eLife: latest articles

Organization of circuits linking descending input to motor output in the Drosophila Male Adult Nerve Cord connectome

jefferis@mrc-lmb.cam.ac.uk (Andrew S Champion) — Mon, 20 Jul 2026 00:00:00 +0000

In most animals, a small number of descending neurons (DNs) connect the brain to circuits and motor neurons (MNs) in the nerve cord. To understand how brain signals generate behavior, it is critical to understand the organization of the neural pathways linking DNs to MNs. In companion papers, we introduced a densely reconstructed connectome of the Drosophila Male Adult Nerve Cord (MANC; Takemura et al., 2024), including cell types and developmental lineages (Marin et al., 2024), which provides complete connectivity of the ventral nerve cord (VNC) at synaptic resolution. Here, we present a first look at the organization of the networks connecting DNs to MNs. We first proofread and curated all DNs and MNs, then systematically matched their morphology to light microscopy data. We report both broad organizational patterns of the entire network and fine-scale analysis of selected circuits of interest. We discover that direct DN-MN connections are infrequent and identify neuron communities putatively linked to control of different motor systems, including walking, flight steering and power generation, and coordinated action of wings and legs. Our analyses generate hypotheses for future functional experiments and empowers others to investigate these and other circuits of the VNC in richer mechanistic detail.

DuoHexaBody-CD37 induces direct cytotoxic signaling in diffuse large B-cell lymphoma

Annemiek.vanSpriel@radboudumc.nl (Annemiek B van Spriel) — Mon, 20 Jul 2026 00:00:00 +0000

Diffuse large B-cell lymphoma (DLBCL) is a common aggressive form of non-Hodgkin lymphoma. Tetraspanin CD37 is highly expressed on mature B cells and being studied as a therapeutic target for NHL, including DLBCL. DuoHexaBody-CD37 is a biparatopic antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes shown to promote complement-dependent cytotoxicity. However, the impact of DuoHexaBody-CD37 on direct cytotoxic signaling has not yet been studied. Here, we demonstrate that DuoHexaBody-CD37 induces direct cytotoxicity in DLBCL-derived tumor cell lines independent of the subtype. DuoHexaBody-CD37 induced significant CD37 clustering and was retained at the cell surface in contrast to rituximab, which was internalized. Unbiased screening identified the modulation of 26 (phospho)proteins upon DuoHexaBody-CD37 treatment of primary B cells or DLBCL cells. Whereas DLBCL cells predominantly upregulated p-SHP1(Y564) upon DuoHexaBody-CD37 treatment, primary B cells showed significantly increased p-AKT(S473) and MAPK signaling which is linked to cell survival. Studies using CD37-mutants identified the N-terminus to be involved in DuoHexaBody-CD37-induced signaling. Finally, DuoHexaBody-CD37 treatment inhibited cytokine pro-survival signaling in DLBCL cells. These findings provide novel insights into the signaling functions of CD37 upon DuoHexaBody-CD37 treatment, and open up opportunities for developing CD37-targeted immunotherapy in combination with small molecule inhibitors to maximize tumor cell death.

Enhanced processivity and collective force production of kinesin-1 at low radial forces

yildiz@berkeley.edu (Ahmet Yildiz) — Mon, 20 Jul 2026 00:00:00 +0000

Kinesin-1 is a robust motor that carries intracellular cargos toward the plus ends of microtubules. However, optical trapping studies reported that kinesin-1 is a slippery motor that quickly detaches from the microtubule, and multiple kinesins are incapable of teaming up to generate large collective forces. This may be due to the vertical (z) forces that the motor experiences in a single bead trapping assay, accelerating the detachment of the motor from a microtubule. Here, we substantially lowered the z-force by using a long DNA handle between the motor and the trapped bead and characterized the motility and force generation of single and multiple human kinesin-1 motors in vitro. Contrary to previous views, we show that kinesin-1 is a robust motor that resists microtubule detachment before it reaches high hindering forces, but it quickly detaches under assisting forces even at low z-forces. We also demonstrate highly efficient collective force generation by multiple kinesin-1 motors. These results provide an explanation for how multiple kinesins team up to perform cellular functions that require higher forces than a single motor can bear.

Neural categorization of visual words of alphabetic and non-alphabetic languages

shan@pku.edu.cn (Guo Zheng) — Mon, 20 Jul 2026 00:00:00 +0000

Languages provide social-category markers that tag people as one or another social group. How does the brain sort words into different language categories as a basis of the social-categorization function of language? The current work addressed this issue by testing neural categorization of visual words of different writing systems in nine studies using electroencephalography, magnetoencephalography, and a repetition suppression paradigm. This work showed that a neural network, including the anterior temporal, insular, orbital frontal, and ventral occipito-temporal cortices in both hemispheres, was engaged in computations of correlation distances between two words to represent intra-language similarity and inter-language difference during categorization of visual words of alphabetic and non-alphabetic languages. These processes occurred as early as 150 ms post-stimulus, recruited within-hemisphere functional connections, operated independently of words’ semantic meanings and pronunciations, and exhibited consistently across individuals with diverse language backgrounds. These findings highlight the neural mechanisms of language-based spontaneous neural categorization of visual words as a basis of the social-categorization function of language.

Serotonergic modulation of motor subspace dynamics drives a sleep-independent quiescent state

ymchai@ustc.edu.cn (Daguang Li) — Mon, 20 Jul 2026 00:00:00 +0000

The dorsal raphe nucleus (DRN) serotonergic (5-HT) system has been implicated in regulating sleep and motor control; however, its specific role remains controversial. In this study, we found that optogenetic activation of DRN 5-HT neurons in larval zebrafish induced a quiescent state and a reduced response to acoustic stimuli. Unlike sleep, the induced quiescent state was not accompanied by a loss of postural control, and nighttime activation of DRN 5-HT neurons led to a subsequent sleep rebound. Whole brain light field imaging combined with demixed principal component analysis (dPCA) revealed distinct neural subspaces related to DRN activation, sound responses, and motor activity. DRN 5-HT activation selectively modulated the motor-related subspace while leaving the sound-evoked subspace unaffected. Unlike DRN activation, sleep induced by mepyramine significantly altered sound-evoked neuronal activity patterns. Further analysis demonstrated that serotonin had a graded effect on the motor subspace, wherein downstream neurons responsible for particular bout types were more significantly influenced. Embedding motor population activity in a curved geometric space revealed that the degree of curvature scales with behavioral suppression across animals, providing a quantitative signature of the quiescent state. Together, these results elucidate that serotonergic modulation promotes behavioral quiescence through selective regulation of motor populations.

The view tolerance of human identity recognition depends on horizontal face information

valerie.goffaux@uclouvain.be (Alexia Roux-Sibilon) — Mon, 20 Jul 2026 00:00:00 +0000

This study investigates which visual information enables humans to recognize facial identity across different viewpoints, a key unresolved question in vision science. Participants completed an identity recognition task using faces rotated across a range of yaw angles and filtered to retain specific orientation ranges of visual information. Regardless of viewpoint, human performance consistently relied on horizontal facial information. To understand why, we used model observers to assess the identity information physically available in the images. A view-selective model, which matched identities within the same viewpoint, indicated that diagnostic identity cues shift from predominantly horizontal in frontal views to more vertical in profile views. In contrast, a view-tolerant model, which matched identities across different viewpoints, revealed that horizontal information provides the most stable and reliable identity cues across views. Furthermore, horizontal facial information best predicted the average appearance of a face across viewpoints, supporting its role in forming stable identity representations. These findings suggest that view-tolerant face representations are acquired through exposure to the stable statistical properties of faces primarily conveyed by horizontal information. By specifying the spatial information underlying recognition across viewpoints, the study offers valuable empirical constraints for the development of theoretical and computational models of face recognition.

Paternal over- and under-nutrition programme fetal and placental development in a sex-specific manner in mice

a.watkins@sheffield.ac.uk (A Augusto Coppi) — Mon, 20 Jul 2026 00:00:00 +0000

The association between sub-optimal paternal diet and offspring well-being is becoming established. However, the underlying mechanisms are yet to be fully defined. The aim of this study was to establish the impact of over- and under-nutrition, with or without macronutrient supplementation, on male reproductive fitness and post-fertilisation development. Male C57BL/6J mice were fed either control diet (CD), isocaloric low-protein diet (LPD), high-fat/sugar ‘Western’ diet (WD), or LPD or WD supplemented with methyl donors and carriers (MD-LPD or MD-WD, respectively) for 8 weeks before mating with virgin C57/BL6J females. Placental tissue was collected at embryonic day (E)8.5 to assess early placental (ectoplacental cone) morphology and metabolism and E17.5 for sex-specific transcriptomic profiling. Post-mating, stud male tissues were harvested for the assessment of testicular morphology and gene expression, gut microbiota composition, and metabolic status. WD and MD-WD males displayed increased adiposity, hepatic cholesterol and free fatty acids, and gut microbiota dysbiosis when compared to CD-fed males. In the testes, WD and MD-WD perturbed the expression of genes associated with metabolism and transcription regulation. Additionally, we observed differential expression of multiple genes within the Wnt signalling pathway, central in the regulation of cellular proliferation, migration, survival, and cell fate determination during development. Despite no impact on fundamental male fertility, significant changes in ectoplacental cone metabolism, fetal growth, and placental gene expression were observed in response to specific dietary regimens. Interestingly, while CD male and female placentas displayed 301 genome-wide, sexually dimorphic genes, LPD, MD-LPD, WD, and MD-WD male and female placentas possessed only 13, 0, 14, and 15 sexually dimorphic genes, respectively. Our data show that while sub-optimal paternal diet has minimal impact on male fertility, fetal and placental development are perturbed in a sex-specific manner.

FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall

wayne.sossin@mcgill.ca (Jewel T-Y Li) — Mon, 20 Jul 2026 00:00:00 +0000

Local protein synthesis is a crucial process that maintains local proteostasis in neurons. A large percentage of mRNAs translated in developing neurons are associated with stalled ribosomes. FMRP, the protein lost in Fragile X syndrome, is highly enriched in RNA granules that contain stalled ribosomes. Previous examination of ribosome-protected fragments (RPFs) from stalled neuronal ribosomes identified sequences that match those found in mRNAs associated with FMRP. To investigate whether FMRP recognition of these sequences is important for determining where ribosomes stall on mRNAs, we examined RPFs isolated from P5 mice of both sexes that lack the FMRP protein. The loss of FMRP had no significant effect on the proteins associated with neuronal stalled ribosomes, on ribosome structure, or the stalling sites (locations where RPFs accumulated). There was a small, but significant decrease in the number of RPFs from mRNAs previously shown to be associated with FMRP by CLIP. Additionally, the number of neuronal RNA granules containing stalled ribosomes, as assayed by ribopuromycylation, decreased. These results suggest a role of FMRP in neuronal RNA granules that contain stalled ribosomes, though loss of FMRP does not influence where ribosomes are stalled or the formation of stalled ribosome.

Serial dependence predicts generalization in perceptual learning

yoram.bonneh@gmail.com (Dov Sagi) — Mon, 20 Jul 2026 00:00:00 +0000

Visual perception is shaped by recent experience, but how these momentary influences accumulate to support long-term learning and generalization remains unclear. Here, we asked whether short-term memory traces, namely attractive serial-dependence effects (SDEs), promote learning generalization. We reanalyzed over 200,000 trials from observers trained on a visual texture-discrimination task under three conditions that differentially modulated generalization. Under certain conditions, SDEs reached further back in time than previously reported and persisted after eight days of practice, despite the non-informative nature of past stimuli. Observers in conditions previously shown to support generalization displayed larger long-range SDEs, and individual SDE magnitude predicted transfer of learning across locations. We propose that SDE is associated with learning flexibility, providing a principled framework for when and why perceptual learning generalizes, which is central to theories of cognitive flexibility. Attractive serial dependence is not an extra mechanism in this model—it is the behavioral footprint of ongoing template plasticity required for flexibility in changing environments.

RNA selectively modulates activity of virulent amyloid PSMα3 and host-defense LL-37 via phase separation and aggregation dynamics

meytal.landau@desy.de (Alexander Kai Buell) — Mon, 20 Jul 2026 00:00:00 +0000

Amyloid-forming peptides are increasingly recognized as dynamic regulators at the host–pathogen interface, yet how environmental factors control their assembly and activity remains poorly understood. Here, RNA acts as a concentration-dependent regulator of two sequence-related α-helical peptides with fundamentally different assembly behaviors: the cross-α amyloid-forming Staphylococcus aureus virulence factor PSMα3 and the non-amyloidogenic human host-defense peptide LL-37. RNA drives PSMα3 through distinct assembly states, from liquid-like condensates to fibrillar polymorphs, while preserving cytotoxic and antimicrobial activity over time. In contrast, RNA attenuates LL-37 cytotoxicity toward host cells while maintaining antibacterial activity, consistent with a host-protective immunomodulatory effect. Together with the opposing effects of epigallocatechin gallate, which redirects both peptides into amorphous assemblies, these findings support a mechanistic model in which biological activity is governed by supramolecular architecture, assembly trajectory, and dynamics rather than by monomer abundance or mature fibrils alone. More broadly, our findings identify RNA as an environmental regulator of α-helical peptide assemblies, and establish assembly-state control as a tunable determinant of virulence and host defense.

Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells

volker_soltys@eva.mpg.de (Dingwen Su) — Mon, 20 Jul 2026 00:00:00 +0000

Gene regulation underpins development and is an intricate biological process involving transcription, typically at promoters within accessible chromatin. To understand cell-type-specific regulatory networks, the ability to capture both transcription and chromatin accessibility simultaneously is crucial. However, joint measurements are technically challenging and current methodologies still face adoption challenges. Here, we present easySHARE-seq, an improvement on SHARE-seq for the simultaneous measurement of ATAC- and RNA-seq in single cells. We address several limitations of the previous method by improving the barcode and streamlining the protocol. As a result, easySHARE-seq libraries have a usable sequence of up to 300 bp (+200 bp increase), making it suitable for, e.g., investigation of allele-specific signals or variant discovery. Furthermore, easySHARE-seq libraries do not require a dedicated sequencing run thus saving costs. We applied easySHARE-seq to murine liver nuclei and recovered 19,664 nuclei with joint chromatin and expression profiles. By benchmarking against other combinatorial indexing-based techniques, we showed that we can recover over 1.5-fold more transcripts per cell while retaining high scalability and low cost. To showcase our method, we identified cell types, exploited the multiomic measurements to link cis-regulatory elements to their target genes and investigated liver-specific micro-scale changes. We conclude that easySHARE-seq improves upon previous methods and can produce high-quality multiomic datasets. We expect it to be applicable to a wide range of study designs.

Cluster size determines internal structure of transcription factories in human cells

gnegro2@ed.ac.uk (Antonio Suma) — Mon, 20 Jul 2026 00:00:00 +0000

Transcription is a fundamental cellular process and the first step of gene expression. In human cells, it depends on the binding to chromatin of various proteins, including RNA polymerases and numerous transcription factors (TFs). Observations indicate that these proteins tend to form macromolecular clusters, known as transcription factories, whose morphology and composition are still debated. While some microscopy experiments have revealed the presence of specialised factories, composed of similar TFs transcribing families of related genes, sequencing experiments suggest instead that mixed clusters may be prevalent, as a panoply of different TFs binds promiscuously to the same chromatin region. The mechanisms underlying the formation of specialised or mixed factories remain elusive. With the aim of finding such mechanisms, here we develop a chromatin polymer model mimicking the chromatin binding-unbinding dynamics of different types of complexes of TFs. Surprisingly, both specialised (i.e. demixed) and mixed clusters spontaneously emerge, and which of the two types forms depends mainly on cluster size. The mechanism promoting mixing is the presence of non-specific interactions between chromatin and proteins, which become increasingly important as clusters become larger. This result, that we observe both in simple polymer models and more realistic ones for human chromosomes, reconciles the apparently contrasting experimental results obtained. Additionally, we show how the introduction of different types of TFs strongly affects the emergence of transcriptional networks, providing a pathway to investigate transcriptional changes following gene editing or naturally occurring mutations.

DNA tensiometer reveals catch-bond detachment kinetics of kinesin-1, -2, and -3

woh1@psu.edu (Crystal R Noell) — Mon, 20 Jul 2026 00:00:00 +0000

Bidirectional cargo transport by kinesin and dynein is essential for cell viability, and defects are linked to neurodegenerative disease. Computational models predict that load-dependent motor detachment strongly determines the outcome of kinesin–dynein tug-of-war, with kinesin-3 and kinesin-2 more load-sensitive than kinesin-1. Yet reconstituted assays show that all three kinesin families compete similarly well against dynein. Previous work demonstrated that vertical forces from optical trapping assays can enhance kinesin-1 dissociation, suggesting that motor behavior may depend strongly on cargo geometry. To measure kinesin detachment and reattachment kinetics under forces applied parallel to the microtubule, we developed a DNA-based tensiometer using an entropic DNA spring linking motors to microtubules. For kinesin-1, –2, and –3, dissociation rates at stall were slower than during unloaded motion, and reattachment kinetics were consistent with a weakly bound slip state preceding detachment. Kinesin-3 behavior further suggested that long KIF1A run lengths arise from multiple short runs connected by diffusive episodes. Stochastic simulations reproduced the measured load-dependent kinetics and enabled direct comparison of transition rates among kinesin families. These results provide insight into how kinesin-1, –2, and –3 transport cargo in complex cellular geometries and compete against dynein during bidirectional transport.

The two faces of JAK-STAT

yingyi_zhang@tju.edu.cn (Qianying Lu) — Thu, 16 Jul 2026 00:00:00 +0000

A signal that can help breast cancer cells grow may also increase immune responses and boost immune therapy.

The effect of physical activity on brain structure and cognitive function in the population-based cohort of LIFE-Adult Study

polona.kalc@med.uni-jena.de (Andrea Zülke) — Wed, 15 Jul 2026 00:00:00 +0000

Physical activity is believed to positively influence brain health and cognition and is considered a modifiable lifestyle factor that may protect against cognitive decline and neurodegeneration. In this observational study, we investigated the cross-sectional and longitudinal effects of self-reported total and moderate-to-vigorous physical activity on cognitive scores on the Trail Making Test (TMT-A and TMT-B), hippocampal volume, and Brain Age Gap Estimate (BrainAGE) in a large population-based cohort from the LIFE-Adult Study (n=2576). Furthermore, we examined the effect of objectively measured physical activity on brain structure in a subgroup with available accelerometry data (n=227). Multiple linear regression analyses did not show any positive effects of self-reported or objectively measured physical activity on hippocampal volume or processing speed and executive function. Longitudinal path analyses suggested a potential for reverse causation, where a higher BrainAGE at baseline was associated with lower physical capacity at follow-up. Additionally, we observed an age-related bias in the self-reporting of physical activity, indicating that older individuals tend to overestimate their level of activity. Future interventions targeting middle-aged adults may be necessary to raise awareness of potential misperception and encourage increased physical activity.

Correction: Control of Arabidopsis shoot stem cell homeostasis by two antagonistic CLE peptide signalling pathways

Tue, 14 Jul 2026 00:00:00 +0000

Understanding the cellular architecture of Huntington’s disease

dorian.pustina@chdifoundation.org (Dorian Pustina) — Tue, 14 Jul 2026 00:00:00 +0000

A new diffusion MRI approach offers a glimpse of the anomalies of cellular architecture underlying basal ganglia degeneration in Huntington’s disease.

The Crunchometer, a low-cost, open-source acoustic analysis of feeding microstructure

ranier@cinvestav.mx (Alam Coss) — Tue, 14 Jul 2026 00:00:00 +0000

Elucidating the neuronal circuits that govern appetite requires precise, high-resolution monitoring of the microstructure of solid food consumption, a need unmet by existing tools, which are either costly or lack the temporal resolution to align feeding events with neuronal activity. To overcome this, we developed the Crunchometer, a low-cost, open-source acoustic system that uses computational algorithms to generate high-resolution feeding ethograms from the sounds produced during solid food consumption. Validation across energy states (hunger/satiety) confirmed its sensitivity to changes in feeding microstructure, and the system reliably detected semaglutide-induced suppression of intake and reduced preference for a high-fat diet. Leveraging its seamless integration with in vivo recordings in freely behaving mice, we paired the Crunchometer with lateral hypothalamus (LH) electrophysiology to identify ‘meal-related’ neurons that track entire meals rather than individual bouts. Calcium imaging further revealed that distinct subsets of LH GABAergic and glutamatergic neurons were tuned to feeding only, to licking only, or to both behaviors. Thus, LH neuronal ensembles differentially encode the consumption of solid food versus liquid sucrose. These findings demonstrate that the Crunchometer is a robust, accessible platform for dissecting the neural correlates of feeding behavior at the resolution of a single bite.

In silico design and validation of high-affinity RNA aptamers for SARS-CoV-2 comparable to neutralizing antibodies

wangzhiye1@zju.edu.cn (Damiano Buratto) — Tue, 14 Jul 2026 00:00:00 +0000

Nucleic acid aptamers hold promise for clinical applications, yet understanding their molecular binding mechanisms to target proteins, and efficiently optimizing their binding affinities, remain challenging. Here, we present CAAMO (Computer-Aided Aptamer Modeling and Optimization), which integrates in silico aptamer design with experimental validation to accelerate the development of aptamer-based RNA therapeutics. Starting from the sequence information of a reported RNA aptamer, Ta, for the SARS-CoV-2 spike protein, our CAAMO method first determines its binding mode with the spike protein’s receptor binding domain (RBD) through a multi-strategy computational approach. We then optimize its binding affinity via structure-based rational design. Among the six designed candidates, five were experimentally verified and exhibited enhanced binding affinities compared to the original Ta sequence. Furthermore, we directly compared the binding properties of the RNA aptamers to neutralizing antibodies and found that the designed aptamer Ta^G34C demonstrated a comparable binding affinity to the RBD compared to the representative neutralizing antibodies analyzed in this study. This highlights its potential as an alternative to existing COVID-19 antibodies. Our work provides a robust approach for the efficient design of a relatively large number of high-affinity aptamers with complicated topologies. This approach paves the way for the development of aptamer-based RNA diagnostics and therapeutics.

Linking germline telomere removal to global programmed DNA elimination in Tetrahymena genome differentiation

kazufumi.mochizuki@igh.cnrs.fr (Alix Lemoine) — Tue, 14 Jul 2026 00:00:00 +0000

In the ciliate Tetrahymena, telomeres of the germline micronucleus (MIC) are removed and replaced by de novo telomere addition during somatic macronuclear (MAC) development. In this study, we investigated the kinetics and mechanism of the MIC telomere elimination. Comparison of the MIC and MAC genome sequences indicated that the MIC telomeres are excised from chromosomes as part of larger MIC-limited sequences (MLSs) through chromosomal breakage. We confirmed this using an optimized oligo-FISH protocol and found that their elimination occurs in parallel with other programmed DNA elimination processes. CRISPR-Cas9 disruption of a MLS-associated Chromosome Breakage Sequence (CBS) showed that elimination of the MLS was not blocked but instead led to loss of its adjacent MAC-destined sequence (MDS), suggesting abnormal co-elimination. In biparental crosses of the CBS mutant, however, both MLS and MDS were retained, DNA elimination was broadly disrupted, and no viable progeny were produced. These findings indicate that chromosome breakage at MLS-associated CBSs is essential for the proper separation of MLSs and MDSs, ensuring correct DNA elimination and successful sexual progeny development. We propose that the MIC telomere elimination is subsumed within the broader process of programmed DNA elimination.

A natural experiment in Kenya reveals durable immunosuppressive effects of early childhood malaria: a longitudinal cohort study

csande@kemri-wellcome.org (Charles J Sande) — Tue, 14 Jul 2026 00:00:00 +0000

Cytoplasmic circular dsDNA is a key constituent of stress granules

natalia.demeshkina@nih.gov (Adrian R Ferré-D'Amaré) — Mon, 13 Jul 2026 00:00:00 +0000

Stress granules are large cytoplasmic bodies formed in response to environmental insults by eukaryotic cells. Stress granule formation is key for post-stress recovery, and many diseases and infections are characterized by dysregulation of these membraneless organelles. How specific and non-specific macromolecular interactions drive the formation of stress granules and other large assemblies is an area of active research. Stress granules are comprised of dense, ~200 nm cores, and these are known to contain numerous RNAs and proteins. Now, we have discovered that more than half of the nucleic acid content of stress granule cores is circular, double-stranded DNA. We demonstrate cytologically that these extrachromosomal circular DNAs (eccDNAs) colocalize cytoplasmically with canonical stress granule marker proteins in HEK293T cells, and through CRISPR targeting in budding yeast, that they are required for stress granule formation upon stress. This discovery thus reveals a key function for eccDNA in the eukaryotic stress response.

Human cerebellum and ventral tegmental area interact during extinction of learned fear

enzo.nio@uk-essen.de (Alice Doubliez) — Mon, 13 Jul 2026 00:00:00 +0000

The key elements for fear extinction learning are unexpected omissions of expected aversive events, which are considered to be rewarding. Given its reception of reward information, we tested the hypothesis that the cerebellum contributes to reward-like prediction error processing driving extinction learning via its connections with the ventral tegmental area (VTA). Forty-three young and healthy participants performed a three-day fear conditioning paradigm in a 7T MR scanner. The cerebellum and VTA were active during unexpected omissions of aversive unconditioned stimuli in the initial extinction trials and in other learning phases, in line with the proposed role of prediction-error processing. Increased functional connectivity was observed between the cerebellum and VTA, indicating that they are functionally coupled during fear extinction learning. These results suggest that an interaction between the cerebellum and VTA should be incorporated into the existing model of the fear extinction network.

Heterozygote advantage cannot explain MHC diversity, but MHC diversity can explain heterozygote advantage

jcherry@ncbi.nlm.nih.gov (Joshua L Cherry) — Mon, 13 Jul 2026 00:00:00 +0000

Several theoretical studies have concluded that heterozygote advantage makes at most a minor contribution to MHC diversity. Siljestam and Rueffler (2024) recently presented models in which heterozygote advantage alone can lead to realistically high diversity. Here I argue that heterozygote advantage cannot by itself explain MHC diversity, and that its contribution to diversity is unlikely to be large in most species. I first show that the high diversity reported by Siljestam and Rueffler is so sensitive to parameter values that the underlying phenomenon cannot explain the widespread diversity of MHC genes. I then consider a fundamental problem with explaining MHC diversity by heterozygote advantage alone: selective forces that favored heterozygotes would lead to the evolution of haplotypes having much higher fitness when homozygous, diminishing or eliminating heterozygote advantage. Diversity maintained by another force, however, might bring about adaptation to the more common heterozygous state at the expense of homozygous fitness. Thus, substantial heterozygote advantage may arise as a consequence of MHC diversity.

Experimental verification of the error minimization theory using non-standard genetic codes constructed in vitro

ichihashi@bio.c.u-tokyo.ac.jp (Norikazu Ichihashi) — Mon, 13 Jul 2026 00:00:00 +0000

All living systems use an almost identical standard genetic code (SGC), in which 20 amino acids are assigned non-randomly. According to the error minimization theory, amino acids are arranged to minimize the mutational effect on protein function, while experimental verification remains limited. Here, we constructed 10 non-standard genetic codes (non-SGCs) in vitro by reassigning three amino acids (Ala, Ser, and Leu) in vacant codons of the minimal genetic code consisting of 21 tRNAs. Most of these non-SGCs have a higher cost of amino acid replacement than the SGC, calculated based on three amino acid properties: polar requirement (PR), molecular volume (MV), and hydropathy index (HI). The protein function of three reporter genes expressed using these non-SGCs decreased similarly when random mutations were introduced into the genes, implying that the effect of mutations was similar across all the non-SGCs tested here. This result provides direct experimental evidence that mutational robustness does not significantly change in individual reporter protein activity within the range of mutational cost tested in this study (Cost_PR: 5.29–5.77, Cost_MV: 1848–2348, and Cost_HI: 3.27–5.10), which covers approximately 18.4% (PR), 37.6% (MV), and 50.8% (HI) of the possible cost range achievable among one million randomly-generated genetic codes.

Anterior cingulate cortex monitors action state and action content in complex associative learning

dw657@drexel.edu (Arron F Hall) — Fri, 10 Jul 2026 00:00:00 +0000

Environmental changes necessitate adaptive responses, and thus the ability to monitor one’s actions and their connection to specific cues and outcomes is crucial for survival. The anterior cingulate cortex (ACC) is implicated in these processes, yet its precise role in action monitoring vs. outcome tracking remains unclear. To investigate this, we developed a novel discrimination–avoidance task for mice, designed with clear temporal separation between actions and outcomes. Our findings show that ACC neurons primarily encode post-action variables over extended periods, reflecting the animal’s preceding actions rather than the outcomes or values of those actions. Specifically, we identified two distinct subpopulations of ACC neurons: one encoding the action state (whether an action was taken) and the other encoding the action content (which action was taken). Importantly, increased post-action ACC activity was associated with better performance in subsequent trials. These findings suggest that the ACC supports complex associative learning through extended signaling of rich action-relevant information, thereby bridging cue, action, and outcome associations.

Kinematic signatures in reaching movements during spaceflight provide evidence that humans underestimate body mass in microgravity

wei.kunlin@pku.edu.cn (Bo Wang) — Thu, 09 Jul 2026 00:00:00 +0000

Astronauts consistently exhibit slower movements in microgravity, even during tasks requiring rapid responses. The sensorimotor mechanisms underlying this general slowing remain debated. Two hypotheses have been proposed: either the sensorimotor system adopts a conservative control strategy for safety and postural stability, or the system underestimates body mass due to reduced inputs from proprioceptive receptors. To dissociate these opinions, we studied 12 taikonauts aboard the China Space Station performing a classical hand-reaching task. Compared to their pre-flight performance and to an age-matched control group, participants showed increased movement durations and altered kinematic profiles in microgravity. Model-based analyses of motor control parameters revealed that these changes stemmed from reduced initial force generation in the feedforward control phase followed by compensatory feedback-based corrections. These findings provide support for the body mass underestimation hypothesis while being inconsistent with the strategic slowing hypothesis. Importantly, the sensory estimate of bodily property in microgravity is biased but immune from sensorimotor adaptation, calling for an extension of existing theories of motor learning.

Inferring variant-specific effective reproduction numbers from combined case and sequencing data

marlinfiggins@gmail.com (Marlin D Figgins) — Thu, 09 Jul 2026 00:00:00 +0000

Accurately estimating relative transmission rates of SARS-CoV-2 variants remains a scientific and public health priority. Recent studies have used the sample proportions of different variants from genetic sequence data to describe variant frequency dynamics and relative transmission rates, but frequencies alone cannot capture the rich epidemiological behavior of SARS-CoV-2. Here, we extend methods for inferring the effective reproduction number of an epidemic using confirmed case data to jointly estimate variant-specific effective reproduction numbers and frequencies of co-circulating variants using cases and sequences across states in the United States from January 2021 to March 2022. Our method can be used to infer structured relationships between effective reproduction numbers across time series, allowing us to estimate fixed variant-specific growth advantages. We use this model to estimate the effective reproduction number of SARS-CoV-2 variants of concern and variants of interest in the United States, and to estimate consistent growth advantages of particular variants across different locations.

Comparing the outputs of intramural and extramural grants funded by National Institutes of Health

bihutchins@wisc.edu (B Ian Hutchins) — Thu, 09 Jul 2026 00:00:00 +0000

Funding agencies use a variety of mechanisms to fund research. The National Institutes of Health in the United States, for example, employs scientists to perform research at its own laboratories (intramural research), and it also awards grants to pay for research at external institutions such as universities (extramural research). Here, using data from 1594 intramural grants and 97,054 extramural grants funded between 2009 and 2019, we compare the scholarly outputs from these two funding mechanisms in terms of number of publications, Relative Citation Ratio, and clinical metrics. We find that extramural awards are more cost-effective for producing outputs commonly used for academic evaluation, such as publications and citations (per dollar), while intramural awards are more cost-effective for generating research that influences future clinical work, more closely in line with the agency’s health goals. These findings provide evidence that institutional incentives associated with different funding mechanisms drive their comparative strengths.

How attention simplifies mental representations for planning

j.castanheira@ucl.ac.uk (Christina Chang He) — Thu, 09 Jul 2026 00:00:00 +0000

Human planning is efficient – it frugally deploys limited cognitive resources to accomplish difficult tasks – and flexible – adapting to novel problems and environments. Computational approaches suggest that people construct simplified mental representations of their environment, balancing the complexity of a task representation with its utility. These models imply a nested optimisation in which planning shapes perception and perception shapes planning – but the perceptual and attentional mechanisms governing how this interaction unfolds remain unknown. Here, we harness virtual maze navigation to characterise how spatial attention controls which aspects of a task representation enter subjective awareness and are available for planning. We find that spatial proximity governs which aspects of a maze are available for planning and that when task-relevant information follows natural (lateralised) contours of attention, people can more easily construct simplified and useful maze representations. This influence of attention varies considerably across individuals, explaining differences in people’s task representations and behaviour. Inspired by the ‘spotlight of attention’ analogy, we incorporate the effects of visuospatial attention into existing computational accounts of value-guided construal. Together, our work bridges computational perspectives on perception and decision-making to better understand how individuals represent their environments in aid of planning.

Theta beta ratio in attention deficit hyperactivity disorder using a multiverse analysis

Dawid.strzelczyk@uzh.ch (Andrea Vetsch) — Thu, 09 Jul 2026 00:00:00 +0000

Attention deficit hyperactivity disorder (ADHD) affects 5–7% of children worldwide, yet diagnosis continues to rely on clinical-behavioral assessments. The theta/beta ratio (TBR) derived from electroencephalography (EEG) has long been proposed as a complementary neurobiological marker of ADHD based on reports of elevated TBR in affected children. However, accumulating evidence has raised concerns about the robustness and generalizability of these findings, pointing to a strong sensitivity to methodological choices. Here, we used multiverse analyses to systematically quantify how researcher degrees of freedom shape conclusions about associations between TBR and ADHD. Across two large, independent datasets (Healthy brain network: N=1499; validation sample: N=381), we evaluated 576 theoretically plausible analytical specifications, varying recording conditions, reference scheme, frequency band definitions, treatment of aperiodic (1/f) activity, regions of interest, sample inclusion criteria, and covariate specifications. Across the multiverse, we found that group differences in TBR were highly contingent on analytical choices, with no evidence for robust main effects of diagnosis, indicating no reliable differences between healthy controls, ADHD-inattentive, and ADHD-combined subtypes. Instead, significant effects emerged primarily as interactions with age and individual alpha frequency (IAF), particularly when TBR was derived from aperiodic-uncorrected power or from the aperiodic signal itself. These interaction patterns replicated across both independent samples and were observed using both categorical and dimensional definitions of ADHD. Together, these findings indicate that previously reported TBR effects are largely driven by variability in aperiodic activity and IAF rather than genuine differences in oscillatory theta-beta dynamics. Our results challenge the interpretation of TBR as a reliable standalone biomarker for ADHD and underscore the importance of multiverse approaches for evaluating candidate neurobiological markers in heterogeneous clinical populations.

Correction: Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue

Thu, 09 Jul 2026 00:00:00 +0000

The targeted cytosolic degradation of class I histone deacetylases is essential for efficient alphaherpesvirus replication

zenglei2021918@163.com (Bei-Bei Chu) — Thu, 09 Jul 2026 00:00:00 +0000

Viral infection triggers a robust DNA damage response (DDR), reshaping the host chromatin landscape to facilitate viral replication. Here, we uncover a novel mechanism by which alphaherpesviruses exploit the DDR pathway. We demonstrated that herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) induced selective degradation of class I histone deacetylases (HDAC1/2), leading to histone hyperacetylation and subsequent DDR activation. Strikingly, viral infection promoted nuclear export of HDAC1/2, followed by MDM2-mediated K63-linked polyubiquitination and proteasomal degradation in the cytoplasm. Pharmacological inhibition of either DDR signaling or HDAC1/2 nuclear export significantly affected viral replication in vitro and in vivo. Our findings reveal a unique viral strategy to hijack host epigenetic regulation for efficient replication, and identify potential therapeutic targets for alphaherpesvirus infections.

The microtubule-binding protein EML3 is required for mammalian embryonic growth and cerebral cortical development, and Eml3 null mice are a model of cobblestone brain malformation

isabelle.carrier@mail.mcgill.ca (Albert M Berghuis) — Thu, 09 Jul 2026 00:00:00 +0000

The cerebral cortex is a multi-layered structure generated through the migration of neural precursors from their birthplace in the ventricular zone to their destination within the cortical plate. Neuronal migration defects are responsible for many human pathologies collectively called neuronal migration disorders, which include subcortical band heterotopia and cobblestone brain (COB) malformation. One example of a protein involved in a neuronal migration disorder is the echinoderm microtubule-associated protein-like 1 (EML1) protein, one of six members of the mammalian EML family. Absence of EML1 protein results in subcortical band heterotopia in mice and humans. Here, we report that the absence of the paralogous protein EML3 leads to delayed embryonic development and small size, and a COB-like phenotype with neuronal ectopias in the dorsal telencephalon. We found that EML3 is expressed in the neuroepithelium and meningeal mesenchyme when those tissues participate in pial basement membrane (PBM) formation. Transmission electron microscopy demonstrated that the extracellular matrix of the PBM is structurally abnormal in Eml3 null mice when the first radially migrating neurons arrive. The reduced structural integrity of the PBM leads to focal over-migration of neurons into the subarachnoid space. These findings strengthen the link between the EML protein family and cortical neuronal migration defects by identifying Eml3 as the first EML family member whose absence leads to over-migration of neuroblasts. Moreover, we report the first COB-like phenotype with PBM structural defects when a single microtubule-associated protein is deleted.

Correction: Asymmetrical diversification of the receptor-ligand interaction controlling self-incompatibility in Arabidopsis

Thu, 09 Jul 2026 00:00:00 +0000

Medial prefrontal cortex encodes but is not required to generate goal-directed actions under threat

mcastro@uchc.edu (Ji Zhou) — Wed, 08 Jul 2026 00:00:00 +0000

Adaptive behavior under threat requires deciding when to act and when to withhold action to avoid harm, often under conditions where movement, arousal, and task demand covary. Medial prefrontal cortex (mPFC) activity is widely associated with such control, yet it remains unclear whether this activity reflects causal action generation or broader evaluative processes shaped by behavioral state. Here, we combined fiber photometry, single-cell calcium imaging, mixed-effects modeling, and optogenetic inhibition to examine how GABAergic neurons in mouse mPFC represent cues, actions, and outcomes during a series of learned avoidance tasks of increasing complexity that promote cautious responding. By explicitly controlling for baseline activity and movement, we show that much apparent task-related activity in mPFC reflects movement and cue-evoked signals that are also present in a control cortical region, the visual cortex. mPFC GABAergic neurons showed little encoding of simple avoidance contingencies but broadly encoded punished outcomes. A small subset of neurons with strong movement sensitivity encoded more demanding avoidance contingencies requiring selection between action generation and deferment. For equivalent avoidance actions, distinct neuronal populations preferentially encoded either cue onset or the action. Despite this encoding, optogenetic inhibition of mPFC had minimal effects on the learning or performance of the different contingencies. These findings reveal a dissociation between neural encoding and causal necessity, indicating that mPFC GABAergic activity primarily reflects evaluative and contextual aspects of cautious avoidance behavior rather than direct control of action execution.

Lenacapavir-induced lattice hyperstabilization is central to HIV-1 capsid failure at the nuclear pore complex and in the cytoplasm

gavoth@uchicago.edu (Arpa Hudait) — Wed, 08 Jul 2026 00:00:00 +0000

Lenacapavir (LEN) is the first human immunodeficiency virus type 1 (HIV-1) capsid inhibitor approved for clinical use in humans. It inhibits multiple steps of the viral life cycle; however, the molecular details of the effect of LEN on capsid structure and the mechanistic steps of the inhibition are not understood. Recent studies show that intact cone-shaped capsids and capsids with LEN-induced breaks can dock at nuclear pore complexes (NPCs), but only intact capsids enter the nucleus. In this work, we combined large-scale coarse-grained molecular dynamics simulations and live-cell imaging to investigate the stepwise mechanism of docking of LEN-treated capsids into the NPC. Capsids bound to substoichiometric concentrations of LEN can reach the NPC central channel. As the capsid advances to the nuclear end, lattice defects are formed at the pentamer-hexamer interface – primarily at the narrower end – leading to pentamer dissociation. Dissociation of pentamers is detrimental to capsid integrity, leading to both rupture of the narrow end and destabilization of the hexamer-hexamer interface. Structural analysis of LEN-capsid complexes in our simulations demonstrates heterogeneous hyperstabilization and loss of the essential pliability of the capsid protein lattice. Live-cell imaging of HIV-1 cores labeled with two different fluorescent markers showed that LEN-treated ruptured capsids were docked at the NPC but were not imported into the nucleus. We conclude that LEN contributes to the loss of capsid elasticity and integrity, inhibiting HIV-1 nuclear entry and replication. Our findings demonstrate that altering viral material properties can be an effective strategy for designing human antiviral drugs.

Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactions

remy.torro@gmail.com (Beatriz Díaz-Bello) — Wed, 08 Jul 2026 00:00:00 +0000

Analysis of multimodal and multidimensional data capturing dynamic interactions between diverse cell populations is a current challenge in bioimaging, especially in the context of immunology and immunotherapy research. Here, we introduce Celldetective, an open-source Python-based software tool designed for high-performance end-to-end analysis of image-based in vitro immune and immunotherapy assays. Celldetective is purpose-built for multicondition, 2D multi-channel time-lapse microscopy of mixed cell populations. Although it is optimised for the needs of immunology assays, it is nevertheless broadly applicable to any biological system involving interacting cell populations. The software seamlessly integrates AI-based segmentation, tracking, and automated single-cell event detection, all within an intuitive graphical interface that supports interactive visualisation, annotation, and training options. We showcase its capabilities with original datasets of single immune effector cell interactions with an activating surface mediated by bispecific antibodies and pairwise interactions in antibody-dependent cell cytotoxicity events.

Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity

thayerm@ohsu.edu (Athanasios E Vouzas) — Wed, 08 Jul 2026 00:00:00 +0000

Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 Mbb in size and can contain both protein-coding and noncoding genes. In different single-cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we identify syntenic loci in the mouse genome that display epigenetic regulation of allelic replication timing, highlighting the genomic organization and conservation of I/SC-associated regulation between human and mouse genomes. The allele-restricted regulation described here creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Alzheimer, Parkinson, epilepsy, deafness, and impaired intellectual development.

Canonical and phosphoribosyl ubiquitination coordinate to stabilize a proteinaceous structure surrounding the Legionella-containing vacuole

Shaeri.Mukherjee@ucsf.edu (Adriana Steinbach) — Wed, 08 Jul 2026 00:00:00 +0000

Legionella pneumophila (L.p.), an intracellular bacterial pathogen, hijacks the ubiquitin signaling network of its eukaryotic host cells to establish infection. Two families of L.p. secreted ubiquitin ligases are instrumental in the maturation of the Legionella-containing vacuole (LCV): the SidC/SdcA family, which catalyzes canonical ubiquitination, and the SidE family, which bypasses the E1-E2-E3 enzymatic cascade and directly conjugates ubiquitin to a target through a phosphoribosyl (PR) linkage. Here, we demonstrate that the coordinated activities of these two effector families generate a hyperstable, ubiquitin-rich structure surrounding the LCV. We propose a model in which an initial wave of SidC/SdcA-mediated canonical ubiquitination around the LCV is further modified by SidE family-driven PR-ubiquitination, resulting in a detergent-resistant ‘cloud’. The ‘cloud’ is transient, breaking down as infection progresses, suggesting that L.p. reshapes the properties of the proteinaceous shell surrounding the vacuole to meet changing needs throughout its intracellular lifecycle. This unusual structure likely stabilizes and protects the LCV, shielding it from host defense mechanisms during early infection. Our findings reveal cellular consequences of effector interplay during infection and provide a foundation for future studies into the structure and function of the proteinaceous ‘cloud’ surrounding the LCV.

Disentangling cephalopod chromatophores motor units with computer vision

g.laurent@brain.mpg.de (Dominic A Evans) — Wed, 08 Jul 2026 00:00:00 +0000

Cephalopod chromatophores are skin pigment organs enabling rapid, neurally controlled camouflage, yet the organization of their motor control remains poorly understood. Previously, we developed CHROMAS, a computer-vision pipeline for high-resolution analysis of chromatophore dynamics (Ukrow et al., 2025). Here, we apply it to investigate motor control and innervation in Euprymna berryi and Sepia officinalis. By segmenting chromatophores into radial slices and analyzing anisotropic deformations, we used dimensionality reduction and source separation to estimate the number and spatial influence of motor neurons controlling individual chromatophores and groups thereof. On average, four independent components were detected per chromatophore, each forming contiguous petal-shaped domains. Clustering thousands of components revealed motor units spanning multiple chromatophores, most involving fewer than 14, with diverse geometries ranging from compact local groups to elongated or fragmented structures; chromatophore pairs were co-innervated more often than expected by chance. Expansion was consistently faster and more stereotyped than relaxation, consistent with active contraction and passive recoil. These results show that chromatophores are not uniform pixels but contrast elements fractionable into sub-territories coordinated across neighbors. This geometry of neural control enables the generation of ‘virtual chromatophores’, that is, functional groupings of adjacent chromatophore territories that act as single units, as well as that of noise in the distribution of pixel shapes.

Cribriform plate microenvironment assembles a suppressive myeloid network during EAE-induced neuroinflammation

zfabry@wisc.edu (Andy Madrid) — Wed, 08 Jul 2026 00:00:00 +0000

During neuroinflammation, CD11c⁺CD11b⁺ myeloid cells accumulate at the cribriform plate, a key cerebrospinal fluid and antigen outflow site in mice. At this site, podoplanin-expressing cells, including lymphatic vessels and meningeal layers, expand to create a distinct drainage microenvironment. In this study, we sought to characterize myeloid cells, which populate this region, using a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis. Utilizing a combination of immunohistochemistry, flow cytometry, and scRNAseq, we report that macrophages and dendritic cells from this region display unique expressional signatures related to tolerance, cell death, and reduced inflammatory profile. Together, this data supports that myeloid retention at the cribriform plate and olfactory bulb meninges promotes a local immunosuppressive environment.

Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia

623056@sdnu.edu.cn (Chunyu Liu) — Wed, 08 Jul 2026 00:00:00 +0000

The central apparatus of motile cilia, consisting of central microtubules and various protein projections, is essential for dictating the ciliary movement. Although three proteins (FAP65, FAP147, and FAP70) have been localized to the C2a projection in Chlamydomonas reinhardtii, the full protein composition and functional roles of the vertebrate C2a remain inadequately defined. Here, we use three knockout mouse models corresponding to their respective homologs (Ccdc108, Mycbpap, and Cfap70) to systematically investigate their functions in vertebrates. Notably, all three knockout strains exhibit distinct phenotypes related to primary ciliary dyskinesia (PCD), including hydrocephalus and sinusitis. The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one another’s stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules, and ultimately alters the ciliary movement pattern. Furthermore, we significantly expand the vertebrate C2a proteome by identifying ARMC3 and MYCBP as additional C2a components. Collectively, our findings illuminate the proteomic composition and strict physiological requirements of the vertebrate C2a projection, providing new insights into the molecular pathogenesis of PCD.

Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis

marcia_haigis@hms.harvard.edu (Arlene H Sharpe) — Wed, 08 Jul 2026 00:00:00 +0000

Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4⁺ T cells. We demonstrate that asparagine depletion at different time points after CD4⁺ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4⁺ T cell differentiation reduces cytokine production in multiple CD4⁺ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4⁺ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.

Dynamic assembly of malate dehydrogenase–citrate synthase multienzyme complex in the mitochondria

tobata2@unl.edu (Connor Pedersen) — Wed, 08 Jul 2026 00:00:00 +0000

The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1–CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1–CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1–CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1–CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.

Visual working memory guides attention rhythmically in humans

ljcps@gzhu.edu.cn (Jiachen Lu) — Wed, 08 Jul 2026 00:00:00 +0000

How does internal representation held in visual working memory (VWM), known as the attentional template, guide attention in humans? A longstanding debate concerns whether only one (Single-Item-Template theory) or multiple (Multiple-Item-Template theory) items serve as attentional templates simultaneously. Here, we propose a Rhythmic-Item-Template hypothesis, successfully reconciling these seemingly contradictory theories. Using the classical VWM-guided attention task with human participants, we found that two VWM items alternately dominate behavioral guidance in theta-rhythmic (4–8 Hz), with anti-correlated activation states in time, and more importantly, this rhythmic oscillation was not driven by the retro-cue processing. Neural recordings revealed that occipital alpha oscillation (8–14 Hz) governed item-specific prioritization, and its amplitude closely tracked subjects’ behavioral guidance, while frontal theta-oscillations phase-led and coupled with occipital alpha oscillations during the item transition. Our Rhythmic-Item-Template results not only resolve previous Single-Item-Template versus Multiple-Item-Template debate but also advance our understanding of how distributed brain rhythms coordinate flexible resource allocation in multi-item memory systems.

TGF-β drives the conversion of conventional NK cells into uterine tissue-resident NK cells to support murine pregnancy

yokoyama@wustl.edu (D Michael Nelson) — Wed, 08 Jul 2026 00:00:00 +0000

Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer (NK) cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-β-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-β receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-β-driven uterine tissue-resident NK cell differentiation during murine pregnancy led to abnormal spiral artery remodeling and increased fetal resorption rates at mid-gestation, ultimately reducing litter sizes at birth. Collectively, these findings define TGF-β as a pivotal driver of tissue-resident NK cell differentiation in the gravid uterus and establish a mechanistic framework through which the uterine microenvironment programs NK cell identity to meet the physiological demands of gestation.

Multiple event segmentation mechanisms in the human brain

n.tan@wustl.edu (Jeffrey M Zacks) — Tue, 07 Jul 2026 00:00:00 +0000

The human brain segments continuous experience into discrete events, with theoretical accounts proposing two distinct mechanisms: creating boundaries at points of high prediction error (mismatch between expected and observed information) and high prediction uncertainty (reduced precision in predictions). Using fMRI and computational modeling, we investigated the neural correlates of error-driven and uncertainty-driven boundaries. We developed computational models that generate boundaries based on prediction error or prediction uncertainty, and examined how both types of boundaries, and human-identified boundaries, related to fMRI pattern shifts and evoked responses. Multivariate analysis revealed a specific temporal sequence of neural pattern changes around human boundaries: early pattern shifts in anterior temporal regions (–11.9 s), followed by shifts in parietal areas (–4.5 s), and subsequent whole-brain pattern stabilization (+11.8 s). The core of this dynamic response was associated with both error-driven and uncertainty-driven boundaries. Critically, both error- and uncertainty-driven boundaries were associated with unique pattern shifts. Error-driven boundaries were associated with early pattern shifts in ventrolateral prefrontal areas, followed by pattern stabilization in prefrontal and temporal areas. Uncertainty-driven boundaries were linked to shifts in parietal regions within the dorsal attention network, with minimal subsequent stabilization. In addition, within the core regions responsive to both types of boundaries, the timing differed significantly. These findings provide evidence for two overlapping brain networks that maintain and update representations of the environment, controlled by two distinct prediction quality signals: prediction error and prediction uncertainty.

Continuous developmental changes in word recognition and language learning across early childhood

mcfrank@stanford.edu (Adrian Steffan) — Tue, 07 Jul 2026 00:00:00 +0000

Being a fluent language user involves recognizing words as they unfold in time. How does this skill develop over the course of early childhood? And how does facility in word recognition relate to the growth of vocabulary knowledge? We address these questions using data from Peekbank, an open database of experiments measuring children’s eye movements during early word recognition. In an observational study of 26 datasets from over 2500 children ages 6 months to 6 years, we show that word recognition becomes faster, more accurate, and less variable across development, consistent with a process of skill learning. Factor analysis reveals covariation of word recognition speed and accuracy with children’s vocabulary size in cross-sectional analysis. Further, across a range of longitudinal models, speed, accuracy, and vocabulary were coupled. Children with overall faster word recognition tended to show faster vocabulary growth, though developmental growth in word recognition skill was not specifically associated with growth in vocabulary. Together, these findings support the view that word recognition is a skill that develops gradually across early childhood and that this skill is deeply intertwined with early language learning.

Ligand-dependent enhancer activation indirectly modulates non-target promoters in a chromatin domain

aprotim@tifrh.res.in (Aprotim Mazumder) — Tue, 07 Jul 2026 00:00:00 +0000

Transcription activation of genes by estrogen is driven by enhancers, which are often located within the same topologically associating domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven activation affects neighbouring non-target genes within the same TAD. Using single-molecule RNA FISH (smFISH), we tracked the transcription of TFF1 (enhancer-target gene) and TFF3 (non-target gene) during estrogen stimulation. We observed mutually exclusive expression patterns: TFF1 expression peaked at 1 hr, while TFF3 reached its peak at 3 hr after TFF1 activation had diminished. Chromatin looping data indicated that the enhancer loops with the TFF1 gene but not TFF3, suggesting that TFF3 upregulation is not due to direct enhancer-promoter interactions. CRISPR deletion of the enhancer affected TFF1 transcription more acutely than TFF3. 1,6-hexanediol (HD) exposure suggested that the TFF1 enhancer:promoter undergoes a potential ERα-mediated condensate formation, which sequesters the transcriptional machinery and inhibits TFF3 expression. As estrogen signaling fades at 3 hr, TFF1 expression declines while TFF3 expression increases. Our findings reveal that enhancer-driven activation can indirectly repress neighboring genes within the same TAD, highlighting a dynamic shift in gene expression as signaling progresses.

Arrayed single-gene perturbations identify drivers of human anterior neural tube closure

roya_huang@berkeley.edu (Chudi Abraham-Igwe) — Tue, 07 Jul 2026 00:00:00 +0000

Genetic studies of human embryonic morphogenesis are constrained by ethical and practical challenges, restricting insights into developmental mechanisms and disorders. Human pluripotent stem cell (hPSC)-derived organoids provide a powerful alternative for the study of embryonic morphogenesis. However, screening for genetic drivers of morphogenesis in vitro has been infeasible due to organoid variability and the high costs of performing scaled tissue-wide single-gene perturbations. By overcoming both these limitations, we developed a platform that integrates reproducible organoid morphogenesis with uniform single-gene perturbations, enabling high-throughput arrayed CRISPR interference screening in hPSC-derived organoids. To demonstrate the power of this platform, we screened 77 transcription factors in an organoid model of anterior neurulation to identify ZIC2, SOX11, and ZNF521 as essential regulators of neural tube closure. We discovered that ZIC2 and SOX11 are required for closure, while ZNF521 prevents ectopic closure points. Single-cell transcriptomic analysis of perturbed organoids revealed co-regulated gene targets of ZIC2 and SOX11 and an opposing role for ZNF521, suggesting that these transcription factors jointly govern a gene regulatory program driving neural tube closure in the anterior forebrain region. Our single-gene perturbation platform enables high-throughput genetic screening of in vitro models of human embryonic morphogenesis.

Optimised genome editing for precise DNA insertion and substitution using prime editors in zebrafish

s.scholpp@exeter.ac.uk (Amir Khan) — Tue, 07 Jul 2026 00:00:00 +0000

CRISPR/Cas9-mediated genome editing has rapidly become a popular tool for studying gene functions and generating genetically modified organisms. However, using this system, stochastic integration of random insertions and deletions restricts precise genome manipulation. Advanced CRISPR/Cas9 technologies using Prime Editors (PEs), Cas9 proteins fused with reverse transcriptase, enable programmed integration of short DNA modifications into the genome. However, its application in precise genome editing in animal models is challenging. Here, we utilise a nickase- and a nuclease-based PE to perform programmed short DNA substitutions and insertions at various loci in the zebrafish genome. Whereas nickase-based PE2 mediated a higher ratio of precise prime edits to the total edits, nuclease-based PEn was more efficient for short DNA modifications, achieving up to 27.3% precise insertion. To further evaluate our approach, we inserted a nuclear localisation signal into a reporter transgene to incorporate longer fragments by prime editing. These gene modifications were transmitted to the next generation. We show that PE-mediated prime editing can efficiently manipulate genome information in zebrafish without using exogenous donor DNA.

Impacts of DNA methylation on H2A.Z deposition and nucleosome stability

funabih@rockefeller.edu (Hide A Konishi) — Tue, 07 Jul 2026 00:00:00 +0000

The histone variant H2A.Z and DNA methylation are enriched at mutually exclusive genomic segments, though its mechanistic bases remain unclear. Here, we examine DNA methylation’s influence on the intrinsic stability of the H2A.Z nucleosome and chaperone-mediated H2A.Z deposition. Cryo-EM and endonuclease analyses suggest that DNA methylation subtly increases the openness and accessibility of the H2A.Z nucleosome on satellite II-derived DNA sequences. In transcriptionally silent Xenopus egg extracts, H2A.Z preferentially associates with unmethylated DNA though a substantial proportion of H2A.Z is recruited to methylated DNA. Preferential H2A.Z deposition to unmethylated DNA depends on the SRCAP complex, whose DNA binding is suppressed by methylation, while an SRCAP-independent and DNA methylation-insensitive mechanism for H2A.Z deposition also exists. Altogether, we propose that SRCAP drives the biased association of H2A.Z to unmethylated DNA, while additional mechanisms, potentially taking advantage of the subtle DNA methylation-induced physical effects, further assist the exclusion of H2A.Z from methylated DNA.

Development of auditory and spontaneous movement responses to music over the first postnatal year

trinh.nguyen@iit.it (Atesh Koul) — Tue, 07 Jul 2026 00:00:00 +0000

Humans across cultures not only share the ability to recognise music but also respond to it through movement. While the sensory encoding of music is well-studied, when and how infants naturally start moving to music is largely unexplored. This study simultaneously investigates infants’ neural (auditory) responses and spontaneous movements to music during the first postnatal year. Neural activity (EEG) and body kinematics (markerless pose estimation) were recorded from 79 infants (aged 3, 6, and 12 months) listening to refrains of children’s music, along with shuffled, high-pitched, and low-pitched versions of the same songs. Neural data revealed that, across all ages, infants exhibit enhanced auditory responses to music compared to shuffled music, indicating that auditory encoding of music emerges early in development. Movement data revealed a different outcome. While coarse auditory-motor coupling is present at all ages, more complex structured movement patterns emerge in response to music only by 12 months. Notably, no age group demonstrated evidence of coordinated movements to music. Additionally, enhanced auditory responses to high vs low pitch were only evident at 6 months, while infants’ movements were better predicted by high-pitched compared to low-pitched music at all ages. This study provides initial insights into how the developing brain gradually transforms music into spontaneous movements of increasing complexity.

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

denard@arizona.edu (David Enard) — Tue, 07 Jul 2026 00:00:00 +0000

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic implications of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions; their expression is biased towards male germ cells, and they are enriched in functions related to meiosis and sperm biology. We tested the role of gorilla relaxed genes previously not implicated in male reproductive function using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

Profiling of terminating ribosomes reveals translational control at stop codons

sq38@cornell.edu (Leiming Dong) — Tue, 07 Jul 2026 00:00:00 +0000

Accurate termination of protein synthesis is paramount for the integrity of the cellular proteome, yet the dynamics and fidelity of ribosome termination remain poorly understood. Here, we establish a profiling strategy to capture terminating ribosomes in mammalian cells and reveal a substantial heterogeneity in ribosome pausing at individual stop codons. We identify a sequence motif upstream of the stop codon that promotes termination pausing, a finding supported by massively parallel reporter assays. Unexpectedly, reduced termination pausing increases the likelihood of stop codon slippage, giving rise to proteins with heterogeneous C-terminal extensions. Mechanistically, we show that sequence-dependent termination pausing is consistent with post-decoding mRNA scanning by the 3′ end of 18 S rRNA. We further uncover tissue-specific patterns of termination pausing that correlate with the stoichiometry of Rps26, which potentially modulates mRNA:rRNA interactions. Together, these results suggest termination pausing as a distinct translational signature shaped by mRNA sequence contexts, ribosome heterogeneity, and cell type-specific translational control.

Mechanistic insights into transcriptional regulation of ARHGAP36 expression identify a factor predictive of neuroblastoma survival

olehmann@ualberta.ca (Armin M Gamper) — Mon, 06 Jul 2026 00:00:00 +0000

Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage-specific transcription factors that regulate neural crest migration, representing frequent drivers of malignancy. One such example is the forkhead transcription factor FOXC1, where gain of function is a feature of diverse cancers that is associated with an unfavorable prognosis. Using RNA-, ChIP-sequencing and CRISPR interference, we show that Foxc1 binds a locus in a region of closed chromatin to induce expression of Arhgap36, a tissue-specific inhibitor of protein kinase A. Because PKA is a core Hedgehog (Hh) pathway inhibitor, Foxc1’s induction of Arhgap36 expression increases Hh activity. The function of Sufu, a PKA substrate, and a second essential Hh pathway inhibitor, is likewise impaired. The resulting increased Hh pathway output is resistant to pharmacological inhibition of Smoothened, a phenotype of more aggressive cancers. The Foxc1–Arhgap36 relationship identified in murine cells was further evaluated in neuroblastoma, a neural crest-derived pediatric malignancy. This demonstrated in a cohort of 1348 patients that high levels of ARHGAP36 are predictive of improved 5-year survival. Accordingly, this study has identified as a novel transcription factor which enhances ARHGAP36 expression, one that induces Hh activity in multiple tissues during development. It also establishes a model by which increased levels of FOXC1 via ARHGAP36 and PKA inhibition dysregulate multiple facets of Hh signaling and provides evidence demonstrating relevance to a common neural-crest-derived malignancy.

SqueakPose Studio, an end-to-end platform for pose estimation and real-time edge-AI deployment

david.haggerty@nih.gov (Caleb Browning Darden) — Mon, 06 Jul 2026 00:00:00 +0000

Accurate pose estimation underpins quantitative analysis of behavior, yet many deep learning-based tracking tools remain optimized for offline workflows that rely on fragmented software pipelines, workstation-grade GPUs, or external middleware to enable real-time deployment. Here, we present an integrated software-hardware ecosystem for pose estimation that spans dataset creation, model training, offline analysis, and real-time deployment on embedded edge-computing devices. SqueakPose Studio provides a software suite for whole-frame, deep learning-based pose estimation that unifies dataset creation, manual and model-assisted labeling, model training, validation, and large-scale offline inference. The system leverages modern object-detection architectures to enable efficient end-to-end training and inference without patch-based sampling or multistage post-processing, and supports execution on CPUs, GPUs, and Apple Silicon. For experimental settings requiring continuous recording and synchronized data acquisition, SqueakView enables real-time model deployment, video capture, and sensor logging on embedded edge-computing hardware, while MouseHouse provides a compact, modular enclosure designed for home cage-based experiments that integrates embedded GPU compute, microcontroller-based timing, and peripheral I/O. A shared data format and deterministic timing architecture ensure consistency across offline analysis and real-time deployment. Together, SqueakPose Studio, SqueakView, and MouseHouse provide a unified platform for pose estimation that supports both conventional offline analysis and embedded, real-time experimentation, without reliance on workstation-grade hardware or external middleware.

Activity-dependent CO₂ production in the axon triggers opening of Connexin32 in the Schwann cell paranode

n.e.dale@warwick.ac.uk (Amol Bhandare) — Mon, 06 Jul 2026 00:00:00 +0000

Loss of function mutations of Cx32, which is expressed in Schwann cells, cause X-linked Charcot-Marie-Tooth disease, a slowly progressive peripheral neuropathy. Action potential propagation causes Cx32 hemichannels in the Schwann cell paranode to open. As Cx32 hemichannels are directly sensitive to CO₂, we have tested whether CO₂ produced in the axon, as a consequence of the energetic demands of action potential propagation, might gate Cx32 hemichannels. Using isolated sciatic nerve from the mouse, we found that the critical components required for intercellular CO₂ signaling are present (nodal mitochondria, the source of CO₂; a CO₂-permeable aquaporin, AQP1; paranodal Cx32; and carbonic anhydrase). We have used a membrane impermeant fluorescent dye, FITC, to demonstrate the opening of Cx32 in Schwann cells in response to an external CO₂ stimulus or during action potential propagation in the isolated nerve. Pharmacological manipulations of AQP1 or carbonic anhydrase activity altered Cx32 gating during action potential firing. Expression of a modified Cx32 subunit, Cx32^DN, that coassembles with Cx32^WT, revealed that the activity-dependent dye loading of Schwann cells depended upon CO₂ binding to Cx32. CO₂ can, therefore, mediate neuron-to-glia signaling via connexins. CO₂ permeable aquaporins and carbonic anhydrase are key components of this signaling mechanism.

Lipid packing contributes to the confinement of caveolae to the plasma membrane

richard.lundmark@umu.se (Aleksei Kabedev) — Mon, 06 Jul 2026 00:00:00 +0000

Lipid packing is a fundamental characteristic of bilayer membranes. Yet, we lack detailed mechanistic understanding of how lipid packing directly affects membrane-associated cellular processes. Here, we address this by focusing on caveolae, small Ω-shaped invaginations of the plasma membrane, which serve as key regulators of cellular lipid sorting and mechano-responses. In addition to caveolae coat proteins, the lipid membrane is a core component of caveolae that critically impacts their biogenesis, morphology, and stability. We show that the small compound Dyngo-4a adsorbs and inserts into the membrane, resulting in a dramatic dynamin-independent inhibition of caveola dynamics. Analysis of model membranes in combination with molecular dynamics simulations revealed that a substantial amount of Dyngo-4a was inserted and positioned at the level of cholesterol in the bilayer, affecting lipid order in a cholesterol-dependent manner. Dyngo-4a treatment resulted in decreased lipid packing of the plasma membrane. This prevented caveolae internalization and lateral diffusion without affecting their morphology, associated proteins, or the overall cell stiffness. Artificially increasing plasma membrane cholesterol levels was found to counteract the block in caveola dynamics caused by Dyngo-4a. Therefore, we propose that the outer leaflet lipid packing of cholesterol in the plasma membrane critically contributes to the confinement of caveolae to the plasma membrane.

A coma pattern-based autofocusing method resolves bacterial cold shock response at single-cell level

shuqiang.huang@siat.ac.cn (Jinjuan Wang) — Mon, 06 Jul 2026 00:00:00 +0000

Imaging-based single-cell physiological profiling holds great potential for uncovering fundamental bacterial cold shock response (CSR) mechanisms, but its application is impeded by severe focus drift during rapid temperature downshifts required for CSR induction. Here, we introduce LUNA (Locking Under Nanoscale Accuracy), an innovative autofocusing method that leverages the coma pattern of detection light to characterize focus drift. LUNA improves the focusing precision down to 3 nm and extends the focusing range to at least 40 times the objective depth of focus. These advancements enable us to investigate the complete dynamics of bacterial single-cell CSR, revealing continuous cellular growth and division. We resolve a three-phase adaptation process characterized by distinct growth deceleration dynamics, and show that bacterial cells maintain robust size regulation and coordinate uniform adaptation to cold shock through synchronized growth and elapsed cycles. Notably, a model based on scattering theory reconciles the paradox between the growth lag of batch culture and continuous single-cell growth. These findings fundamentally transform our understanding of bacterial CSR and highlight LUNA’s excellent potential for expanding state-of-the-art research in biology.

Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy

jiouw@jhu.edu (Hao Chen) — Fri, 03 Jul 2026 00:00:00 +0000

We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent non-canonical amino acid Anap. By integrating the genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags, and enabling physiologically relevant visualization of protein pathobiology.

Navigating the path: Advice to physician-scientists on choosing a clinical specialty

christopher.williams@vanderbilt.edu (Ali Zarrinpar) — Fri, 03 Jul 2026 00:00:00 +0000

Choosing a clinical specialty is a critical decision for physician-scientist trainees, influencing both clinical practice and research trajectory. This article provides a structured approach to specialty selection, emphasizing the importance of aligning clinical interests with long-term research goals, evaluating training pathways, and considering lifestyle implications. Physician-scientists, including MD-PhD and other dual-degree graduates, as well as MD graduates with research-intensive training, often pursue specialties with established research pathways. We outline key decision-making factors, including mentorship, clinical exposure, research commitment, and financial sustainability. Additionally, we compare research track and categorical residency pathways, detailing differences in training structure, funding opportunities, and career outcomes. The article explores the evolving role of physician-scientists across career stages, from residency through senior faculty leadership, highlighting strategies to maintain research engagement while balancing clinical responsibilities. By critically evaluating these factors and leveraging mentorship and institutional support, physician-scientists can make informed decisions that align with their aspirations, ensuring a fulfilling and impactful career in both medicine and research.

TopoMetry systematically learns and evaluates the latent geometry of single-cell data

david.oliveira@dpag.ox.ac.uk (Ana I Domingos) — Fri, 03 Jul 2026 00:00:00 +0000

Reconstructing and investigating the geometry underlying data is a fundamental task in single-cell analysis, yet no unified framework exists for learning, evaluating, and diagnosing representations that faithfully preserve it. We present TopoMetry, a geometry-aware framework that learns intrinsic coordinate systems directly from the data and refines them into high-fidelity spectral scaffolds. These scaffolds capture both local neighborhoods and global structures, supporting downstream analyses such as clustering and visualization. In benchmarks across diverse single-cell datasets, TopoMetry preserved geometry more reliably than standard workflows and revealed biological signals otherwise obscured, including unexpected transcriptional diversity among T cells and links between RNA-defined subpopulations, and clonal expansion. The full analysis can be executed with a single line of code to generate a comprehensive report, making the framework both powerful and accessible. Beyond individual findings, TopoMetry warrants a shift of focus from static two-dimensional projections to the systematic learning and evaluation of geometry itself, enabling more accurate exploration of cellular diversity.

Analysis of dendritic input currents during place field dynamics

ujfalussy.balazs@koki.hu (Balazs B Ujfalussy) — Fri, 03 Jul 2026 00:00:00 +0000

Neuronal activity is driven by the complex interplay between various membrane currents, often located in distinct domains of the spatially extended dendritic tree. How the effect of these currents propagates to the soma and contributes to neuronal output under in vivo conditions is not fully understood. Here, we develop a new method to measure and visualize the contributions of individual membrane currents to the somatic response in spatially extended biophysical model neurons. Our approach relies on the iterative decomposition of the axial current flowing between neighbouring compartments in proportion to the underlying membrane currents measured in the model. We apply this method to visualize the inputs driving hippocampal place cell activity. Our method provides a compact and intuitive description of the various dendritic events underlying subthreshold activity, spiking, or burst firing. By contrasting the dendritic input currents preceding spiking and bursting, we demonstrate that both could occur at highly variable input levels to proximal dendrites (basal and oblique), and that strong distal inputs facilitate, rather than control, the generation of complex spike bursts. Our method opens a novel window onto single-neuron computations that will help to design better models and to interpret the results of in vivo imaging experiments.

Neural activity profiles reveal overlapping, intermingled subpopulations spanning area borders in mouse sensorimotor cortex

mattkaufman@uchicago.edu (Harrison Grier) — Fri, 03 Jul 2026 00:00:00 +0000

Cortical control of movement is a distributed computation spanning multiple densely interconnected regions. Although we have rich anatomical atlases and a coarse understanding of how function maps to areas and subregions, we lack a detailed account of how behaviorally relevant activity is organized across the cortical sheet. Here, we trained head-fixed mice to perform a 15-target reach-to-grasp task while we performed cellular-resolution, two-photon calcium imaging across five regions of sensorimotor cortex (>39,000 layer 2/3 neurons). We characterized each neuron’s trial-averaged peri-event activity with interpretable metrics and mapped these response properties across areas, revealing large-scale spatial structure. Neuronal response profiles often shifted abruptly at anatomical borders: motor areas showed sharper tuning and more linear relationships with target location, whereas somatosensory areas displayed more heterogeneous response patterns. Neural response properties also differed according to somatotopic representation. Nonlinear dimensionality reduction of the neural feature matrix revealed that areas varied in their average response profiles, but that areas did not have well-separated feature distributions; instead, each area contained subpopulations. Neurons in each subpopulation had characteristic response profiles and were distributed across multiple cortical areas. The spatial distributions of the subpopulations overlapped, with neurons from different subpopulations salt-and-pepper intermingled in the overlap zones. Together, these results describe novel activity structure across sensorimotor cortex and identify several distinct but spatially overlapping subpopulations with characteristic activity patterns during reach-to-grasp behavior.

The exquisite mechanics of a tsetse bite

aacosta3@nd.edu (Álvaro Acosta-Serrano) — Thu, 02 Jul 2026 00:00:00 +0000

Specialized anatomical structures in the mouth and feet of tsetse flies help them feed on blood from a variety of hosts.

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation

jalees@uic.edu (Chinnaswamy Tiruppathi) — Wed, 01 Jul 2026 00:00:00 +0000

Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

Distinct involvements of the subthalamic nucleus subpopulations in reward-biased decision-making in monkeys

lding@pennmedicine.upenn.edu (Joshua I Gold) — Wed, 01 Jul 2026 00:00:00 +0000

The subthalamic nucleus (STN) is a part of the indirect and hyperdirect pathways in the basal ganglia (BG) and has been implicated in movement control, impulsivity, and decision-making. We recently demonstrated that, for perceptual decisions, the STN includes at least three subpopulations of neurons with different decision-related activity patterns (Branam et al., 2024). Here, we show that, for decisions that require both perceptual and reward-based processing, many STN neurons are sensitive to both sensory evidence and reward expectations. Within a drift-diffusion framework, three STN subpopulations show different relationships to model components reflecting the formation of the decision variable, dynamics of the decision bound, and non-decision-related processes. Many STN neurons also represent quantities related to decision evaluation, including choice accuracy and reward expectation. These results help to further delineate the multiple roles that STN plays in forming and evaluating complex decisions that combine multiple sources of information.

Experimental evolution to thermal stress indicates climate resilience in a cosmopolitan arthropod

sjyou@fafu.edu.cn (Fengluan Yao) — Tue, 30 Jun 2026 00:00:00 +0000

Adaptive evolution enables species to survive and thrive under changing environmental conditions. In the face of accelerating global climate change, thermal stress represents a major challenge to the persistence of terrestrial arthropods. Understanding the genetic mechanisms underlying thermal adaptation is therefore critical for predicting species’ evolutionary potential and future success. Here, we combine experimental evolution, phenotypic assays, and multi-omics analyses to investigate the adaptive responses of the diamondback moth (Plutella xylostella), a globally destructive pest of cruciferous crops, to contrasting thermal environments. Populations evolved under hot (32 °C/27 °C) and cold (15 °C/10 °C) regimes exhibited distinct life history and fitness traits relative to those maintained under favorable conditions (26 °C). The hot strain showed accelerated development, higher fecundity, and increased survival under extreme heat, while the cold strain exhibited lower supercooling and freezing points, indicating enhanced cold hardiness. Integrated transcriptomic and metabolomic analyses revealed extensive transcriptional reprogramming and convergent metabolic adjustments, notably a reduction in lipid metabolism to conserve energy under thermal stress. Crucially, non-synonymous mutations in PxSODC enhance superoxide scavenging efficiency, enabling effective oxidative stress management at lower gene expression levels. Furthermore, we identified epigenetic regulation via DNA methylation as a key mediator of this thermal tolerance. Together, these coordinated mutational, epigenetic, and metabolic insights highlight this arthropod’s capacity for global dispersal and likely persistence under climate change, establishing a framework for understanding equivalent effects in other species.

Restraint of melanoma progression by cells in the local skin environment

richard.white@ludwig.ox.ac.uk (Emily Montal) — Tue, 30 Jun 2026 00:00:00 +0000

Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an epithelial-mesenchymal transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT-transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b–jam3b and pgrn–sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell–cell interactions.

Brawn before bite in endemic Asian eutherian mammals after the end-Cretaceous extinction

zjt@berkeley.edu (Qian Li) — Tue, 30 Jun 2026 00:00:00 +0000

The first 10 million years (Myr) following the Cretaceous-Paleogene (K-Pg) mass extinction marked a period of global greenhouse conditions and dramatic rise of placental mammals. Because ~80% of known terrestrial sections capturing post-K-Pg mammal recovery come from North America, a substantial knowledge gap exists in the tempo and mode of recovery in Asia, where only 3% of global sites are located and most contain species found nowhere else. We show that isolated Paleocene eutherian assemblages from China (1) exhibited high mean tooth size and disparity early in the Paleocene, (2) shifted in their dental shape in parallel with regional and global environmental changes later in the Paleocene, and (3) achieved maximum dental shape-performance covariation near the end of the first 10 Myr post-K-Pg. This ‘brawn before bite’ transformation, coupled with prolonged dental shape versus performance variability, favors a scenario whereby many living orders of eutherian mammals were borne out of phenotypically and functionally plastic ancestral assemblages, including those in tropical South China, during the Paleocene.

Correlates of protection against African swine fever virus identified by a systems immunology approach

artur.summerfield@unibe.ch (Artur Summerfield) — Mon, 29 Jun 2026 00:00:00 +0000

African swine fever virus (ASFV) causes a fatal hemorrhagic disease in domestic pigs and wild boars, which poses severe threats to the global pork industry. Despite the promise of live attenuated vaccines (LAVs), their narrow margin between efficacy and residual virulence presents major safety challenges. This study bridges a critical knowledge gap in ASF vaccinology by identifying innate and adaptive correlates of protection. This was achieved by using an established model with two groups of pigs differing in baseline immunological status (farm and specific pathogen-free [SPF]). The animals were immunized with an attenuated ASFV strain and subsequently challenged with a related, highly virulent genotype II strain. By applying a systems immunology approach, we correlated kinetic data, including serum cytokines, blood transcription modules (BTMs), T-cell responses, and antibody levels, with clinical outcomes to track protective and detrimental immune responses to the virus over time. Key innate correlates of protection included early and sustained IFN-α response, activation of antigen presentation BTMs, and controlled IL-8 levels during immunization. Lower baseline immune activation observed in SPF pigs in steady state was linked to increased protection. Adaptive correlates encompassed cell cycle, plasma cell, and T-cell BTM responses lasting until day 15 post-immunization. Consequently, an effective response from ASFV-specific T_h cells prior to challenge indicated protection. After the challenge, an early IFN-α response, along with low levels of pro-inflammatory cytokines and a strong induction of memory T_h and T_c cells, correlated with improved clinical outcomes. The model highlights the critical role of host-specific factors in vaccine efficacy and provides a valuable framework for optimizing ASFV vaccine design while distinguishing between protective and detrimental immune responses.

Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2/Gli1/Sf1 signaling axis

wdeshou@swu.edu.cn (Changle Zhao) — Mon, 29 Jun 2026 00:00:00 +0000

Desert Hedgehog (Dhh) mutations cause Leydig cell dysfunction, yet the mechanisms governing Leydig lineage commitment through Dhh-mediated receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, using CRISPR/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh/Patched 2 (Ptch2)/Glioma-associated oncogene homolog 1 (Gli1)/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (Oreochromis niloticus). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of ptch1 and ptch2 in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where ptch2 mutation did not impair testicular development, yet completely rescued the testicular defects in dhh mutants—consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector and transactivates sf1 expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLC differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas sf1-mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development.

Retrosplenial cortex enables context-dependent goal-directed sensorimotor transformation

pol.bechvilaseca@epfl.ch (Anthony Renard) — Mon, 29 Jun 2026 00:00:00 +0000

The ability to dynamically adjust a behavioral response to a stimulus depending on context is of critical importance for animals. To investigate the neural basis supporting context-dependent sensory processing, we developed a behavioral task in which mice changed their response to a single whisker deflection according to a continuously present contextual cue. Through unbiased optogenetic inactivation mapping, we found that neuronal activity in sensory and motor cortices contributed to task execution and, interestingly, we uncovered an unexpected role of the retrosplenial cortex (RSC) for contextual integration. Widefield calcium imaging revealed that the RSC was the first dorsal cortical area to show context discrimination in response to whisker stimulation, followed by the whisker motor cortex. Finally, we combined optogenetic inactivation with calcium imaging to define causal context-dependent changes in sensorimotor processing. Our cortex-wide mapping experiments thus begin to define key cortical nodes for context-dependent sensorimotor transformation and highlight an important contribution of RSC.

Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation

phsyuh@nus.edu.sg (Christopher Zhe Wei Lee) — Mon, 29 Jun 2026 00:00:00 +0000

As the resident tissue macrophage of the liver, Kupffer cells (KCs) play an important role in homeostasis and tissue support. However, current in vitro liver models often ignore the contribution of these KCs towards the proper response and function of the tissue. This is especially relevant when we consider the implications of immune-mediated drug injuries. To address this issue, we developed an isogenic co-culture system utilising iPSC-derived macrophages (iMacs) and hepatocytes (iHeps). Directly co-culturing iHeps with iMacs improved the differentiation and maturation of the iHeps, with significant downregulation of fetal hepatocyte markers as well as upregulation of cytochrome genes. Furthermore, the co-culture also imparted stronger KC identity to the iMacs in a contact-dependent manner, with iMacs cultured in iHep conditioned media alone showing weaker expression of key KC markers. Finally, challenging the iHep-iMac co-culture system with seven paradigm hepatotoxic compounds showed dose-dependent cytokine response in the five compounds associated with immune-mediated liver injuries while no significant changes were observed in the two compounds with no reported immune-dependent complications. This effect was also not recapitulated when the co-culture was instead performed with human peripheral blood monocyte-derived macrophages, suggesting that iMacs are essential for liver toxicity response. Taken together, our study shows not only the importance of macrophages in tissue systems, but also that the source of macrophages is critical to the development of accurate in vitro human models.

Frequency-dependent modulation of foveal contrast sensitivity by fine-scale exogenously triggered attention

yzh191@u.rochester.edu (Martina Poletti) — Mon, 29 Jun 2026 00:00:00 +0000

Exogenous attention is a rapid, involuntary mechanism that automatically reallocates processing resources toward salient stimuli. It enhances visual sensitivity in the vicinity of the salient stimulus, both in extrafoveal regions and within the high-acuity foveola. While the spatial frequencies (SFs) modulated by exogenous attention in extrafoveal vision are well characterized, it remains unknown how this mechanism operates within the foveola, which can resolve SFs up to 30 cycles per degree (CPD). Here, we examined which SFs were enhanced by fine-grained deployments of exogenous attention within this highest-acuity region of the visual field. Using high-precision eye-tracking to precisely localize gaze during attentional allocation, we found that exogenous attention at the foveal scale selectively enhances contrast sensitivity for low- to mid-range SFs (4–8 CPD), with no significant benefits for higher SFs (12–20 CPD). In contrast, attention-related benefits on asymptotic performance at the highest contrast were observed across a wide range of SFs. These results indicate that, despite the high-resolution capacity of the foveola, exogenous attention remains an inflexible mechanism that, even at this scale, selectively enhances contrast gain for lower SFs—mirroring its behavior in extrafoveal vision.

Disinformation elicits learning biases

juan.perez.21@ucl.ac.uk (Juan Vidal-Perez) — Fri, 26 Jun 2026 00:00:00 +0000

In open societies, disinformation is often considered a threat to the very fabric of democracy. However, we know little about how disinformation exerts its impact, especially its influence on individual learning processes. Guided by the notion that disinformation exerts its pernicious effects by capitalizing on learning biases, we ask which aspects of learning from potential disinformation align with ideal ‘Bayesian’ principles, and which exhibit biases deviating from these standards. To this end, we harnessed a reinforcement learning framework, offering computationally tractable models capable of estimating latent aspects of a learning process as well as identifying biases in learning. In two experiments, participants completed a two-armed bandit task, where they repeatedly chose between two lotteries and received outcome-feedback from sources of varying credibility, who occasionally disseminated disinformation by lying about true choice outcome (e.g., reporting non-reward when a reward was truly earned or vice versa). Computational modelling indicated that learning increased in tandem with source credibility, consistent with ideal-Bayesian principles. However, we also observed striking biases reflecting divergence from idealized Bayesian learning patterns. Notably, in one experiment individuals learned from sources that should have been ignored, as these were known to be fully unreliable. Additionally, the presence of disinformation elicited exaggerated learning from trustworthy information (akin to jumping to conclusions) and exacerbated a normalized measure of ‘positivity bias’ whereby individuals self-servingly boost their learning from positive, relative to negative, choice feedback. Thus, in the face of disinformation we identify specific cognitive mechanisms underlying learning biases, with potential implications for societal strategies aimed at mitigating its harmful impacts.

Differential regulation of hepatic macrophage fate by Chi3l1 in metabolic dysfunction-associated steatotic liver disease

shanzhaolab@163.com (Bo Chen) — Fri, 26 Jun 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression involves the replacement of protective embryo-derived Kupffer cells (KCs) by inflammatory monocyte-derived macrophages (MoMFs), yet the regulatory mechanisms remain unclear. Here, we identify chitinase 3-like 1 (Chi3l1/YKL-40) as a critical metabolic regulator of hepatic macrophage fate. We observed high expression of Chi3l1 in both KCs and MoMFs during MASLD development. Genetic deletion of Chi3l1 specifically in KCs significantly exacerbated MASLD severity and metabolic dysfunction, whereas MoMF-specific Chi3l1 deletion showed minimal metabolic effects. Mechanistic studies revealed that this cell type-specific regulation arises from differential metabolic requirements: KCs display elevated glucose metabolism compared to MoMFs. Chi3l1 directly interacts with glucose to inhibit its cellular uptake, thereby selectively protecting glucose-dependent KCs from metabolic stress-induced cell death while having negligible effects on less glucose-dependent MoMFs. These findings uncover a novel Chi3l1-mediated metabolic checkpoint that preferentially maintains KCs populations through glucose metabolism modulation, providing important new insights into the pathogenesis of MASLD and potential therapeutic strategies targeting macrophage-specific metabolic pathways.

Deciphering interferon functions in avian influenza using receptor knockout models in the natural host

benjamin.schusser@tum.de (Arne Reich) — Fri, 26 Jun 2026 00:00:00 +0000

The rapid cross-species transmission of highly pathogenic avian influenza presents a significant zoonotic threat. Elucidating the avian interferon (IFN) system, the primary antiviral defense in chickens, is critical for controlling the virus at its source and preventing its spillover into humans and other species. We engineered type I (IFN-α/β) and type III (IFN-λ) IFN receptor knockout chickens to dissect the role of IFNs in viral infections. Results revealed that type I IFN predominantly modulates innate immune cell populations, T cell subsets, and their contribution to antibody production following immunization under physiological conditions. In ovo and in vivo challenge experiments utilizing diverse influenza A virus strains demonstrated strain-specific roles of both IFN-α/β and IFN-λ in orchestrating viral pathogenesis, immunological responses, and tissue-tropism effects. Notably, type I IFN was particularly crucial in the initial defense mechanisms against H3N1 avian influenza A virus infection. These novel models offer unprecedented insights into avian IFN biology within the context of avian influenza, which is essential for developing more effective strategies to prevent and control this public health challenge.

Conformational variability of HIV-1 Env trimer and viral vulnerability

wonpil@lehigh.edu (Wonpil Im) — Fri, 26 Jun 2026 00:00:00 +0000

Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) is critical for viral fusion and entry into host cells and remains a primary target for vaccine and antiviral drug development. Advances in soluble gp140 trimer design have provided insight into the ectodomain structure and dynamics. While structural information is available for the membrane-proximal external region (MPER) and transmembrane domain (TMD), these regions remain comparatively understudied. Furthermore, high-resolution structural information for the cytoplasmic tail (CT), particularly within the context of the intact trimer, is limited and largely uncertain. Additionally, previous studies have typically treated the ectodomain and TMD as separate entities. To investigate the trimeric gp120–gp41 as a complete entity and its structural flexibility, we built a full-length model of the gp120–gp41 trimer that is fully glycosylated with N-linked glycans and embedded in a lipid bilayer, and performed all-atom molecular dynamics simulations. Our results show that the ectodomain maintains a rigid internal structure stable in the prefusion state, whereas the intrinsic flexibility of the MPER enables the ectodomain to adopt a range of tilted orientations, potentially enhancing spatial alignment for receptor engagement. The centrally positioned R696 residue in the TMD interacts with lipid headgroups, ions, and CT residues, resulting in conformational variability in the TMD and perturbations in the surrounding membrane that may facilitate the fusion process. Finally, we demonstrate how simulation trajectories can be leveraged to evaluate the accessibility of antibody epitopes across different regions of the protein.

Correction: Generation of a transparent killifish line through multiplex CRISPR/Cas9mediated gene inactivation

Fri, 26 Jun 2026 00:00:00 +0000

Estimating probabilities of malaria importation in southern Mozambique through modelling P. falciparum genomics and mobility patterns

arnau.pujol@isglobal.org (Alfredo Mayor) — Fri, 26 Jun 2026 00:00:00 +0000

Imported malaria is a critical obstacle to achieving elimination in low transmission settings, but importation classification tools combining human mobility and parasite genomics are lacking. A Bayesian model combining epidemiological, human mobility, and parasite genetic data was developed to estimate malaria importation and geographic origins of Plasmodium falciparum cases. Using microhaplotype-based genetic relatedness from 1605 samples across nine Mozambican provinces in 2022, the study focused on two low-transmission districts in the south: Magude and Matutuine. Parasites from southern Mozambique showed lower genetic relatedness to those from northern/central regions (0.021) than the national average (0.034, p<0.001), indicating limited connectivity. Overall, 42% (88/207) of infections in these districts were classified as imported, mainly originating from Inhambane province (63% [55/88]). Imported cases showed higher parasite complexity than local ones (odds ratios [OR] = 1.3). Importation rates differed markedly between districts – Matutuine (48.60%, 87/179) was far more affected than Magude (10.71%, 3/28) – highlighting the need for localised rather than uniform elimination strategies. In Matutuine, importation appears to be actively sustaining transmission, suggesting that reducing malaria burden in source regions (particularly Inhambane) and targeting travellers from central and northern Mozambique would have the greatest elimination impact.

Intrinsic properties link a network model to zebra finch song

nelsmedina010@gmail.com (Dan Margoliash) — Thu, 25 Jun 2026 00:00:00 +0000

Neuronal intrinsic excitability is a mechanism implicated in learning and memory that is distinct from synaptic plasticity. Prior work in songbirds established that intrinsic properties (IPs) of premotor basal-ganglia-projecting neurons (HVC_X) relate to learned song. Here, we find that temporal song structure is related to specific HVC_X IPs: HVC_X from birds who sang longer songs, including longer invariant vocalizations (harmonic stacks), had IPs that reflected increased post-inhibitory rebound. This suggests a rebound excitation mechanism underlying the ability of HVC_X neurons to integrate over long periods of time throughout the song and represent sequence information. To explore this, we constructed a network model of realistic neurons showing how in vivo HVC bursting properties link rebound excitation to network structure and behavior. These results demonstrate an explicit link between neuronal IPs and learned behavior. We propose that sequential behaviors exhibiting temporal regularity require IPs to be included in realistic network-level descriptions.

A cell atlas of the developing human outflow tract of the heart and its adult aortic valve derivatives

simon.bamforth@newcastle.ac.uk (Andrew D Sharrocks) — Thu, 25 Jun 2026 00:00:00 +0000

The outflow tract (OFT) of the heart carries blood away from the heart into the great arteries. During embryogenesis, the OFT divides to form the aorta and pulmonary trunk, creating the double circulation present in mammals. Defects in this area account for one-third of all congenital heart defect cases. Here, we present comprehensive transcriptomic data on the developing OFT at two distinct time points (embryonic and fetal) and its adult derivatives, the aortic valves, and use spatial transcriptomics to define the distribution of cell populations. We uncover that distinctive embryonic signatures persist in adult cells and can be used as labels to retrospectively attribute relationships between cells separated by a large timescale. Single-cell regulatory network inference identifies GATA6, a transcription factor linked to common arterial trunk and bicuspid aortic valve, as a key regulator of valve precursor cells. Its downstream network reveals candidate drivers of human cardiac defects and illuminates the molecular mechanisms of both normal and pathological valve development. Our findings define the cellular and molecular signatures of the human OFT and its distinct cell lineages, which is critical for understanding congenital heart defects and developing cardiac tissue for regenerative medicine.

Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation

serafinia@yahoo.it (Acely Garza-Garcia) — Thu, 25 Jun 2026 00:00:00 +0000

In this study, we investigated how iron limitation alters central metabolism in Mycobacterium tuberculosis using metabolomics and stable isotope tracing. Our findings reveal a well-orchestrated metabolic programme to enable Krebs cycle activity despite the inefficient action of its iron-dependent enzymes. Under such conditions, carbon flux through the oxidative branch of the Krebs cycle is stalled, resulting in the accumulation of metabolites that are partially secreted. As a result, carbon flux from glycolysis is partially diverted to the reductive branch of the Krebs cycle to support the production of oxaloacetate and malate through the activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase. Both branches terminate with the synthesis of malate, which is secreted. This unprecedented split of the Krebs cycle and malate secretion in a bacterial pathogen facilitates the continuous flow of carbon through the core of carbon metabolism, overcoming the metabolic stalling triggered by iron starvation.

Controlling the synchronization and symmetry breaking of coupled bacterial pili on active biofilm carpets

akocabas@ku.edu.tr (Alp Ünlü) — Thu, 25 Jun 2026 00:00:00 +0000

In the low Reynolds number regime, active biological systems utilize nonreciprocal cyclic activities to achieve motility, as seen in the spinning of bacterial flagella and the beating of cilia. Coupling among these active mechanical components leads to synchronization and emergence of metachronal waves. Here, we report that biofilms of Pseudomonas nitroreducens form active carpet-like surfaces textured with diverse topological defects, generating Mexican-wave-like collective behavior in which bacteria periodically lift up. On these active surfaces, non-reciprocally coupled extension and retraction activities of bacterial pili drive these collective oscillations. Surprisingly, this collective behavior exhibits left-right asymmetry across the biofilm driving unidirectionally propagating waves. We discover that this directionality is primarily governed by an aging-related frequency gradient across the biofilm. Leveraging these insights, we further demonstrate the ability to control the collective dynamics of these waves, including symmetry breaking, transitions from spiral waves into target and propagating plane waves by manipulating the elastic properties of biofilms. Overall, our findings illuminate the fundamental role of nonreciprocally interacting active components in regulating synchronization, collective dynamics, and symmetry-breaking phenomena in biological systems.

SynaptoTagMe, a toolkit for in vivo mapping and modulating neurotransmission at single-cell resolution

daniel.colon-ramos@yale.edu (Aaron Wolfe) — Thu, 25 Jun 2026 00:00:00 +0000

Understanding the organization and regulation of neurotransmission at the level of individual neurons and synapses requires tools that can track and manipulate transmitter-specific vesicles in vivo. Here, we present SynaptoTagMe, a suite of genetic tools in Caenorhabditis elegans to fluorescently label and conditionally ablate the vesicular transporters for glutamate, GABA, acetylcholine, and monoamines. Using a structure-guided approach informed by protein topology and evolutionary conservation, we engineered endogenously tagged versions for each transporter that maintain their physiological function while allowing for cell-specific, bright, and stable visualization. We also developed conditional knockout strains that enable targeted disruption of neurotransmitter synthesis or packaging in single neurons. We applied this toolkit to map co-expression of vesicular transporters across the C. elegans nervous system, revealing that over 10% of neurons exhibit co-transmission. Using the ADF sensory neuron as a case study, we demonstrate that serotonin and acetylcholine are trafficked in partially distinct vesicle pools. Our approach provides a powerful platform for mapping, monitoring, and manipulating neurotransmitter identity and use in vivo. The molecular strategies described here are likely applicable across species, offering a generalizable approach to dissect synaptic communication in vivo.

Systematic characterisation of site-specific proline hydroxylation using hydrophilic interaction chromatography and mass spectrometry

Sonia.Rocha@liverpool.ac.uk (Angus I Lamond) — Thu, 25 Jun 2026 00:00:00 +0000

We have developed a robust workflow to identify proline hydroxylation sites in proteins, combining hydrophilic interaction chromatography (HILIC) enrichment and high-resolution nano-liquid chromatography-mass spectrometry (LC-MS) with refining and filtering parameters during data analysis. Using this approach, we have combined data from cell lines treated with either the prolyl hydroxylase (PHD) inhibitor, Roxadustat (FG-4592), or with the proteasome inhibitor MG-132, or with a DMSO control, to identify a total of 4993 and 3247 proline hydroxylation sites, respectively, in HEK293 and RCC4 cells. Of these, 1954 (HEK293) and 1253 (RCC4) high-confidence non-collagen sites were inhibited by FG-4592. Hydroxylated peptides showed consistent characteristics across both datasets, including enrichment in more hydrophilic HILIC fractions and distinct charge and mass distributions compared to unmodified or oxidised peptides. The intensity of the diagnostic hydroxyproline immonium ion varied with MS collision energy, peptide concentration, and adjacent amino acid sequence. Using synthetic peptides, we demonstrate that combining LC retention time with optimised MS parameters enables reliable site identification, even with multiple proline residues present. Proteins with FG-4592-inhibited hydroxylation sites were enriched for roles in RNA metabolism, mRNA splicing, and cell cycle regulation, including the phosphatase 1 regulatory subunit Repo-Man (CDCA2).

Structural insights into the recruitment of viral type 2 IRES to ribosomal preinitiation complex for protein synthesis

hussain@iisc.ac.in (Deepakash Das) — Thu, 25 Jun 2026 00:00:00 +0000

Picornaviruses employ internal ribosome entry sites (IRESs) in their genomic RNA to hijack the host’s translational machinery. The picornavirus, encephalomyocarditis virus, employs a type 2 IRES present in its 5’ untranslated region (5’UTR) and requires 43S ribosomal preinitiation complex (PIC), the central domain of eukaryotic initiation factor (eIF) 4G, eIF4A, and an essential ITAF (IRES trans-acting factor)-polypyrimidine tract binding protein 1 (PTB1) to form 48S PIC. In this study, we have used cryo-electron microscopy (cryo-EM) to determine the structure of encephalomyocarditis virus (EMCV) IRES-bound mammalian 48S PIC in a scanning-arrested closed state at the start codon. The EMCV IRES domains contact initiator tRNA (tRNA_i) and 40S head at the inter-subunit interface, which reveals an altogether unique mechanism used by viruses to capture host translational machinery for its protein synthesis. The tRNA_i is held away from the 40S body in contrast to canonical cap-dependent translation while the domain I apical region of EMCV IRES mimics 28S rRNA of 60S to interact with 40S ribosomal head proteins uS13 and uS19. The structural analysis accounts for numerous previously reported biochemical studies on type 2 IRES and shows how type 2 IRES interacts with 43S PIC to form 48S PIC. This study provides mechanistic insights for understanding EMCV IRES-mediated translation initiation, which could be extrapolated to other IRESs sharing similar motifs and factor requirements, including type 1 viral IRESs.

PHD1-dependent hydroxylation of RepoMan (CDCA2) on P604 modulates the control of mitotic progression

j.r.swedlow@dundee.ac.uk (Adrian T Saurin) — Thu, 25 Jun 2026 00:00:00 +0000

Prolyl-hydroxylases (PHDs) are oxygen-sensing enzymes that mediate the hydroxylation of proline residues. In mammals, three PHD isoforms (PHD1–3) are responsible for proline hydroxylation of hypoxia-inducible factor (HIF) alpha, a key regulator of the hypoxia response. In the accompanying paper (Jiang et al., 2025), we report development of a mass spectrometry-based method to reliably identify proline hydroxylation (OH-Pro) sites on proteins and use this to identify a PHD-dependent OH-Pro modification at Pro604 on the protein RepoMan (CDCA2), a regulatory subunit for protein phosphatase PP1γ with important roles in mitotic progression and cell viability. Here, we investigate the functional significance of hydroxylation of RepoMan at P604. During M phase, the PP1-RepoMan complex dephosphorylates Thr3 of Histone H3 (H3T3) on chromosome arms to ensure the correct localisation of the chromosomal passenger complex (CPC) at centromeres. We show that siRNA depletion of PHD1, but not PHD2, increases H3T3 phosphorylation in prometaphase-arrested cells. In cells depleted of endogenous RepoMan, exogenous expression of wild-type RepoMan, but not a RepoMan-P604A mutant, restored normal H3T3 phosphorylation localisation in prometaphase arrested cells. RepoMan-P604 is located proximal to the short linear motifs (SLiMs) that function as binding sites for the serine/threonine protein phosphatase 2A (PP2A). The interaction of RepoMan and PP2A-B56γ is reduced in cells expressing RepoMan-P604A. Moreover, analyses in both fixed and live cells released from a prometaphase arrest show that expression of the RepoMan-P604A mutant delays completion of mitosis, results in defects in chromosome alignment and segregation, and increases levels of cell death. These data support a role for PHD1-mediated prolyl hydroxylation in controlling progression through mitosis, acting, at least in part, via hydroxylation of RepoMan at P604 regulating the interaction of RepoMan with PP2A during chromosome alignment and thereby controlling the levels of Histone H3 phosphorylation at Thr3.

A pilot study for whole proteome tagging in Caenorhabditis elegans

me2839@columbia.edu (Matthew Eroglu) — Wed, 24 Jun 2026 00:00:00 +0000

Tagging all proteins encoded by an animal genome with a fluorescent tag would open many windows to the discovery of unexpected patterns of protein expression and localization. To scale such an approach, it would be beneficial to introduce multiple, spectrally distinct fluorophore tags in parallel. As proof of concept for scalable pooled tagging, we undertook a pilot study in the nematode Caenorhabditis elegans, in which we set out to tag 30 different genetic loci with three different fluorophores, with three tags being introduced at a time. By choosing essential genes, predicted based on transcriptomics to cover a range of expression levels, we explore issues relating to disrupting gene function and visibility of tagged proteins. We demonstrate that such a tagging approach is highly efficient and indeed reveals unanticipated patterns of cellular and subcellular sites of protein expression and localization. We hope that this pilot study will motivate attempts to scale this tagging approach to more loci and, ultimately, the whole genome.

Arousal modulates functional connectivity through structured and hemispherically asymmetric community architecture during wakefulness

gaolang.gong@bnu.edu.cn (Gaolang Gong) — Wed, 24 Jun 2026 00:00:00 +0000

Arousal fluctuates continuously during wakefulness, yet how these moment-to-moment variations shape large-scale functional connectivity (FC) remains unclear. Here, we combined 7T fMRI with concurrent pupillometry to quantify, for every functional connection, how time-varying FC covaries with spontaneous arousal in the awake human brain. Rather than exerting a uniform influence across the connectome, arousal organized FC into a low-dimensional set of seven connectivity communities, each defined by characteristic network compositions. These communities exhibited systematic hemispheric asymmetries, specifically identifying a ‘left-hemisphere centripetal architecture’ where the left hemisphere serves as a structural sink for the asymmetric convergence of arousal-modulated signals. Importantly, hemispheric asymmetry did not arise from global shifts in connectivity strength but instead reflected structured spatial heterogeneity embedded within community architecture. This modular and asymmetric organization was highly preserved during naturalistic movie watching, indicating that arousal-related modulation of FC reflects intrinsic principles that generalize across awake cognitive contexts. Together, these findings demonstrate that moment-to-moment arousal fluctuations shape large-scale FC through structured, hemispherically asymmetric network organization during wakefulness.

Verbal Episodic Processing in Newborns

silvia.benavidesvarela@unipd.it (Ana Fló) — Wed, 24 Jun 2026 00:00:00 +0000

During the first period of life, human infants rapidly and effortlessly acquire the languages they are exposed to. Although memory is central to this process, the nature of early verbal memory systems, and the factors that determine retention and forgetting, remain largely unknown. Behavioral and brain measures have demonstrated memory formation in newborns. However, word traces fade in the face of acoustic overlap, leading to interference and forgetting. Here, we investigate whether speakers' identity changes facilitate the separation into distinct acoustic episodes and the creation of non-overlapping verbal memories. Newborns (0–4 days-old) were tested in a familiarization-interference-test protocol, while neural cortical activity was recorded using functional Near-Infrared Spectroscopy (fNIRS). The results showed higher neural activation to novel words than to familiar ones during the test phase, indicating that the infants recognized the familiar words despite potentially interfering sounds. The recognition response was measured over the left inferior frontal gyrus (IFG) and superior temporal gyrus (STG) areas known to be crucial for encoding auditory information and language processing. The neural response also included the right IFG and STG, involved in interpreting vocal social cues and speaker recognition. The results indicate that speaker identity is a key feature in the formation of verbal memories from birth, facilitating separability, possibly through early source–content binding (i.e. what–who), a precursor to fully mature episodic memory.

Correction: SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion

Wed, 24 Jun 2026 00:00:00 +0000

Building bundles by the numbers

andela.saric@ist.ac.at (Anđela Šarić) — Tue, 23 Jun 2026 00:00:00 +0000

The size and shape of cytoskeletal bundles, essential regulators of cell function, emerge from collective filament assembly rather than precise size-control mechanisms.

Patient-specific midbrain organoids with CRISPR correction recapitulate neuronopathic Gaucher disease phenotypes and enable evaluation of novel therapies

ying.sun@cchmc.org (Ahmet Kaynak) — Tue, 23 Jun 2026 00:00:00 +0000

Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with GBA1^L444P/P415R and GBA1^{L444P/RecNcil} mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.

From multiplicity of infection to force of infection in sparsely sampled high-transmission Plasmodium falciparum populations

qz1111@stanford.edu (Karen P Day) — Tue, 23 Jun 2026 00:00:00 +0000

High multiplicity of infection (MOI), the number of genetically distinct parasite strains co-infecting a host, characterizes falciparum malaria and other infectious diseases under high transmission. High MOI in Plasmodium falciparum accompanies high prevalence of asymptomatic infection despite high exposure, creating a large transmission reservoir that challenges intervention. This pattern is enabled by parasite immune evasion through extensive antigenic diversity. The force of infection (FOI), the number of new infections acquired by an individual host over a given time interval, is the dynamic counterpart of MOI and a key epidemiological parameter for monitoring antimalarial interventions. FOI is difficult and costly to measure, especially in high-transmission regions, requiring cohort studies or model-based inference from repeated cross-sectional surveys. Here, we apply queuing theory to estimate FOI from MOI with two approaches: a two-moment approximation and Little’s Law. We illustrate these methods using MOI estimates obtained under sparse sampling schemes with the ‘varcoding’ approach. Both methods rely on infection duration data from naive malaria therapy patients and are therefore suitable for subpopulations with limited immunity, such as toddlers. We evaluate their performance using output from a stochastic agent-based model and apply the methods to an interrupted time-series study in northern Ghana, before and immediately after a three-round transient indoor residual spraying intervention. By accounting for sampling limitations with a Bayesian framework and bootstrap imputation, both methods yield good and replicable FOI estimates across various simulated scenarios. Their application to the surveys of 1- to 5-year-old children in Ghana indicates a larger than 70% reduction in annual FOI immediately after intervention.

Intraflagellar transport protein IFT172 contains a C-terminal ubiquitin-binding U-box-like domain involved in ciliary signaling

bhogaraju@embl.fr (Anna Lorentzen) — Tue, 23 Jun 2026 00:00:00 +0000

Intraflagellar transport (IFT) is a fundamental process driving ciliogenesis in most eukaryotic organisms. IFT172, the largest protein of the IFT complex, plays a crucial role in cilium formation, and several disease-causing IFT172 variants have been identified in ciliopathy patients. While IFT172 is tethered to the IFT-B complex via its N-terminal domains, the function of its C-terminal domains has remained elusive. Here, using both human and Chlamydomonas reinhardtii IFT172, we reveal that the C-terminal part of IFT172 interacts with IFT-A complex subunits, providing a molecular basis for the role of IFT172 in bridging IFT-A and IFT-B complexes. We determine the crystal structure of the C-terminal part of IFT172, uncovering a conserved U-box-like domain often found in E3 ubiquitin ligases. This domain exhibits ubiquitin-binding properties, and IFT172 undergoes ubiquitin conjugation in vitro, an activity that is reduced in the C1727R patient ciliopathy variant. We use CRISPR-engineered RPE-1 cells to demonstrate that the U-box-like domain is essential for IFT172 protein stability and proper cilium formation. Notably, RPE-1 cells with heterozygous deletion of the U-box domain show altered TGF-β signaling responses, particularly in SMAD2 phosphorylation levels and AKT activation. Our findings suggest that IFT172, beyond its structural role in bridging IFT-A and IFT-B complexes within IFT trains, harbors a conserved U-box-like domain with potential involvement in ciliary ubiquitination processes and signaling, providing new insights into the molecular mechanisms underlying IFT172-related ciliopathies.

Paraventricular thalamus hyperactivity mediates stress-induced sensitization of unlearned fear but not stress-enhanced fear learning (SEFL)

kjn549@eid.utexas.edu (Denisse Paredes) — Mon, 22 Jun 2026 00:00:00 +0000

Exposure to stress can cause long-lasting enhancement of fear and other defensive responses that extend beyond the cues or contexts associated with the original traumatic event. These nonassociative consequences of stress, referred to as fear sensitization, are thought to underlie some symptoms of trauma-related disorders. Fear sensitization has been predominantly studied using the stress-enhanced fear learning (SEFL) paradigm, which models the stress-induced amplification of fear learning. Less is known about the mechanisms through which unlearned fear responses are sensitized by stress. Here, we investigated the neural mechanisms for sensitization of unlearned fear responses using a paradigm we termed stress-enhanced fear responding (SEFR). In this model, mice exposed to a single session of footshock stress exhibit enhanced freezing to a novel tone stimulus. To investigate brain regions that might mediate SEFR, we first used c-Fos mapping to identify neural activity changes associated with stress-induced enhancement of unlearned fear. Our c-Fos screen identified the posterior paraventricular thalamus (pPVT) as a region that was persistently hyperactive after footshock stress and whose activity correlated with behavioral expression of SEFR. Using fiber photometry, we observed that SEFR, but not SEFL, was associated with increased activity in the pPVT. Next, we found that chemogenetic inhibition of the pPVT blocked both the induction of SEFR during stress and its later expression, while artificial stimulation of pPVT in stress-naive mice was sufficient to recapitulate SEFR. Interestingly, pPVT inhibition or stimulation did not affect acquisition or expression of SEFL. In conclusion, our results indicate that sensitization of fear learning (SEFL) and sensitization of unlearned fear (SEFR) have distinct neural mechanisms. Our results identify pPVT hyperactivity as a mechanism for stress-induced sensitization of unlearned fear and highlight pPVT as a potential target for treating arousal and reactivity symptoms of trauma- and stressor-related disorders.