabilization of inhibitory postsynapses to maintain E/I balance as well as the pathogenesis of epilepsy.

The influence of temporal context on vision over multiple time scales

reuben.rideaux@sydney.edu.au (Kacie Lee) — Wed, 01 Oct 2025 00:00:00 +0000

Past sensory experiences influence perception of the present. Multiple research subfields have emerged to study this phenomenon at different temporal scales. These phenomena fall into three categories: the influence of immediately preceding sensory events (micro), expectations established by short sequences of events (meso), and regularities over long sequences of events (macro). In a single paradigm, we examined the influence of temporal context on human perception at each scale. By integrating behavioral and pupillometry recordings with electroencephalographical recordings from a previous study, we identify two distinct mechanisms that operate across all scales. The first is moderated by attention and supports rapid motor responses to expected events. The second operates independently of task demands and dampens the feedforward neural responses produced by expected events, leading to unexpected events eliciting earlier and more precise neural representations.

Micro-scale control of oligodendrocyte morphology and myelination by the intellectual disability-linked protein acyltransferase ZDHHC9

shin.kang@temple.edu (Dale DO Martin) — Wed, 01 Oct 2025 00:00:00 +0000

Mutations in the X-linked ZDHHC9 gene cause cognitive deficits in humans, with a subset of patients suffering from epilepsy. X-linked intellectual disability (XLID) is often ascribed to neuronal deficits, but here we report that expression of human and mouse ZDHHC9 orthologs is far higher in myelinating oligodendrocytes (OLs) than in other CNS cell types. ZDHHC9 codes for a protein acyltransferase (PAT), and we found that ZDHHC9 is the most highly expressed PAT in OLs. Wild-type ZDHHC9 localizes to Golgi outposts in OL processes, but other PATs and XLID mutant forms of ZDHHC9 are restricted to OL cell bodies. Using genetic tools for OL progenitor fate tracing and sparse cell labeling, we show that mice lacking Zdhhc9 have grossly normal OL development but display extensive morphological and structural myelin abnormalities. Consistent with the hypothesis that these deficits are OL-autonomous, they are broadly phenocopied by acute Zdhhc9 knockdown in cultured conditions. Finally, we found that ZDHHC9 palmitoylates Myelin Basic Protein (MBP) in heterologous cells, and that palmitoylation of MBP is impaired in the Zdhhc9 knockout brain. Our findings provide critical insights into the mechanisms of ZDHHC9-associated XLID and shed new light on the palmitoylation-dependent control of myelination.

Patchy striatonigral neurons modulate locomotor vigor in response to environmental valence

da-ting.lin@nih.gov (Bin Song) — Wed, 01 Oct 2025 00:00:00 +0000

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs—and optical activation of striatonigral neurons in particular—reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

Tracing cell fates in embryos

yingzhanglab@gmail.com (Qi Chen) — Wed, 01 Oct 2025 00:00:00 +0000

Differences in the activity of an enzyme called CARM1 influence the timing of blastomere polarization and whether they become part of the embryo or the placenta.

Adaptations in wing morphology rather than wingbeat kinematics enable flight in small hoverfly species

camille.leroy@wur.nl (Camille Le Roy) — Tue, 30 Sep 2025 00:00:00 +0000

Due to physical scaling laws, size greatly affects animal locomotor ability and performance. Whether morphological and kinematic traits always jointly respond to size variation remains poorly known. Here, we examine the relative importance of morphological and kinematic changes in mitigating the consequence of size reduction on aerodynamic force production for weight support, focusing on the flight of hoverflies (Syrphidae). We compared the morphology of 28 hoverfly species, and the flight biomechanics and aerodynamics of eight species with body masses ranging from 5 to 100 mg. Our study reveals no significant effect of body mass on wingbeat kinematics among species, suggesting that morphological rather than kinematics changes compensate for the reduction in weight support associated with an isometric reduction in wing size. Computational fluid dynamics simulations confirmed that adaptations in wing morphology drive the ability of small hoverfly species to generate weight support, although variations in wingbeat kinematics among species cannot be entirely ignored. We show that smaller hoverflies have evolved relatively larger wings and aerodynamically more effective wing shapes, mitigating the reduction in aerodynamic weight support associated with isometric size reduction. Altogether, these results suggest that hoverfly flight underpins highly specialised wingbeat kinematics, largely conserved throughout evolution; instead, evolutionary adaptations in wing morphology enabled flight of small hoverflies.

Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning

xmou@bcm.edu (Daoyun Ji) — Tue, 30 Sep 2025 00:00:00 +0000

Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are reactivated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and interact with hippocampal replay to guide subsequent spatial navigation.

Pesticide-induced resurgence in brown planthoppers is mediated by action on a suite of genes that promote juvenile hormone biosynthesis and female fecundity

wusf@njau.edu.cn (Chris Bass) — Tue, 30 Sep 2025 00:00:00 +0000

Pesticide-induced resurgence, increases in pest insect populations following pesticide application, is a serious threat to the sustainable control of many highly damaging crop pests. Resurgence can result from pesticide-enhanced pest reproduction; however, the molecular mechanisms mediating this process remain unresolved. Here we show that brown planthopper (BPH) resurgence in rice crops following exposure to sublethal doses of the pesticide emamectin benzoate (EB) results from the coordinated action of a suite of genes that regulate juvenile hormone (JH) levels, resulting in increased JH titer in adult females and enhanced fecundity. We demonstrate that EB treatment at sublethal levels results in profound changes in female BPH fitness, including increased egg maturation and oviposition. This enhanced reproductive fitness results from the EB-mediated upregulation of key genes involved in the regulation of JH, including JHAMT and Kr-h1 and the downregulation of allatostatin (AstA) and allatostatin receptor (AstAR) expression. AstA signaling is known to inhibit the production of JH in the corpora allata and hence EB exposure diminishes this inhibitory action. We find that the changes in gene expression following EB exposure are caused by the allosteric action of this insecticide on its molecular target, the glutamate-gated chloride channel (GluClα). Collectively, these results provide mechanistic insights into the regulation of negative pesticide-induced responses in insects and reveal some key actors involved in the JH-signaling pathway that underpin pesticide resurgence.

Targeting chromatin remodeling complexes to treat uveal melanoma

jonas.a.nilsson@surgery.gu.se (Jonas A Nilsson) — Tue, 30 Sep 2025 00:00:00 +0000

A novel compound that inhibits the BAF chromatin remodeling complex causes regression in an animal model of the incurable cancer uveal melanoma.

Nuclear and cytosolic J-domain proteins provide synergistic control of Hsf1 at distinct phases of the heat shock response

fden@uni-bonn.de (Aseem Shrivastava) — Tue, 30 Sep 2025 00:00:00 +0000

The heat shock response (HSR) is the major defense mechanism against proteotoxic stress in the cytosol and nucleus of eukaryotic cells. Initiation and attenuation of the response are mediated by stress-dependent regulation of heat shock transcription factors (HSFs). Saccharomyces cerevisiae encodes a single HSF (Hsf1), facilitating the analysis of HSR regulation. Hsf1 is repressed by Hsp70 chaperones under non-stress conditions and becomes activated under proteotoxic stress, directly linking protein damage and its repair to the HSR. J-domain proteins (JDPs) are essential for targeting of Hsp70s to their substrates, yet the specific JDP(s) regulating Hsf1 and connecting protein damage to HSR activation remain unclear. Here, we show that the yeast nuclear JDP Apj1 primarily controls the attenuation phase of the HSR by promoting Hsf1’s displacement from heat shock elements in target DNA. In apj1Δ cells, HSR attenuation is significantly impaired. Additionally, yeast cells lacking both Apj1 and the major JDP Ydj1 exhibit increased HSR activation even in non-stress conditions, indicating their distinct regulatory roles. Apj1’s role in both nuclear protein quality control and Hsf1 regulation underscores its role in directly linking nuclear proteostasis to HSR regulation. Together, these findings establish the nucleus as key stress-sensing signaling hub.

Design principles of transcription factors with intrinsically disordered regions

wencheng.ji@weizmann.ac.il (Ariel Amir) — Tue, 30 Sep 2025 00:00:00 +0000

Transcription factors (TFs) are proteins crucial for regulating gene expression. Effective regulation requires the TFs to rapidly bind to their correct target, enabling the cell to respond efficiently to stimuli such as nutrient availability or the presence of toxins. However, the search process is hindered by slow diffusive movement and the presence of ‘false’ targets – DNA segments that are similar to the true target. In eukaryotic cells, most TFs contain an intrinsically disordered region (IDR), which is commonly assumed to behave as a long, flexible polymeric tail composed of hundreds of amino acids. Recent experimental findings indicate that the IDR of certain TFs plays a pivotal role in the search process. However, the principles underlying the IDR’s role remain unclear. Here, we reveal key design principles of the IDR related to TF binding affinity and search time. Our results demonstrate that the IDR significantly enhances both of these aspects. Furthermore, our model shows good agreement with experimental results, and we propose further experiments to validate the model’s predictions.

Non-cognate immunity proteins provide broader defenses against interbacterial effectors in microbial communities

kagibbs@berkeley.edu (Abigail Knecht) — Tue, 30 Sep 2025 00:00:00 +0000

Dense microbial communities, like the gut and soil microbiomes, are dynamic societies. Bacteria can navigate these environments by deploying proteins that alter foreign cells’ behavior, such as interbacterial effectors. Current models suggest that adjacent sibling cells are protected by an immunity protein, as compared to toxin-antitoxin systems that act only within the effector-producing cell. A prevailing hypothesis is that immunity proteins binding to specific (cognate) protein partners is sufficient to disrupt effector function. Further, there is little-to-no crosstalk with other non-cognate effectors. In this research, we build on sporadic reports challenging these hypotheses. We show that immunity proteins from a newly defined protein family can bind and protect against non-cognate PD-(D/E)XK-containing effectors from diverse phyla. We describe the domains essential for binding and function and show that binding alone is insufficient for protective activity in Proteus mirabilis. Moreover, we found that these effector and immunity genes co-occur in individual human microbiomes. These results expand the growing repertoire of bacterial protection mechanisms and the models on how non-cognate interactions impact community structure within complex ecosystems.

A drug repurposing approach reveals targetable epigenetic pathways in Plasmodium vivax hypnozoites

STEVEN.MAHER@uga.edu (Agnes Orban) — Tue, 30 Sep 2025 00:00:00 +0000

Radical cure of Plasmodium vivax malaria must include elimination of quiescent ‘hypnozoite’ forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants

tibalazs@gmail.com (Annelies Janssens) — Tue, 30 Sep 2025 00:00:00 +0000

Rapamycin (sirolimus), a macrolide compound isolated from the bacterium Streptomyces hygroscopicus, is widely used as oral medication for the prevention of transplant rejection and the treatment of lymphangioleiomyomatosis. It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin’s in vivo activities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here, we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy, and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to human TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.

Astrocytic modulation of population encoding in mouse visual cortex via GABA transporter 3 revealed by multiplexed CRISPR/Cas9 gene editing

msur@mit.edu (Arundhati Natesan) — Tue, 30 Sep 2025 00:00:00 +0000

Astrocytes, which are increasingly recognized as pivotal constituents of brain circuits governing a wide range of functions, express GABA transporter 3 (Gat3), an astrocyte-specific GABA transporter responsible for maintenance of extra-synaptic GABA levels. Here, we examined the functional role of Gat3 in astrocyte-mediated modulation of neuronal activity and information encoding. First, we developed a multiplexed CRISPR construct applicable for effective genetic ablation of Gat3 in the visual cortex of adult mice. Using in vivo two-photon calcium imaging of visual cortex neurons in Gat3 knockout mice, we observed changes in spontaneous and visually driven single neuronal response properties such as response magnitudes and trial-to-trial variability. Gat3 knockout exerted a pronounced influence on population-level neuronal activity, altering the response dynamics of neuronal populations and impairing their ability to accurately represent stimulus information. These findings demonstrate that Gat3 in astrocytes profoundly shapes the sensory information encoding capacity of neurons and networks within the visual cortex.

Telomeres control human telomerase (TERT) expression through non-telomeric TRF2

shantanuc@igib.in (Akshay Sharma) — Tue, 30 Sep 2025 00:00:00 +0000

The function of the human telomerase reverse transcriptase (referred hereafter as TERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influence TERT regulation is relatively less studied. We found TERT was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the TERT promoter. TERT promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to the TERT promoter. Cell lines from different tissue types fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening, gave an increase/decrease in TERT, respectively. Mechanistically, we show TERT promoter-bound non-telomeric TRF2 recruits the canonical PRC2-complex, inducing repressor histone H3K27-trimethylation in a TL-dependent fashion. This was further supported by TL-dependent promoter activity from an exogenously inserted TERT reporter. Increase in TL over days followed by a gradual decline, resulted in activation followed by repression of TERT in a concerted manner, further implicating TL as a key factor for TERT regulation. Notably, on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from the TERT promoter was evident along with telomere elongation and TERT upregulation. Conversely, on telomere shortening in iPSCs, TERT promoter-bound TRF2 was restored with a marked reduction in TERT, further supporting the causal role of TL in TERT transcription. Mechanisms of tight control of TERT by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency.

Nonlinear feedback modulation contributes to the optimization of flexible decision-making

yangzhou1@pku.edu.cn (Xuanyu Wu) — Tue, 30 Sep 2025 00:00:00 +0000

Neural activity in the primate brain correlates with both sensory evaluation and action selection aspects of decision-making. However, the intricate interaction between these distinct neural processes and their impact on decision behaviors remains unexplored. Here, we examined the interplay of these decision processes in posterior parietal cortex (PPC) when monkeys performed a flexible decision task. We found that the PPC activity related to monkeys’ abstract decisions about visual stimuli was nonlinearly modulated by monkeys’ following saccade choices directed outside each neuron’s response field. Recurrent neural network modeling indicated that the feedback connections, matching the learned stimuli-response associations during the task, might mediate such feedback modulation. Further analysis on network dynamics revealed that selectivity-specific feedback connectivity intensified the attractor basins of population activity underlying saccade choices, thereby increasing the reliability of flexible decisions. These results highlight an iterative computation between different decision processes, mediated primarily by precise feedback connectivity, contributing to the optimization of flexible decision-making.

Viral genome sequence datasets display pervasive evidence of strand-specific substitution biases that are best described using non-reversible nucleotide substitution models

rita@aims.ac.za (Christopher Brian Currin) — Tue, 30 Sep 2025 00:00:00 +0000

Most phylogenetic trees are inferred using time-reversible evolutionary models that assume that the relative rates of substitution for any given pair of nucleotides are the same regardless of the direction of the substitutions. However, there is no reason to assume that the underlying biochemical mutational processes that cause substitutions are similarly symmetrical. We consider two non-reversible nucleotide substitution models: (1) a 6-rate non-reversible model (NREV6) that is applicable to analysing mutational processes in double-stranded genomes, in that complementary substitutions occur at identical rates and (2) a 12-rate non-reversible model (NREV12) that is applicable to analysing mutational processes in single-stranded (ss) genomes, in that all substitution types are free to occur at different rates. Using likelihood ratio and Akaike information criterion-based model tests, we show that, surprisingly, NREV12 provided a significantly better fit than the general time reversible (GTR) and NREV6 models to 21/31 dsRNA and 20/30 dsDNA datasets. As expected, however, NREV12 provided a significantly better fit to 24/33 ssDNA and 40/47 ssRNA datasets. We tested how non-reversibility impacts the accuracy with which phylogenetic trees are inferred. As simulated degrees of non-reversibility (DNRs) increased, the tree topology inferences using both NREV12 and GTR became more accurate, whereas inferred tree branch lengths became less accurate. We conclude that while non-reversible models should be helpful in the analysis of mutational processes in most virus species, there is no pressing need to use these models for routine phylogenetic inference.

Representation of male features in the female mouse accessory olfactory bulb, and their stability during the estrus cycle

yoramb@ekmd.huji.ac.il (Oksana Cohen) — Tue, 30 Sep 2025 00:00:00 +0000

Most behaviors result from integration of external and internal inputs. For example, social behavior requires information about conspecifics and internal physiological states. Like many other mammals, female mice undergo a reproductive cycle during which their physiology and behavioral responses to males change dramatically: during estrus, they are more receptive to male mating attempts. A critical element in reproductive behavior is the investigative stage, which in mice and many other species, strongly relies on chemosensation. While the initial approach mostly involves the main olfactory system (MOS), once physical contact is established, the vomeronasal system (VNS) is engaged to provide information about potential partners’ characteristics. Given the estrus-stage-dependent behavioral response, we asked whether representations of male features in the first brain relay of the VNS, namely, the accessory olfactory bulb (AOB), change during the cycle. To this end, we used a stimulus set comprising urine samples from males of different strains and virility levels, as well as from estrus and non-estrus females. The stimulus set was designed to reveal if response patterns of AOB neurons conform to ethologically relevant dimensions such as sex, strain, and particularly, male virility state. Using extracellular recordings in anesthetized female mice, we find that most ethological categories contained in our dataset are not overrepresented by AOB neurons, suggesting that early stages of VNS processing encode conspecific information efficiently. Then, comparing neuronal activity in estrus and non-estrus females, we found that overall, response characteristics at the single neuron and population levels remain stable during the reproductive cycle. The few changes that do occur are not consistent with a systematic modulation of responses to male features. Our findings imply that the AOB presents a stable account of conspecific features to more advanced processing stages.

Matrix-associated extracellular vesicles modulate human smooth muscle cell adhesion and directionality by presenting collagen VI

Alexander.kapustin@kcl.ac.uk (Aled Clayton) — Tue, 30 Sep 2025 00:00:00 +0000

The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here, we show that FN stimulates human VSMCs to secrete small extracellular vesicles (sEVs) by activating the β1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery preventing cellular spreading and adhesion. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI on the sEV surface. In vitro assays identified collagen VI as playing a key role in cell adhesion and invasion directionality. Taken together, our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collagen VI enriched sEVs by VSMCs. These sEVs stimulate directional invasion, most likely by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction force to enable VSMC movement within the complex vascular ECM network.

Diverse calcium dynamics underlie place field formation in hippocampal CA1 pyramidal cells

makara.judit@koki.hu (Gaspar Olah) — Tue, 30 Sep 2025 00:00:00 +0000

Every explored environment is represented in the hippocampus by the activity of distinct populations of pyramidal cells (PCs) that typically fire at specific locations called their place fields (PFs). New PFs are constantly born even in familiar surroundings (during representational drift), and many rapidly emerge when the animal explores a new or altered environment (during global or partial remapping). Behavioral time scale synaptic plasticity (BTSP), a plasticity mechanism based on prolonged somatic action potential (AP) bursts induced by dendritic Ca²⁺/NMDA plateau potentials, was recently proposed as the main cellular mechanism underlying new PF formations (PFFs), but it is unclear whether burst-associated large somatic [Ca²⁺] transients are always necessary and/or sufficient for PFF. To address this issue, here we performed in vivo two-photon [Ca²⁺] imaging of hippocampal CA1 PCs in head-restrained mice to investigate somatic [Ca²⁺] dynamics underlying PFFs in familiar and novel virtual environments. Our results demonstrate that although many PFs are formed by BTSP-like events, PFs also emerge with initial [Ca²⁺] dynamics that do not match any of the characteristics of BTSP. BTSP- and non-BTSP-like new PFFs occur spontaneously in familiar environments, during neuronal representational switches, and instantaneously in new environments. Our data also reveal that solitary [Ca²⁺] transients with larger amplitudes than those evoking BTSP-like PFFs frequently occur without inducing PFs, demonstrating that large [Ca²⁺] transients per se are not sufficient for PFF.

Sparse innervation and local heterogeneity in the vibrissal corticostriatal projection

ingrid.bureau@inserm.fr (Agnès Baude) — Tue, 30 Sep 2025 00:00:00 +0000

The density and overlap of cortical axons in the dorsolateral striatum (DLS) have suggested that striatal neurons integrate widespread information from cortical regions that are functionally related. However, in vivo, DLS neuronal responses to sensory stimuli have shown unexpectedly high selectivity, raising questions about the actual degree of convergence of functional corticostriatal projections on individual striatal cells. Here, we investigated this question by focusing on the projections from different whisker cortical columns in mice, as they overlap in the striatum and are co-active during behavior. Using ex vivo patch-clamp recordings in the DLS and glutamate uncaging for focal stimulations in the barrel cortex, we were able to map the location of presynaptic neurons to individual striatal projection neurons (SPNs). We found that each SPN was innervated by cells located in a small number of whisker cortical columns scattered across the barrel field in the slice. Connectivity of single SPNs with cortical neurons was thus highly discontinuous horizontally, despite the presence of more potential connections. Moreover, connectivity patterns were specific to each cell, with neighboring SPNs sharing few common clusters of presynaptic cells in the cortex. Despite this sparse and distinct innervation of individual SPNs, the projection was topographically organized at the population level. Finally, we found similar innervation patterns for D1- and D2-type SPNs, but observed differences in synaptic strength in their connections with certain cortical layers, notably the associative layer 2/3. Our results suggest that the high convergence of somatosensory inputs to the striatum, enabled by diffuse and overlapping cortical innervation, is accomplished through sparse yet complementary connectivity to individual SPNs.

Spatial frequency adaptation modulates population receptive field sizes

altan.ecem@hotmail.com (Catherine A Morgan) — Fri, 26 Sep 2025 00:00:00 +0000

The spatial tuning of neuronal populations in the early visual cortical regions is related to the spatial frequency (SF) selectivity of neurons. However, there has been no direct investigation into how this relationship is reflected in population receptive field (pRF) sizes despite the common application of pRF mapping in visual neuroscience. We hypothesised that adaptation to high/low SF would decrease the sensitivity of neurons with respectively small/large receptive field sizes, resulting in a change in pRF sizes as measured by functional magnetic resonance imaging (fMRI). To test this hypothesis, we first quantified the SF aftereffect using a psychophysical paradigm where human observers made SF judgments following adaptation to high/low SF noise patterns. We then incorporated the same adaptation technique into a standard pRF mapping procedure to investigate the spatial tuning of the early visual cortex following SF adaptation. Results showed that adaptation to a low/high SF resulted in smaller/larger pRFs, respectively, as hypothesised. Our results provide the most direct evidence to date that the spatial tuning of the visual cortex, as measured by pRF mapping, is related to the SF selectivity of visual neural populations. This has implications for various domains of visual processing, including size perception and visual acuity.

Segment-specific axon guidance by Wnt/Fz signaling diversifies motor commands in Drosophila larvae

nose@k.u-tokyo.ac.jp (Akinao Nose) — Thu, 25 Sep 2025 00:00:00 +0000

Functional diversification of homologous neuronal microcircuits is a widespread feature observed across brain regions, as well as across species, while its molecular and developmental mechanisms remain largely unknown. We address this question in Drosophila larvae by focusing on segmentally homologous Wave command-like neurons, which diversify their wiring and function in a segment-specific manner. Anterior Wave (a-Wave) neurons extend axons anteriorly and connect to circuits inducing backward locomotion, whereas posterior Wave (p-Wave) neurons extend axons posteriorly and trigger forward locomotion. Here, we show that Frizzled receptors DFz2 and DFz4, together with the DWnt4 ligand, regulate the segment-specific Wave axon projection. DFz2 knockdown (KD) not only reroutes Wave axons to posterior neuromeres but also biases its motor command to induce forward instead of backward locomotion as tactile response. Thus, segment-specific axon guidance diversifies the function of homologous command neurons in behavioral regulation. Since control of anterior-posterior (A-P) axon guidance by Wnt/Fz signaling is evolutionarily conserved, our results reveal a potentially universal molecular principle for formation and diversification of the command system in the nerve cord. Furthermore, this work indicates that sensorimotor transduction can be rerouted by manipulating a single gene in a single class of neurons, potentially facilitating the evolutionary flexibility in action selection.

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

lilei64@pumch.cn (Guanghao Wu) — Thu, 25 Sep 2025 00:00:00 +0000

This study investigated 17α-estradiol’s effects on aged hypothalamic physiological activity via long-term administration. Single-nucleus transcriptomic sequencing (snRNA-seq) was performed on pooled hypothalami from each group: aged male Norway brown rats treated with 17α-estradiol (O.T), aged controls (O), and young controls (Y). Supervised clustering of neurons (based on neuropeptides/receptors) evaluated subtype responses to aging and 17α-estradiol. Aging-induced elevation of neuronal cellular metabolism, stress, and reduced synapse formation-related pathways were significantly attenuated by 17α-estradiol. Neuron population analysis showed that subtypes regulating food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17α-estradiol. 17α-estradiol increased serum oxytocin (Oxt) and hypothalamic-pituitary-gonadal (HPG) axis activity (elevated plasma Gnrh, total testosterone; reduced estradiol). Gnrh1 upregulation mediated its effects on energy homeostasis, neural synapse, and stress response. Notably, Crh neurons in O.T showed prominent stress phenotypes, distinct from Agrp/Ghrl neurons. Thus, HPG axis and energy metabolism may be key 17α-estradiol targets in male hypothalamus. Additionally, our results demonstrate that supervised clustering (based on neuropeptides/receptors) effectively assesses the responses of hypothalamic neuron subtypes to aging and 17α-estradiol treatment.

The molecular infrastructure of glutamatergic synapses in the mammalian forebrain

R.Frank@leeds.ac.uk (Charlie Lovatt) — Thu, 25 Sep 2025 00:00:00 +0000

Glutamatergic synapses form the vast majority of connections within neuronal circuits, but how these subcellular structures are molecularly organized within the mammalian brain is poorly understood. Conventional electron microscopy using chemically fixed, metal-stained tissue has identified a proteinaceous, membrane-associated thickening called the ‘postsynaptic density’ (PSD). Here, we combined mouse genetics and cryo-electron tomography to determine the 3D molecular architecture of fresh isolated and anatomically intact synapses in the adult forebrain. The native glutamatergic synapse did not consistently show a higher density of proteins at the postsynaptic membrane, thought to be characteristic of the PSD. Instead, a ‘synaptoplasm’ consisting of cytoskeletal elements, macromolecular complexes, and membrane-bound organelles extended throughout the pre- and post-synaptic compartments. Snapshots of active processes gave insights into membrane remodeling processes. Clusters of up to 60 ionotropic glutamate receptors were positioned inside and outside the synaptic cleft. Together, these information-rich tomographic maps present a detailed molecular framework for the coordinated activity of synapses in the adult mammalian brain.

Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain

rajiv.joshi@college-de-france.fr (Berangere Lombard) — Thu, 25 Sep 2025 00:00:00 +0000

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant, and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly, which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.

Dimerization and dynamics of human angiotensin-I converting enzyme revealed by cryo-EM and MD simulations

wtang@bsd.uchicago.edu (Jordan M Mancl) — Wed, 24 Sep 2025 00:00:00 +0000

Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing four analogous catalytic sites, and exists in membrane-bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryo-EM structures. Here, we report the cryo-EM structure of the glycosylated full human sACE dimer. We resolved four structural states at 2.99 – 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.

Forecasting protein evolution by integrating birth-death population models with structurally constrained substitution models

marenas@uvigo.es (Ana Prado-Comesaña) — Wed, 24 Sep 2025 00:00:00 +0000

Evolutionary studies in population genetics and ecology were mainly focused on predicting and understanding past evolutionary events. Recently, however, a growing trend explores the prediction of evolutionary trajectories toward the future promoted by its wide variety of applications. In this context, we introduce a forecasting protein evolution method that integrates birth-death population models with substitution models that consider selection on protein folding stability. In contrast to traditional population genetics methods that usually make the unrealistic assumption of simulating molecular evolution separately from the evolutionary history, the present method combines both processes to simultaneously model forward-in-time birth-death evolutionary trajectories and protein evolution under structurally constrained substitution models that outperformed traditional empirical substitution models. We implemented the method into a freely available computer framework. We evaluated the accuracy of the predictions with several monitored viral proteins of broad interest. Overall, the method showed acceptable errors in predicting the folding stability of the forecasted protein variants, but, expectedly, the errors were larger in the prediction of the corresponding sequences. We conclude that forecasting protein evolution is feasible in certain evolutionary scenarios and provide suggestions to enhance its accuracy by improving the underlying models of evolution.

Conformational changes, excess area, and elasticity of the Piezo protein-membrane nanodome from coarse-grained and atomistic simulations

thomas.weikl@mpikg.mpg.de (Frank Noé) — Wed, 24 Sep 2025 00:00:00 +0000

The mechanosensitive ion channels Piezo 1 and 2 induce a curved protein-membrane nanodome that flattens with increasing membrane tension γ. The tension-induced flattening of the nanodome is associated with Piezo activation and driven by the energy γΔA where ΔA is the excess area of the curved nanodome relative to its planar projected area. Based on extensive coarse-grained and atomistic simulations of membrane-embedded Piezo 1 and 2 proteins, we report here an excess area ΔA for the Piezo protein-membrane nanodome of about 40 nm² in tensionless membranes, and a half-maximal reduction of ΔA at tension values of about 3–4 mN/m, which is within the range of experimentally determined values for the half-maximal activation of Piezo 1. In line with recent experimental investigations of Piezo proteins in cell membranes and membrane vesicles, the membrane-embedded Piezo proteins adopt conformations in our simulations that are significantly less curved than the protein conformation in the detergent micelles of cryo-EM structures. An elasticity analysis of the nanodome shapes and protein conformations obtained from our simulations leads to an elastic model for Piezo activation that distinguishes the different energy components of the protein and the membrane in the tension-induced flattening of the nanodome. According to this model, the Piezo proteins resist flattening with a force constant of about 60 pN/nm.

Capturing enzymes in motion

akendrick@salk.edu (Agnieszka A Kendrick) — Wed, 24 Sep 2025 00:00:00 +0000

A combination of cryogenic electron microscopy and molecular simulations has been used to study the structure and dynamics of an enzyme called ACE.

Online reinforcement learning of state representation in recurrent network supported by the power of random feedback and biological constraints

morita@p.u-tokyo.ac.jp (Arvind Kumar) — Wed, 24 Sep 2025 00:00:00 +0000

Representation of external and internal states in the brain plays a critical role in enabling suitable behavior. Recent studies suggest that state representation and state value can be simultaneously learned through Temporal-Difference-Reinforcement-Learning (TDRL) and Backpropagation-Through-Time (BPTT) in recurrent neural networks (RNNs) and their readout. However, neural implementation of such learning remains unclear as BPTT requires offline update using transported downstream weights, which is suggested to be biologically implausible. We demonstrate that simple online training of RNNs using TD reward prediction error and random feedback, without additional memory or eligibility trace, can still learn the structure of tasks with cue–reward delay and timing variability. This is because TD learning itself is a solution for temporal credit assignment, and feedback alignment, a mechanism originally proposed for supervised learning, enables gradient approximation without weight transport. Furthermore, we show that biologically constraining downstream weights and random feedback to be non-negative not only preserves learning but may even enhance it because the non-negative constraint ensures loose alignment—allowing the downstream and feedback weights to roughly align from the beginning. These results provide insights into the neural mechanisms underlying the learning of state representation and value, highlighting the potential of random feedback and biological constraints.

Ubiquitination-activated TAB–TAK1–IKK–NF-κB axis modulates gene expression for cell survival in the lysosomal damage response

endo-ak@igakuken.or.jp (Akinori Endo) — Wed, 24 Sep 2025 00:00:00 +0000

The lysosomal damage response is important for the maintenance of cellular homeostasis in human cells. Although the mechanisms underlying the repair and autophagic elimination of damaged lysosomes have been elucidated, the early signal transduction pathways and genes induced in response to lysosomal damage remain elusive. We performed transcriptome and proteome analyses and found that the TAB–TAK1–IKK–NF-κB axis is activated by K63-linked ubiquitin chains that accumulate on damaged lysosomes. This activates the expression of various transcription factors and cytokines that promote anti-apoptosis and intercellular signaling. The findings highlight the crucial role of ubiquitin-regulated signal transduction and gene expression in cell survival and cell–cell communication in response to lysosomal damage. The results suggest that the ubiquitin system is not only involved in the removal of damaged lysosomes by lysophagy, but also functions in the activation of cellular signaling for cell survival.

Restoration of locomotor function following stimulation of the A13 region in Parkinson’s mouse models

whelan@ucalgary.ca (Adam Lognon) — Tue, 23 Sep 2025 00:00:00 +0000

Parkinson’s disease (PD) is characterized by extensive motor and non-motor dysfunction, including gait disturbance, which is difficult to treat effectively. This study explores the therapeutic potential of targeting the A13 region, a heterogeneous region of the medial zona incerta (mZI) containing dopaminergic, GABAergic, and glutamatergic neurons that has shown relative preservation in PD models. The A13 is identified to project to the mesencephalic locomotor region, with a subpopulation of cells displaying activity correlating to movement speed, suggesting its role in locomotion. We show that photoactivation of this A13 region can alleviate bradykinesia and akinetic features, while increasing turning in a mouse model of PD. These effects combine disease-specific rescue of function with a possible gain of function. We identified areas of preservation and plasticity within the A13 region using whole-brain imaging. Our findings suggest a global remodeling of afferent and efferent projections of the A13 region, highlighting the zona incerta’s role as a crucial hub for the rapid selection of motor function. The study unveils the significant pro-locomotor effects of the A13 region and suggests its promising potential as a therapeutic target for PD-related gait dysfunction.

SARS-CoV-2 NSP13 interacts with TEAD to suppress Hippo-YAP signaling

jfmartin@bcm.edu (Bing Xie) — Tue, 23 Sep 2025 00:00:00 +0000

The Hippo pathway controls organ development, homeostasis, and regeneration primarily by modulating YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it is largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and SARS-CoV-2-infected human lung samples, and observed a decrease in YAP target gene expression. In screening SARS-CoV-2 nonstructural proteins, we found that nonstructural protein 13 (NSP13), a conserved coronavirus helicase, inhibits YAP transcriptional activity independent of the upstream Hippo kinases LATS1/2. Consistently, introducing NSP13 into mouse cardiomyocytes suppresses an active form of YAP (YAP5SA) in vivo. Subsequent investigations on NSP13 mutants revealed that NSP13 helicase activity, including DNA binding and unwinding, is crucial for suppressing YAP transactivation in HEK293T cells. Mechanistically, TEAD4 serves as a platform to recruit NSP13 and YAP. NSP13 likely inactivates the YAP/TEAD4 transcription complex by remodeling chromatin to recruit proteins, such as transcription termination factor 2 (TTF2), to bind the YAP/TEAD/NSP13 complex. These findings reveal a novel YAP/TEAD regulatory mechanism and uncover molecular insights into Hippo-YAP regulation after SARS-CoV-2 infection in humans.

Oxytocin restores context-specific hyperaltruistic preference

niyinmei@pku.edu.cn (Hong Zhang) — Tue, 23 Sep 2025 00:00:00 +0000

Recent advances in moral decision-making research show people are hyperaltruistic by being more willing to sacrifice monetary gains to spare others from suffering than to spare themselves. Yet other studies indicate an opposite egoistic bias: subjects are less willing to harm themselves for others’ benefits than for their own. These results underscore the complexities of moral decisions and demand a mechanistic explanation for hyperaltruistic preferences. We investigated hyperaltruism using trade-off choices combining monetary gains and painful electric shocks and choices combining monetary losses and shocks. Study 1 revealed that switching the decision context from gains to losses effectively eliminated the hyperaltruistic preference, accompanied by the altered relationship between subjects’ instrumental harm (IH) trait attitudes and relative pain sensitivities. In the pre-registered study 2, we found that oxytocin, a neuropeptide linked to parochial altruism, restored the context-dependent hyperaltruistic preference. Furthermore, oxytocin increased the degree to which subjects framed the task as harming others, which mediated the correlation between IH and relative pain sensitivities. Thus, the loss decision context and oxytocin diminished and restored the mediation effect of subjective harm framing, respectively. Our results help elucidate the psychological processes underpinning the contextual specificity of hyperaltruism and carry implications in promoting prosocial interactions.

Sulfation affects apical extracellular matrix organization during development of the Drosophila embryonic salivary gland tube

seyeonchung@lsu.edu (Jeffrey Matthew) — Tue, 23 Sep 2025 00:00:00 +0000

The apical extracellular matrix (aECM) plays a critical role in epithelial tube morphogenesis during organ formation, but its composition and organization remain poorly understood. Using the Drosophila embryonic salivary gland (SG) as a model, we identify Papss, an enzyme that synthesizes the universal sulfate donor PAPS, as a critical regulator of tube lumen expansion. Papss mutants show a disorganized apical membrane, condensed aECM, and disruptions in Golgi structures and intracellular trafficking. SG-specific expression of wild-type Papss, but not the catalytically inactive form, rescues the defects in Papss mutants, suggesting that defects in sulfation are the underlying cause of the phenotypes. Additionally, we identify two zona pellucida (ZP) domain proteins, Piopio (Pio), and Dumpy (Dpy), as key components of the SG aECM. In the absence of Papss, Pio is gradually lost in the aECM, while the Dpy-positive aECM structure is condensed and dissociates from the apical membrane, leading to a thin lumen. Mutations in dpy or pio, or in Notopleural, which encodes a matriptase that cleaves Pio to form the luminal Pio pool, result in a SG lumen with alternating bulges and constrictions, with the loss of pio leading to the loss of Dpy in the lumen. Our findings underscore the essential role of sulfation in organizing the aECM during tubular organ formation and highlight the mechanical support provided by ZP domain proteins in maintaining luminal diameter.

Hierarchical encoding of natural sound mixtures in ferret auditory cortex

agnes.landemard@hotmail.fr (Agnès Landemard) — Tue, 23 Sep 2025 00:00:00 +0000

Extracting relevant auditory signals from complex natural scenes is a fundamental challenge for the auditory system. Sounds from multiple sources overlap in time and frequency. In particular, dynamic ‘foreground’ sounds are often masked by more stationary ‘background’ sounds. Human auditory cortex exhibits a hierarchical organization where background-invariant representations are progressively enhanced along the processing stream, from primary to non-primary regions. However, we do not know whether this organizational principle is conserved across species and which neural mechanisms drive this invariance. To address these questions, we investigated background invariance in ferret auditory cortex using functional ultrasound imaging, which enables large-scale, high-resolution recordings of hemodynamic responses. We measured responses across primary, secondary, and tertiary auditory cortical regions as ferrets passively listened to mixtures of natural sounds and their components in isolation. We found a hierarchical gradient of background invariance, mirroring findings in humans: responses in primary auditory cortex reflected contributions from both foreground and background sounds, while background invariance increased in higher-order auditory regions. Using a spectrotemporal filter-bank model, we found that in ferrets this hierarchical structure could be largely explained by tuning to low-order acoustic features. However, this model failed to fully account for background invariance in human non-primary auditory cortex, suggesting that additional, higher-order mechanisms are crucial for background segregation in humans.

Multiphase separation in postsynaptic density regulated by membrane geometry via interaction valency and volume

takada@biophys.kyoto-u.ac.jp (Giovanni B Brandani) — Tue, 23 Sep 2025 00:00:00 +0000

Biomolecular condensates are found at various cellular locations, nucleus, cytoplasm, and membrane. These condensates often contain multiple components and can separate into multiple phases with various morphologies such as core-shell droplets, implicating functional roles. Demixing and arrangements of condensates are determined by competitive interactions and their locations. Recent studies reported a puzzling multiphase morphology in postsynaptic density components: AMPA receptor, NMDA receptor, PSD-95, and CaMKII. The multiphase morphology appears reversed when transitioning from the solution to the membrane. Using this system as a model, we study the multiphase behavior of condensates in solution (3D) and domain formation on and beneath the membrane (2D) and elucidate molecular mechanisms behind the puzzle. Our simulations reproduce the core-shell structure in 3D in vitro solution, where AMPA-receptor/PSD-95 form the core and NMDA-receptor/CaMKII form the shell, triggered by CaMKII activation. Then, we obtain a reversed morphology on the membrane. This reversal is primarily driven by CaMKII’s high valency and large volume. We find that, in solution, CaMKII’s non-specific volume interaction dominates, while on the membrane, specific multivalent interactions overcome the excluded volume interaction of CaMKII. The layered structures of receptors and CaMKIIs reduce the excluded volume effects of CaMKII on receptors, making the multivalent interaction dominant. These findings highlight the differences between condensate formation in solution and membrane domain formation, modulated by their layered arrangement.

Strip cropping shows promising increases in ground beetle community diversity compared to monocultures

luuk.croijmans@wur.nl (Dirk F van Apeldoorn) — Tue, 23 Sep 2025 00:00:00 +0000

Global biodiversity is declining at an unprecedented rate, with agriculture as one of the major drivers. There is mounting evidence that intercropping can increase insect biodiversity while maintaining or increasing yield. Yet, intercropping is often considered impractical for mechanized farming systems. Strip cropping is a type of intercropping that is compatible with standard farm machinery and has been pioneered by Dutch farmers since 2014. Here, we present ground beetle data from four organically managed experimental farms across four years. Ground beetles are sensitive to changes in habitats and disturbances, and hold keystone positions in agroecosystem food webs. We show that strip cropping systems can enhance ground beetle biodiversity, while other studies showed that these increases have been achieved without incurring major yield loss. Strip-cropped fields had on average 15% more ground beetle species and 30% more individuals than monocultural fields. The higher ground beetle richness in strip crops was explained by the merger of crop-related ground beetle communities, rather than by ground beetle species unique to strip cropping systems. The increase in field-level beetle species richness in organic agriculture through strip cropping approached increases found for other readily deployed biodiversity conservation methods, like shifting from conventional to organic agriculture (+19% –+23%). This indicates that strip cropping is a potentially useful tool supporting ground beetle biodiversity in agricultural fields without compromising food production.

Rab10 inactivation promotes AMPAR trafficking and spine enlargement during long-term potentiation

ryohei.yasuda@mpfi.org (Elwy Okaz) — Tue, 23 Sep 2025 00:00:00 +0000

Rab-dependent membrane trafficking is critical for changing the structure and function of dendritic spines during synaptic plasticity. Here, we developed highly sensitive sensors to monitor Rab protein activity in single dendritic spines undergoing structural long-term potentiation (sLTP) in rodent organotypic hippocampal slices. During sLTP, Rab10 was persistently inactivated (>30 min) in the stimulated spines, whereas Rab4 was transiently activated over ~5 min. Inhibiting or deleting Rab10 enhanced sLTP, electrophysiological LTP, and AMPA receptor (AMPAR) trafficking during sLTP. In contrast, disrupting Rab4 impaired sLTP only in the first few minutes and decreased AMPAR trafficking during sLTP. Thus, our results suggest that Rab10 and Rab4 oppositely regulate AMPAR trafficking during sLTP, and inactivation of Rab10 signaling facilitates the induction of LTP and associated spine structural plasticity.

Neural dynamics of reversal learning in the prefrontal cortex and recurrent neural networks

chrismkkim@gmail.com (Bruno B Averbeck) — Tue, 23 Sep 2025 00:00:00 +0000

In probabilistic reversal learning, the choice option yielding reward with higher probability switches at a random trial. To perform optimally in this task, one has to accumulate evidence across trials to infer the probability that a reversal has occurred. We investigated how this reversal probability is represented in cortical neurons by analyzing the neural activity in the prefrontal cortex of monkeys and recurrent neural networks trained on the task. We found that in a neural subspace encoding reversal probability, its activity represented integration of reward outcomes as in a line attractor model. The reversal probability activity at the start of a trial was stationary, stable, and consistent with the attractor dynamics. However, during the trial, the activity was associated with task-related behavior and became non-stationary, thus deviating from the line attractor. Fitting a predictive model to neural data showed that the stationary state at the trial start serves as an initial condition for launching the non-stationary activity. This suggested an extension of the line attractor model with behavior-induced non-stationary dynamics. The non-stationary trajectories were separable indicating that they can represent distinct probabilistic values. Perturbing the reversal probability activity in the recurrent neural networks biased choice outcomes demonstrating its functional significance. In sum, our results show that cortical networks encode reversal probability in stable stationary state at the start of a trial and utilize it to initiate non-stationary dynamics that accommodates task-related behavior while maintaining the reversal information.

The increase in cell volume and nuclear number of the koji-fungus Aspergillus oryzae contributes to its high enzyme productivity

takeshita.norio.gf@u.tsukuba.ac.jp (Ayaka Itani) — Tue, 23 Sep 2025 00:00:00 +0000

While the ratio of nuclei to cell volume is well regulated, it remains largely unexplored in multinucleate organisms. The koji-fungus Aspergillus oryzae, traditionally used in Japanese brewing and fermentation for over a thousand years, is now widely utilized in modern biotechnology as a host for enzyme production. We discovered that, over time in culture, hyphae become thicker, resulting in a tenfold increase in cell volume, and the number of nuclei in hyphal cells also increases tenfold, exceeding 200. The increase in cell volume and nuclear number is unique among the investigated Aspergillus species and correlates with its high enzyme production capabilities. Since nuclear number and cell volume are correlated, both must increase simultaneously for either to expand. Our analyses identified genetic factors and nutritional environmental signals involved in each of these increases. Increases in nuclear number and cell volume were also observed in other fungi bred for industrial use. This study not only deepens our understanding of the evolutionary processes that promote high enzyme productivity through fungal breeding, but also provides insights into the molecular mechanisms regulating cell volume and nuclear number in multinucleate organisms.

Identification of type 2 diabetes- and obesity-associated human β-cells using deep transfer learning

johnstrs@iu.edu (Alex M Mawla) — Mon, 22 Sep 2025 00:00:00 +0000

Diabetes affects >10% of adults worldwide and is caused by impaired production or response to insulin, resulting in chronic hyperglycemia. Pancreatic islet β-cells are the sole source of endogenous insulin, and our understanding of β-cell dysfunction and death in type 2 diabetes (T2D) is incomplete. Single-cell RNA-seq data supports heterogeneity as an important factor in β-cell function and survival. However, it is difficult to identify which β-cell phenotypes are critical for T2D etiology and progression. Our goal was to prioritize specific disease-related β-cell subpopulations to better understand T2D pathogenesis and identify relevant genes for targeted therapeutics. To address this, we applied a deep transfer learning tool, DEGAS, which maps disease associations onto single-cell RNA-seq data from bulk expression data. Independent runs of DEGAS using T2D or obesity status identified distinct β-cell subpopulations. A singular cluster of T2D-associated β-cells was identified; however, β-cells with high obese-DEGAS scores contained two subpopulations derived largely from either non-diabetic (ND) or T2D donors. The obesity-associated ND cells were enriched for translation and unfolded protein response genes compared to T2D cells. We selected CDKN1C and DLK1 for validation by immunostaining in human pancreas sections from healthy and T2D donors. Both CDKN1C and DLK1 were heterogeneously expressed among β-cells. CDKN1C was increased in β-cells from T2D donors, in agreement with the DEGAS predictions, while DLK1 appeared depleted from T2D islets of some donors. In conclusion, DEGAS has the potential to advance our holistic understanding of the β-cell transcriptomic phenotypes, including features that distinguish β-cells in obese ND or lean T2D states. Future work will expand this approach to additional human islet omics datasets to reveal the complex multicellular interactions driving T2D.

My grandmother’s rug

marder@brandeis.edu (Eve Marder) — Mon, 22 Sep 2025 00:00:00 +0000

The objects that migrants carry with them are tethers to the lives they have left behind.

A SHERLOCK toolbox for eco-epidemiological surveillance of African trypanosomes in domestic pigs from Western Africa

lucy.glover@pasteur.fr (Abdoulaye Dansy Camara) — Mon, 22 Sep 2025 00:00:00 +0000

Animal African trypanosomosis (AAT), caused by protist parasites of the genus Trypanosoma, puts upward of a million head of livestock at risk across 37 countries in Africa. The economic impact of AAT and the presence of human-infectious trypanosomes in animals place a clear importance on improving diagnostics for animal trypanosomes to map the distribution of the veterinary parasites and identify reservoirs of human-infectious trypanosomes. We have adapted the CRISPR-based detection toolkit SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) for trypanosomatid parasites responsible for AAT (SHERLOCK4AAT) including Pan-trypanosomatid, Trypanozoon, T. vivax, T. congolense, T. theileri, T. simiae, and T. suis assays. To test the applicability of this technique in the field, we analysed dried blood spots collected from 200 farm and 224 free-ranging pigs in endemic and historical human African trypanosomiasis foci in Guinea and Côte d’Ivoire, respectively. The results revealed that SHERLOCK4AAT can detect and discriminate between trypanosome species involved in multiple infections with a high sensitivity. 62.7% [58.1, 67.3] of pigs were found infected with at least one trypanosome species. T. brucei gambiense, a human-infectious trypanosome, was found in one animal at both sites, highlighting the risk that these animals may act as persistent reservoirs. These data suggest that, due to their proximity to humans and their attractiveness to tsetse flies, pigs could act as sentinels to monitor T. b. gambiense circulation using the SHERLOCK4AAT toolbox.