eLife: latest articles

Optimising the tilt increment for in situ cryo-electron tomography

Martin.Beck@biophys.mpg.de (Beata Turoňová) — Mon, 24 Aug 2026 00:00:00 +0000

Cryo-electron tomography (cryo-ET) enables high-resolution, three-dimensional imaging of cellular structures in their native, frozen state. However, image quality is limited by a trade-off between angular sampling and radiation damage. Therefore, the choice of the angular increment during data collection is a critical parameter that affects tomogram quality and downstream analyses. Optimising this increment is challenging due to the high demands on microscope time, storage, and computation. In this study, we systematically evaluated tilt increments of 1°, 2°, 3°, 5°, and 10° using lamellae from Dictyostelium discoideum cells. We found that at a constant total electron dose, finer tilt increments (1–3°) produced better-aligned tomograms with higher signal-to-noise ratios and improved outcomes in template matching and subtomogram averaging. A 3° increment emerged as the optimal balance between data quality, alignment accuracy, dose per image, and processing efficiency. This practical recommendation supports both high-throughput and high-resolution structural studies and can guide future cryo-ET data acquisition strategies.

Correction: p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle

Fri, 21 Aug 2026 00:00:00 +0000

Crickets evade bats via olfaction beyond acoustic cues

fengj@nenu.edu.cn (Aiqing Lin) — Fri, 21 Aug 2026 00:00:00 +0000

The evolutionary arms race between insectivorous bats and their insect prey is a classic paradigm of acoustic predation and evasion, with insects having evolved sophisticated auditory countermeasures. Both bats and insects also rely heavily on olfaction for key behaviors, such as social communication. Moreover, predator-derived odors are well established as risk cues in many other predator–prey systems. However, whether olfaction plays a role in the bat–insect arms race remains unknown. Here, we unveil a previously unknown olfactory dimension to this interaction. We demonstrated that the body odor of the insectivorous bat Scotophilus kuhlii triggered robust avoidance and electrophysiological antennal responses in a common cricket prey, Loxoblemmus equestris. We identified limonene as a behaviorally active volatile in bat odor that elicited electrophysiological responses in cricket antennae and was sufficient to elicit avoidance in crickets. Field experiments confirmed that limonene exposure reduced cricket calling activity, demonstrating the ecological relevance of this cue. Our findings establish that insects can detect and initiate avoidance of phylogenetically distant vertebrate predators via olfaction, a process that could be mediated by the elemental perception of individual odor compounds. This work broadens the sensory framework of a classic predator–prey system and highlights olfactory eavesdropping as a functional strategy in phylogenetically distant predator–prey systems.

Visuomotor mismatch EEG responses over occipital cortex of freely moving human subjects

magdalena.solyga@fmi.ch (Georg B Keller) — Thu, 20 Aug 2026 00:00:00 +0000

Likely the strongest predictor of visual feedback is self-motion. In mice, the coupling between movement and visual feedback is learned with first visual experience of the world, and brief perturbations of the coupling result in strong visuomotor mismatch responses in visual cortex that possibly reflect prediction errors. In humans, predictive coding has primarily been studied using oddball paradigms, which rely on violations of stimulus probability based on recent sensory history. It was still unclear, however, whether humans exhibit visuomotor mismatch responses similar to those observed in mice. This question was important for two reasons. First, visuomotor mismatch responses in humans constitute a basis to start translating the mechanistic understanding of the circuit that computes these responses from mouse to human cortex. Second, a paradigm that can trigger strong prediction error responses and consequently requires shorter recording times would simplify experiments in a clinical setting. Here, by combining a wireless EEG recording system with a virtual reality headset, we found robust visuomotor mismatch responses in human cortex that were characterized by a reversed polarity relative to visual-evoked responses and a greater signal power than both visual responses and oddball mismatch responses.

Multiple molecular pathways to longevity with opposing gene expression programs defining distinct aging strategies in Caenorhabditis elegans

jeremy.vanraamsdonk@mcgill.ca (Aura A Tamez Gonzalez) — Thu, 20 Aug 2026 00:00:00 +0000

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived Caenorhabditis elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

Viral commitment to infection depends on host metabolism

anmaran@protonmail.com (Anastasios Marantos) — Thu, 20 Aug 2026 00:00:00 +0000

Viral infection begins with attachment to host surface structures such as receptors, pili, or porins. While prior research has focused on structural compatibility and recognition, the role of host physiology, particularly metabolic state, on viral commitment to infection remains underexplored. Here, we measured the adsorption rates (η) of five Escherichia coli phages representing various life cycles and entry pathways under controlled metabolic conditions. Four phages showed significantly reduced adsorption under energy-limited states, with weaker-binding phages being more sensitive. Using E. coli and its phages allowed us to institute a number of control infections that would be difficult with other organisms. Our findings support a two-step infection model where bound phages may disengage under unfavorable conditions, reducing commitment to non-productive infections. We observed a correlation between adsorption rates under energy-competent conditions and sensitivity to host metabolic state. Our results highlight host physiology as a key factor in virus–host interactions under energy-limited conditions.

Neural computations in the foveal and peripheral visual fields during active search

zhouhh@pcl.ac.cn (Hossein Esteky) — Thu, 20 Aug 2026 00:00:00 +0000

Active vision requires coordinated attentional processing across both foveal and peripheral receptive fields (RFs), yet the underlying neural dynamics and computational mechanisms remain poorly understood. Previous research has predominantly focused on attention in the visual periphery, leaving the role of foveal processing in naturalistic tasks largely unexplored. Here, we recorded neural activity from both foveal and peripheral RFs in areas V4 and IT of monkeys during free-gaze visual search among complex stimuli. We found robust feature-based attentional enhancements in foveal units, challenging the prevailing view that such modulation is predominantly peripheral. By integrating data from foveal and peripheral recordings, we revealed a non-uniform, dynamically distributed pattern of feature attention across the visual field. Behaviorally, foveal attentional enhancements promoted sustained or repeated fixations on targets, while peripheral attentional signals facilitated target detection and guidance of future saccades. These findings suggest that foveal and peripheral attention operate in a complementary fashion and highlight the critical role of foveal feature attention in shaping global attention allocation and fixation behavior during active vision. This work advances our understanding of the neural computations that support complex visual search and underscores the need to account for foveal processing in models of attention.

Thymic selection of the T cell receptor repertoire is biased toward autoimmunity in females

david.klatzmann@sorbonne-universite.fr (Adrien Six) — Thu, 20 Aug 2026 00:00:00 +0000

Women represent about 80% of patients with autoimmune diseases. This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females. To investigate this, we analyzed sex-specific differences in TCR generation and selection. We examined TCR repertoires in double-positive thymocytes and single-positive thymic cells, including CD8⁺ and CD4⁺ effector T cells and regulatory T cells (Tregs), derived from male and female organ donors. Minimal sex-based differences were observed in V and J gene usage, and there were no notable differences in TCR repertoire diversity, complementarity-determining region 3 (CDR3) length, amino acid composition, or network structure. No TCR sequences were exclusive to either sex. However, female effector T cells exhibited a significantly higher prevalence of TCRs specific to self-antigens implicated in autoimmunity compared to males, while female Tregs showed a reduced frequency of such TCRs. These differences were not observed for TCRs targeting self-antigens unrelated to autoimmunity or antigens associated with cancer or viruses. Our findings identify a sex-specific imbalance in thymic selection of TCRs with autoimmunity-associated specificities, providing mechanistic insight into the increased susceptibility of women to autoimmune diseases.

Heterogeneity of use, access, and retention of insecticide-treated nets: Implications for subnational tailoring to maximise malaria control

a.glover18@imperial.ac.uk (Andrew C Glover) — Thu, 20 Aug 2026 00:00:00 +0000

Three metabolic pathways replenishing the one-carbon pool collectively support growth and virulence of Listeria monocytogenes

sascha.kahlfuss@med.ovgu.de (Dunja Bruder) — Wed, 19 Aug 2026 00:00:00 +0000

The bacterium Listeria monocytogenes can grow in the cytoplasm of infected human cells, but there it relies on specific biosynthetic pathways for intracellular nutrient supply. We previously found that the glycine cleavage system (GCS) is needed for intracellular growth. The GCS decarboxylates glycine for generation of 1C-tetrahydrofolates (1C-THF), folate-dependent one-carbon donors needed for biosynthesis of other metabolites. We continued our studies on the GCS and showed that a L. monocytogenes ΔgcvPAB mutant, lacking the GCS glycine dehydrogenase, is attenuated without resembling the phenotype of classical virulence factor mutants. The ΔgcvPAB mutant also grew poorly in synthetic medium, explained by the presence of glycine that was toxic for this strain. Selection of glycine-resistant suppressors yielded a survivor, in which the N- and C-terminal parts of the formate-tetrahydrofolate ligase (fhs) gene, which is naturally separated into two parts by a premature stop codon in the L. monocytogenes reference strain EGD-e were reassembled into a full-length open-reading frame. Like the GCS, Fhs also feeds the 1C-THF pool, and its restoration cured the virulence defects of the ΔgcvPAB mutant. Another suppressor had a mutated glyA gene, encoding serine hydroxymethyltransferase, and combinatorial deletions of gcvPAB and glyA in fhs⁻ and fhs⁺ backgrounds demonstrated a role of GlyA in 1C-THF metabolism. Our results show that three pathways feed the 1C-THF pool to support growth and virulence of L. monocytogenes and represent the first example of the spontaneous reactivation of an L. monocytogenes gene that is inactivated by a premature stop codon.

Replicative slender bloodstream forms complete transmission of Trypanosoma brucei without prior differentiation into stumpy forms

markus.engstler@biozentrum.uni-wuerzburg.de (Anna Sophie Kreis) — Wed, 19 Aug 2026 00:00:00 +0000

We have previously shown that the slender form of Trypanosoma (T.) brucei is able to infect teneral tsetse flies, develop to the first fly form, which is the procyclic form, and complete the life cycle in the insect vector (Schuster et al., 2021). Further, analysis of the transmission index (TI; defined as the number of salivary gland infections relative to the number of midgut infections) revealed a higher TI for slender as compared to stumpy forms under laboratory conditions, which included the addition of N-acetylglucosamine (NAG) to the infective bloodmeal. Here, we show that slender trypanosomes can establish infections in both male and female tsetse flies and in both teneral and non-teneral flies without requiring supplements in the bloodmeal. Additionally, an RNA sequencing time course was performed on both slender and stumpy cells during their transition into procyclic forms. This analysis revealed that slender- and stumpy-form trypanosomes remain transcriptionally distinct throughout differentiation into the procyclic form. Furthermore, while the protein associated with differentiation 1 (PAD1) remains essential for the transition, slender cells do not require expression of other hallmark stumpy-form traits, such as cell-cycle arrest or the shortening of their flagella or microtubule corset. Instead, slender trypanosomes are able to transition directly into procyclic forms. Taken together, these findings demonstrate that slender cells of T. brucei can follow a distinct transcriptional trajectory towards the procyclic form and can establish infections in teneral and non-teneral tsetse flies, thereby contributing to the transmission and spread of these African parasites.

Overt visual attention modulates decision-related signals in the frontal cortex

krajbich@ucla.edu (Aidan Makwana) — Wed, 19 Aug 2026 00:00:00 +0000

When indicating a preference between two options, decision makers are thought to compare and accumulate evidence in an attention-guided process. Little is known about this process’s neural substrates or how visual attention affects the representations of accumulated evidence. We conducted a simultaneous eye-tracking and fMRI experiment in which human subjects gradually learnt about the value of two food-lotteries. With this design, we were able to extend decisions over a prolonged time-course, manipulate the temporal onset of evidence, and therefore, dissociate sampled and accumulated evidence. We observed inconsistent correlations of both sampled and accumulated evidence with activity in the ventromedial prefrontal cortex (vmPFC), the ventral striatum, and the intraparietal sulcus (IPS), and more consistent correlations of accumulated evidence with activity in the dorsolateral prefrontal cortex (dlPFC) and pre-supplementary motor area (pre-SMA). We also found that more gaze on an option increased its choice probability and that gaze consistently amplified accumulated-value signals above and beyond the non-gaze-modulated signals in the pre-SMA and partially in the dlPFC, providing novel evidence that visual attention has lasting effects on decision variables and suggesting that activity in the pre-SMA and dlPFC reflects gaze-weighted accumulated evidence. These results shed new light on the neural mechanisms underlying gaze-driven decision processes.

Scientific writing is not a murder mystery

c.a.dodson@bath.ac.uk (Charlotte A Dodson) — Wed, 19 Aug 2026 00:00:00 +0000

What murder mysteries can tell us about how not to write a scientific article.

TLR4 signaling drives tissue inflammation, Claudin-5 internalization, and vascular barrier breakdown in a mouse model of neonatal meningitis

jnathans@jhmi.edu (Amir Rattner) — Tue, 18 Aug 2026 00:00:00 +0000

Neonatal bacterial meningitis is a leading cause of infant morbidity and mortality, yet the molecular and cellular basis of the leptomeningeal response to infection remains poorly defined. Here, we study a mouse model of neonatal Escherichia coli meningitis, combining conditional gene knockouts, leptomeningeal single-nucleus RNA sequencing, and endothelial cell culture to explore the role of Toll-like receptor 4 (TLR4) signaling in the host response to infection. Deletion of Tlr4 in non-myeloid cells dramatically reduced the inflammatory response in all leptomeningeal cell types and abrogated the infection-associated increase in vascular permeability. In a brain endothelial cell line (bEnd.3 cells), exposure to E. coli triggered NF-κB activation, selective internalization of Claudin-5, and increased monolayer permeability, responses that were eliminated by Tlr4 knockout. RNA-seq showed that TLR4 controls an NF-κB–driven transcriptional program that orchestrates the endothelial response to E. coli. These findings reveal multiple TLR4-dependent host responses to neonatal Gram-negative bacterial meningitis.

Local inhibitory dynamics underpin temporal integration and functional segregation between barrels and septa in the mouse barrel cortex

argunsah@hifo.uzh.ch (Alexander van der Bourg) — Tue, 18 Aug 2026 00:00:00 +0000

Mice, like humans, enhance tactile perception through repeated sampling of spatially segregated sensory inputs. In the whisker system, individual whisker identity is preserved along the whisker-brainstem-thalamus-cortex pathway, culminating in distinct cortical domains: barrels and septa. Using simultaneous in vivo recordings from barrel and septal domains, we identify a progressive divergence in spiking activity during repeated single- and multi-whisker stimulation. While the multi- to single-whisker response ratio remains stable in barrels, it increases progressively in septa, suggesting recruitment of local inhibitory circuits. Genetic fate mapping and tissue clearing revealed distinct laminar and regional distributions of SST+ and VIP+ interneurons in barrel and septal domains. Calcium imaging showed that both interneuron types respond to whisker stimulation, but SST+ interneurons were preferentially recruited during repeated multi-whisker stimulation. Deletion of Elfn1, a regulator of excitatory synaptic dynamics onto SST+ interneurons, abolished the progressive increase in septal multi- to single-whisker response ratios. Temporal decoding analyses further demonstrated a loss of barrel-septa functional segregation in Elfn1 knockout mice. Finally, viral tracing combined with whole-brain clearing revealed distinct projection patterns from barrels and septa to secondary somatosensory (S2) and motor (M1) cortices. Together, these findings support a model in which Elfn1-dependent recruitment of SST+ interneurons contributes to preferential multi-whisker integration and functional specialization within the mouse somatosensory cortex.

α/β-Hydrolase domain-containing 6 (ABHD6) accelerates the desensitization and deactivation of TARP γ-2-containing AMPA receptors

yunshi@nju.edu.cn (Chen Zhang) — Tue, 18 Aug 2026 00:00:00 +0000

AMPA receptors (AMPARs) mediate most of the fast excitatory synaptic transmission in the mammalian brain. Their efficacy in responding to presynaptic glutamate release depends on their kinetics, which are determined by AMPARs and their auxiliary subunit composition. α/β-Hydrolase domain-containing 6 (ABHD6) is an AMPAR auxiliary subunit that has been shown to negatively regulate the surface delivery of AMPARs and AMPAR-mediated currents. Overexpression of ABHD6 has been shown to decrease the rising slope and increase the decay τ of mEPSCs. However, whether ABHD6 is involved in regulating AMPAR kinetics remains unclear. Here, we found that ABHD6 itself had no effect on the gating kinetics of GluA1 and GluA2(Q) containing homomeric receptors. However, in the presence of the auxiliary subunit TARP γ-2, ABHD6 accelerated the deactivation and desensitization of both GluA1 and GluA2(Q) containing homomeric receptors independent of their splicing isoforms (flip and flop) and the editing isoforms of GluA2 (R or G at position 764), except for the deactivation of GluA2(Q)i-G isoform. Besides, the recovery from desensitization of GluA1 with flip splicing isoform was slowed by the co-expression of ABHD6 in the presence of TARP γ-2. Furthermore, ABHD6 accelerated the deactivation and desensitization of GluA1i/GluA2(R)i-G and GluA2(R)i-G/GluA3(R)i heteromeric receptors in the presence of TARP γ-2. We also found that ABHD6-knockout neurons displayed slower deactivation and desensitization. Therefore, these results demonstrate that ABHD6 regulates AMPAR gating kinetics in a TARP γ-2-dependent manner.

MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide

berenice.benayoun@usc.edu (Bérénice A Benayoun) — Tue, 18 Aug 2026 00:00:00 +0000

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the 12 S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, interferon gamma (IFNγ), lipopolysaccharides (LPS), and differentiation signals each induced the expression of endogenous MOTS-c. Notably, exogenous MOTS-c, applied during primary mouse monocyte differentiation, reprogrammed the cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicate that our immune system is not only encoded by the nuclear genome but also by the co-evolved mitochondrial genome.

Latent gene network expression underlies partial re-evolution of a polyphenic trait in the worker caste of ants

abouheif@zju.edu.cn (Angelly Vasquez-Correa) — Tue, 18 Aug 2026 00:00:00 +0000

Polyphenisms–where alternative phenotypes develop from a single genome in response to environmental cues–are not only widespread in nature, but also occur at multiple levels of biological organization, from cells to individuals to societies. Polyphenism is thought to promote phenotypic diversification through the gain, loss, and re-evolution of alternative phenotypes. After the origin of a polyphenism, one of the alternative phenotypes often retains the developmental capacity to produce the ancestral trait, thereby permitting the other to evolve rapidly. Yet, little is known about the developmental processes underlying the re-evolution of polyphenic traits, and how they may produce phenotypic diversification. Here, we address this question by focusing on the caste polyphenism in ant societies, which produces a winged queen caste and a wingless worker caste in a single colony in response to environmental cues. We show, in a hyperdiverse group of ants, that a caste-specific trait called the ocelli (three simple eyes on the dorsal head) is always present across queen castes but was lost and partially re-evolved multiple times, giving rise to novel patterns (one ocelli) in the worker castes. Surprisingly, we discovered that a hidden (latent) expression of the ocelli gene regulatory network in worker castes that lost ocelli underlies the partial re-evolution of ocelli in this group. We therefore propose that latent developmental potentials may generally persist across polyphenic systems, including ant castes, and may facilitate the partial re-evolution of novel phenotypic patterns.

Economic and social modulations of innate decision-making in mice exposed to visual threats

yatangli@cibr.ac.cn (Jiahui Wang) — Tue, 18 Aug 2026 00:00:00 +0000

When confronted by predators, animals make innate decisions with rapid reaction times—a trait shaped by natural selection to maximize survival. However, rapid reactions are effective only when grounded in accurate judgments and appropriate choices, which often require cognitive control. To address how such choices are shaped, we developed a behavioral paradigm to investigate how threat intensity, reward value, and social hierarchy influence decision-making in foraging mice exposed to overhead visual threats. Using a machine learning-based approach, we classified defensive responses into four distinct decision types. Mice showed rapid habituation to repeated looming threats, with substantial inter-individual variability in the rate of habituation. Across both early and late phases of habituation, threat intensity emerged as the primary determinant of decision-making, strongly biasing behavior toward escape. In contrast, the influence of reward value was context-dependent and became evident primarily in the late phase: under low-threat conditions, higher reward value suppressed defensive responses, consistent with value-based decision theory; whereas under high-threat conditions, higher reward value promoted escape, potentially reflecting heightened vigilance. Innate decision-making was further modulated by social hierarchy, with dominant mice showing greater vigilance and a stronger bias toward risk-averse behaviors, while subordinates were more reward-driven. To understand the underlying decision-making process, we developed a drift-diffusion leaky integrator model that successfully captures how threat intensity, reward value, and vigilance interact to shape defensive decisions. Together, these findings reveal how economic and social factors modulate innate decisions and provide a computational framework for understanding the interplay between instinctive reactions and cognitive control.

A behavioral architecture for realistic simulations of Drosophila larva locomotion and foraging

p.sakagiannis@uni-koeln.de (Anna-Maria Jürgensen) — Mon, 17 Aug 2026 00:00:00 +0000

The Drosophila larva is extensively used as a model organism in neuroethological studies where precise behavioral tracking enables the statistical analysis of individual and population-level behavioral metrics that can inform mathematical models of larval behavior. Here, we propose a hierarchical model architecture comprising three layers to facilitate modular model construction, closed-loop simulations, and direct comparisons between empirical and simulated data. At the motor layer, the autonomous locomotory model is capable of performing exploration. Based on novel kinematic analyses, our model features intermittent forward crawling that is phasically coupled to lateral bending. At the second layer, navigation is achieved via active sensing in a simulated environment, and top-down modulation of locomotion. At the top layer, behavioral adaptation entails associative learning. We evaluate virtual larval behavior across agent-based simulations of autonomous free exploration, chemotaxis, and odor preference testing. Our behavioral architecture is ideally suited for the modular combination of neuromechanical, neural, or mere statistical model components, facilitating their evaluation, comparison, extension, and integration into multifunctional control architectures.

How monkeys carve up the visual world

binxu_wang@hms.harvard.edu (Binxu Wang) — Mon, 17 Aug 2026 00:00:00 +0000

Monkeys generalize many visual categorization rules, such as animate versus inanimate, but fail on culturally defined ones, placing their behavior closer to networks trained on images alone than to humans.

Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy

leonardo.sacconi@cnr.it (Beatrice Scellini) — Mon, 17 Aug 2026 00:00:00 +0000

This study explores the use of polarized second-harmonic generation (pSHG) to investigate myosin conformation in the relaxed state, differentiating between the actin-available, disordered (ON) state and the energy-conserving, ordered (OFF) state. By shifting the ON/OFF equilibrium using both physical and chemical manipulations, we demonstrate the sensitivity of pSHG in quantifying the ON/OFF ratio in skeletal and cardiac tissues. Comparisons with X-ray diffraction measurements further validate our findings. Applying this approach to a sarcomeric mutation associated with hypertrophic cardiomyopathy, we show that R403Q/MYH7-mutated minipig ventricle tissue exhibits a higher ON fraction compared to controls. This difference is abolished under high concentrations of a myosin activator (2-deoxyATP) and an inhibitor (Mavacamten), indicating structural similarity between R403Q and controls in these two states. ATPase assays reveal increased resting ATPase activity in R403Q samples, which persists even in the presence of 2-deoxyATP, suggesting that the elevated energy consumption in the R403Q mutation is driven by both a population shift toward the ON state and enhanced myosin ATPase activity per motor head.

Cryo-EM structure of the bicarbonate receptor GPR30

awatanabe-tky@umin.ac.jp (Airi Jo-Watanabe) — Fri, 14 Aug 2026 00:00:00 +0000

G-protein-coupled receptor 30 (GPR30) is a bicarbonate receptor that plays a vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with bicarbonate ions remain elusive. There is no consensus on a drug that targets GPR30, and difficulties in pharmacological analyses have limited biological and drug discovery research on GPR30. Here, we present the cryo-electron microscopy structure of human GPR30 in the presence of bicarbonate ions at 3.15 Å resolution. Our structure reveals unique extracellular pockets and critical residues for bicarbonate binding and activation. Functional assays demonstrate that mutations in these residues impair bicarbonate-induced GPR30 activation, underscoring their importance in receptor function. This study also provides insights into G-protein coupling, highlighting the structural divergence between GPR30 and other G-protein-coupled receptors (GPCRs). Our findings not only advance the understanding of the role of GPR30 in pH homeostasis but also pave the way for the development of high-affinity drugs targeting GPR30 for therapeutic interventions in diseases associated with acid-base imbalance.

Sibling chimerism among microglia in marmosets

rcdelros@broadinstitute.org (Alec Wysoker) — Fri, 14 Aug 2026 00:00:00 +0000

Chimerism happens rarely among most mammals, but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12–80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney, and many brain regions across a number of marmosets, using transcribed single-nucleotide polymorphisms (SNPs) to identify cells with the sibling’s genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20–52%) and macrophages (18–64%) but not among other resident cell types (neurons, glia, or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by genetic-sibling microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to recognize the effects of genes, mutations, and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.

Parkinson’s disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss

roman.praschberger@i-med.ac.at (Ayse Kilic) — Thu, 13 Aug 2026 00:00:00 +0000

Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG), cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG, in turn, disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

How to give cells an identity crisis

hollien@biology.utah.edu (Julie Hollien) — Thu, 13 Aug 2026 00:00:00 +0000

The transcription factor CHOP helps cells switch from an emergency stress response to a chronic one, where cells survive but lose some of the functions that define their identity.

Nucleation-dependent propagation of Polycomb modifications emerges during the Drosophila maternal to zygotic transition

shelby.blythe@northwestern.edu (Corinne Croslyn) — Thu, 13 Aug 2026 00:00:00 +0000

During zygotic genome activation in Drosophila, broad domains of Polycomb-modified chromatin are rapidly established across the genome. Here, we investigate the spatial and temporal dynamics by which Polycomb group (PcG) histone modifications, H3K27me3 and H2Aub, emerge during early embryogenesis. Using ChIP-seq and live imaging of CRISPR-engineered GFP-tagged PcG components, we show that PRC2-dependent H3K27me3 accumulates adjacent to a subset of E(z)-bound prospective Polycomb response elements (PREs) beginning in nuclear cycle 14 (NC14), with patterns indicative of nucleation followed by spreading. Surprisingly, PRE-binding factors Pho, Combgap, and GAGA-factor are excluded from interphase nuclei prior to NC10, despite nuclear localization of E(z) throughout early interphases. Loss-of-function studies further demonstrate that GAGA-factor is largely dispensable for PcG domain establishment, whereas the pioneer factor Zelda is required for proper deposition of H3K27me3 and H2Aub at a subset of Polycomb domains. The role of Zelda at Polycomb domains is context-dependent; a subset of targets requires Zelda not for E(z) recruitment, but instead to license an E(z)-loaded PRE to deposit H3K27me3. Our findings support a model where licensing of PcG domains is an initial step in the regulatory processes governing Polycomb-regulated developmental genes.

Aging-associated increase of GATA4 levels in articular cartilage is linked to impaired regenerative capacity of chondrocytes and osteoarthritis

hal46@pitt.edu (Alyssa Aguglia) — Wed, 12 Aug 2026 00:00:00 +0000

Although the causal association between aging and osteoarthritis (OA) has been documented, our understanding of the underlying mechanism remains incomplete. To define the regulatory molecules governing chondrocyte aging, we performed transcriptomic analysis of young and old human chondrocytes from healthy donors. The data predicted that GATA-binding protein 4 (GATA4) may play a key role in mediating the difference between young and old chondrocytes. Results from immunostaining and western blot showed significantly higher GATA4 levels in old human or mouse chondrocytes when compared to young cells. Moreover, overexpressing GATA4 in young chondrocytes remarkably reduced their cartilage-forming capacity in vitro and induced the upregulation of proinflammatory cytokines. Conversely, suppressing GATA4 expression in old chondrocytes, through either siRNA or a small-molecule inhibitor NSC140905, increased the production of aggrecan and collagen type II, and also decreased levels of matrix-degrading enzymes. In OA mice induced by surgical destabilization of the medial meniscus, intra-articular injection of lentiviral vectors carrying mouse Gata4 resulted in a higher OA severity, synovial inflammation, and pain level when compared to control vectors. Mechanistically, we found that overexpressing GATA4 significantly increased the phosphorylation of SMAD1/5. Our work demonstrates that the aging-associated increase of GATA4 in chondrocytes plays a vital role in OA progression, which may also serve as a target to reduce OA in the older population.

Five-layer systems analysis of Leishmania stage differentiation reveals an essential role for protein degradation in parasite development

pascale.pescher@pasteur.fr (Anne Boland) — Wed, 12 Aug 2026 00:00:00 +0000

Vector-borne, protist parasites have evolved complex developmental programs to adapt to very distinct host environments. How these important pathogens transition between insect and mammalian stages is only poorly understood. Here, we investigated stage differentiation in Leishmania donovani, a trypanosomatid parasite with constitutive gene transcription, offering a model to study post-transcriptional regulation. Using a five-layer integrative systems analysis (genome to metabolome), we compared hamster-derived amastigotes and culture-derived promastigotes. Genomic adaptation was excluded as a major driver of differentiation, while differential mRNA turnover emerged as a key mechanism of stage-specific gene expression. Transcriptomic and proteomic comparisons revealed a broad dynamic range of protein abundance changes that correlated poorly with mRNA levels. This discrepancy was linked to (i) altered snoRNA expression and rRNA modifications, indicating stage-specific tuning of translation, and (ii) differential protein degradation, supported by proteomics following proteasome inhibition with lactacystin. Lactacystin impaired amastigote-to-promastigote differentiation, highlighting the importance of proteasomal activity. Overall, our analysis links Leishmania development to coordinated post-transcriptional regulatory networks. Our findings provide a powerful new resource for research programs that aim to dissect the emergent properties of regulatory networks and feedback loops underlying Leishmania stage differentiation, serving as a blueprint for other vector-borne pathogens that rely on disease-associated developmental transitions.

Human brain-wide activation of sleep rhythms

jgao@pku.edu.cn (Haiteng Wang) — Wed, 12 Aug 2026 00:00:00 +0000

During sleep, our brain undergoes highly synchronized activity, orchestrated by distinct neural rhythms. Little is known about the associated brain activation during these sleep rhythms, and even less about their functional implications. In this study, we investigated the brain-wide activation underlying human sleep rhythms by employing simultaneous electroencephalography and functional magnetic resonance imaging in 107 participants during nocturnal naps (first half of the night). We identified robust coupling between slow oscillations (SOs) and fast spindles during deep non-rapid eye movement sleep (N2/3 stages), with spindle peaks consistently occurring just before the SO UP-state. This SO-spindle coupling was linked to elevated activation in both the thalamus and hippocampus, alongside increased functional connectivity from the hippocampus to the thalamus and from the thalamus to the medial prefrontal cortex. An open-ended cognitive state decoding analysis suggested that these activations may relate to episodic memory processes, yet were distinct from task-related networks. Together, these findings highlight the thalamus as a key coordinator of hippocampal–cortical communication during sleep and provide new insights into the mechanisms by which synchronized sleep rhythms may support memory consolidation.

Spine nanostructure profiling of cultured neurons from mouse models reveals a schizophrenia-linked role for Ecrg4

shigeo.okabe@riken.jp (Atsu Aiba) — Tue, 11 Aug 2026 00:00:00 +0000

Dendritic spine dysfunction may contribute to the etiology and symptom expression of neuropsychiatric disorders. The intimate relationship between spine morphology and function suggests that decoding disease-related abnormalities from spine morphology can aid in developing synapse-targeted interventions. Here, we describe a population analysis of dendritic spine nanostructure applied to the objective grouping of multiple mouse models of neuropsychiatric disorders. This method has identified two major groups of spine phenotypes linked to schizophrenia and autism spectrum disorder (ASD). An increase in spine subpopulation with small volumes characterized the spines of schizophrenia-associated mouse models, whereas a spine subset with large volumes increased in ASD models. Schizophrenia-associated mouse models showed higher similarity in spine morphology, driven by reduced size and growth of nascent spines. The expression of Ecrg4, a gene encoding small secretory peptides, was increased in schizophrenia-associated mouse models, and functional studies confirmed its critical involvement in impaired spine dynamics and shape. These results suggest that population-level spine analysis provides rich insights into heterogeneous spine pathology, facilitating the identification of new molecular targets related to core synaptic dysfunction.

In vivo mapping of striatal neurodegeneration in Huntington’s disease with Soma and Neurite Density Imaging

Metzler-BaddeleyC@cardiff.ac.uk (Anne Rosser) — Tue, 11 Aug 2026 00:00:00 +0000

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The objectives of this study were to characterise HD-related microstructural abnormalities in the BG using SANDI and to examine relationships between SANDI and volumetric measurements and motor performance. T1- and diffusion-weighted images (b-values 200–6000 s/mm²) were acquired on a 3T Siemens Connectom scanner (300 mT/m) in 56 individuals with HD and 57 age- and sex-matched controls. HD participants completed Quantitative Motor (Q-Motor) tasks, summarised using principal component analysis. SANDI estimated apparent soma and neurite density, apparent soma size, and extracellular signal fraction. Microstructural and volumetric indices were extracted from bilateral caudate, putamen, pallidum and thalamus regions, compared between groups, and correlated with Q-Motor performance. HD was associated with reduced apparent soma density and increased apparent soma size and extracellular signal fraction in the BG but not the thalami. No group differences were present for apparent neurite density. SANDI metrics correlated with Q-Motor performance and explained up to 63% of striatal atrophy in HD. SANDI indices detected HD-related striatal neurodegeneration, explained atrophy, and correlated with motor impairments, demonstrating its potential as an in vivo biomarker and surrogate clinical outcome measure for HD and other neurodegenerative diseases.

Divergent C. elegans toxin alleles are suppressed by distinct mechanisms

szdralje@gmail.com (Daniel HW Leighton) — Tue, 11 Aug 2026 00:00:00 +0000

Toxin-antidote elements (TAs) are selfish DNA sequences that bias their transmission to the next generation. TAs typically consist of two linked genes: a toxin and an antidote. The toxin kills progeny that do not inherit the TA, while the antidote counteracts the toxin in progeny that inherit the TA. We previously discovered two TAs in Caenorhabditis elegans that follow the canonical TA model of two linked genes: peel-1/zeel-1 and sup-35/pha-1. Here, we report a new TA that exists in three distinct states across the C. elegans population. The canonical TA, which is found in isolates from the Hawaiian Islands, consists of two genes that encode a maternally deposited toxin (TMRL-1) and a zygotically expressed antidote (AMRL-1). The toxin induces larval lethality in embryos that do not inherit the antidote gene. A second version of the TA has lost the toxin gene but retains a partially functional antidote. Most C. elegans isolates, including the standard laboratory strain N2, carry a highly divergent allele of the toxin that has retained its activity, but have lost the antidote through pseudogenization. Multiple lines of evidence suggest that the N2 tmrl-1 allele is likely recognized by piRNAs, leading to MUT-16-dependent 22G small interfering RNA (siRNA) production and post-transcriptional silencing of the transcript. The N2 haplotype represents the first naturally occurring unlinked toxin-antidote system where the toxin is post-transcriptionally suppressed by endogenous small RNA pathways.

Global relationships between body size and urban affinity across more than 30,000 plant and animal species

c.callaghan@ufl.edu (Brittany M Mason) — Tue, 11 Aug 2026 00:00:00 +0000

Urbanization is a major global driver of biodiversity change, with species responses to urban settings ranging from avoidance to exploitation. To better understand these responses, we conducted a global analysis of urban relative affinity inferred from occurrence data across more than 30,000 animal and plant species. Our synthesis showed a consistent pattern across taxa and biogeographic regions: many species are urban avoiders, while few thrive as urban exploiters—a pattern we coin ‘species urbanness distribution’. We then assessed whether body size, an integrative ecological trait fundamental to space use, mobility, metabolism, and environmental sensitivity, showed consistent associations with urban affinity among species and across 371 taxonomic families. Analyses were conducted at the interspecific level and focused primarily on variation among taxonomic families (with an accompanying application to view results available for each family here: https://globalecologyresearchgroup.github.io/Callaghan_et_al-2026-eLife-ShinyApp/). Larger body sizes were generally associated with greater urban affinity in plants compared to animals, though these size-affinity relationships showed considerable variability among families. Our findings highlight the heterogeneous relationship between body size and urban affinity across the tree of life, underscoring the importance of tailored strategies to support urban biodiversity. This research advances ecological understanding of urban filtering and provides a framework for guiding biodiversity-sensitive urban planning amid accelerating global urbanization.

A dual role for PGLYRP1 in host defense and immune regulation during B. pertussis infection

cskerry@som.umaryland.edu (Ciaran Skerry) — Tue, 11 Aug 2026 00:00:00 +0000

Bordetella pertussis, the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed. Host recognition of bacterial peptidoglycan (PGN), including B. pertussis extracellular PGN fragment tracheal cytotoxin (TCT) shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved innate immune family that bind bacterial PGN and are primarily known for bactericidal activity in mammals; however, their immune modulatory roles are beginning to gain appreciation. The role of PGLYRPs in mammalian host defenses to Gram-negative pathogens, such as B. pertussis, remains largely unknown. Here, using knockout mice, single-cell and bulk transcriptomics, and functional assays, we identify a dual role for PGLYRP1 in modulating host immune responses to B. pertussis. PGLYRP1 contributes to antibacterial responses and paradoxically dampens inflammatory responses and inhibits bacterial killing later in infection. Mechanistically, PGLYRP1 enhances NOD1 signaling in response to TCT while suppressing NOD2− and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria. These findings demonstrate that B. pertussis co-opts PGLYRP1 to alter immune signaling, revealing a novel immune evasion mechanism with implications for vaccine design and host-directed therapeutics.

A novel prognostic score based on carbohydrate antigen 125, alpha-fetoprotein and carcinoembryonic antigen for Predicting postoperative prognosis in endometrial cancer: Results from a retrospective cohort study

yangh9@sj-hospital.org (Bo Wang) — Mon, 10 Aug 2026 00:00:00 +0000

Background: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence. While several serum biomarkers have been studied for EC, their combined prognostic value remains unclear. This study aimed to evaluate the prognostic significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP levels in EC patients and develop a risk score for predicting survival outcomes.

A tool to pulse-label yeast nuclear pore complexes in imaging and biochemical experiments

l.m.veenhoff@rug.nl (Annemiek C Veldsink) — Mon, 10 Aug 2026 00:00:00 +0000

Nuclear pore complexes (NPCs) are key gateways to the nucleus and major organizers of genome architecture. Despite their importance, it is still not fully understood how NPCs are formed and degraded. Tools to track specific NPCs over time or under stress could unlock critical insights into these questions. Here, we demonstrate that a brief pulse of expression of a previously developed nanobody against baker’s yeast nucleoporin Nup84 (Nordeen et al., 2020) enables a robust, rapid, and straightforward method for pulse-labeling NPCs in both imaging and affinity purification experiments. This approach offers an alternative to permanent, yet less rapid, genetic fluorophore- or tag-switching techniques, and provides a powerful tool for studying NPC inheritance and turnover through both microscopy and biochemical methods.

Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2

J.Guy@ed.ac.uk (Adrian Bird) — Mon, 10 Aug 2026 00:00:00 +0000

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

A unifying model of T-cell signaling protein condensates in reconstitution experiments

yadomar@mit.edu (Arup K Chakraborty) — Mon, 10 Aug 2026 00:00:00 +0000

The formation of condensates by the Linker for the Activation of T-cells (LAT) is a key signal gating and amplification step in the T-cell receptor signaling pathway. LAT condensation is challenging to study in-vivo and is therefore often investigated using reconstitution experiments. While these experiments recapitulate key aspects of LAT condensation, they also exhibit some puzzling features. Here, we describe the mechanisms underlying these observations using two complementary models. First, we employ a Smoluchowski aggregation model to show that the delay time before condensation is observed arises from a low effective binding probability between LAT monomers. Second, we propose a field-theoretic model that reproduces all condensate morphologies observed in experiments, showing that they can arise from common underlying dynamics modulated by variations in experimental conditions. This result unifies different experimental observations reported previously. While this article addresses open questions regarding the formation of LAT condensates, our results also provide a common framework for understanding condensation of other multivalent membrane proteins such as EGFR, FGFR2, and nephrin.

Mood computational mechanisms underlying increased risk behavior in adolescent suicidal patients

hzl_811015@126.com (Bastien Blain) — Fri, 07 Aug 2026 00:00:00 +0000

Suicidal thoughts and behaviors (STB) are among the leading causes of death worldwide. Although previous research has consistently documented elevated risk-taking in individuals with STB and identified mood disturbances as central features of suicidality, the precise cognitive and affective computational mechanisms underlying this increased risky behavior remain poorly understood. Here, 83 adolescent inpatients with affective disorders—including 58 patients with STB (S⁺) and 25 without STB (S⁻)—and 118 age- and sex-matched healthy controls (HC) completed a decision-making task involving choices between certain and gamble options, alongside momentary mood ratings. Behavioral analyses showed that S⁺ exhibited greater risk-taking than both S⁻ and HC. Computational modeling of choice behavior using a prospect-theory framework augmented with value-insensitive approach–avoidance parameters indicated that this increase in risky behavior was specifically driven by an elevated approach parameter in S⁺. In addition, mood-model analyses revealed reduced sensitivity to certain rewards in S⁺ relative to S⁻ and HC. Importantly, these computational signatures predicted suicidal symptom severity and showed generalizability in an independent general-population sample (n = 747). In S⁺, lower mood sensitivity to certain rewards was associated with greater gambling, providing a computational affective account of increased risk-taking in STB. These findings remained robust after adjusting for demographic, clinical, and medication-related variables. Overall, our study identifies cognitive and affective computational mechanisms contributing to elevated risk-taking in STB and highlights their potential relevance for the early identification and prevention of suicidality.

Evaluating the applicability of replication success metrics in animal-to-human translation: A simulation study

rachel.heyard@uzh.ch (Benjamin Victor Ineichen) — Fri, 07 Aug 2026 00:00:00 +0000

Translation failure, in which promising animal study results cannot be reproduced in human trials, is a challenge in biomedical research. Metrics for replication success are widely used to evaluate reproducibility, that is the extent to which the results of a study agree with those of replication studies. The relevance of these metrics in assessing animal-to-human translation success (or failure) is unclear. We conducted a simulation study to examine whether these metrics can quantify translation success, and how their performance varies under different conditions. Using parameters from a meta-analysis on prenatal amino acid supplementation and maternal blood pressure, we simulated animal and human studies under 648 scenarios, varying effect sizes, heterogeneity, animal sample sizes, and number of pooled animal studies. Nine metrics were assessed, namely the two-trials rule, meta-analysis, replication Bayes factor, unweighted and weighted Edgington’s methods, golden skeptical p-value, and three versions of controlled skeptical p-value. Most metrics, except meta-analysis and replication Bayes factor, controlled false positive rates under no heterogeneity, but became liberal as heterogeneity increased, particularly between human studies. Translation power (i.e. the probability of true positive translation success) was constrained by the weaker evidence of the two findings; for example, small sample size in the animal studies resulted in lower translation power. The metric based on meta-analysis frequently indicated success when either of the species found strong evidence, while skeptical p-values were more conservative. The skeptical p-value that controls overall type-one error and the weighted version of Edgington’s method performed relatively consistently across scenarios. However, no metric was uniformly optimal. Metrics developed for replication studies can inform assessments of translation, but their utility depends on the underlying evidence and assumptions. Using multiple metrics in combination, with attention to their strengths and limitations, is recommended for evaluating the translation of animal findings to human outcomes.

Using mathematical models to optimise mosquito net distribution

prete@unicamp.br (Carlos A Prete Jr) — Fri, 07 Aug 2026 00:00:00 +0000

Tailoring malaria control interventions to regional transmission dynamics and behavioural characteristics can optimise them in resource-limited settings.

Functional specialization of mPFC-BLA and mPFC-NAc pathways in affective state representation

huilu@gwu.edu (Chen Zeng) — Fri, 07 Aug 2026 00:00:00 +0000

Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA), and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC→BLA and mPFC→NAc pathways in representing affective states remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC→BLA neurons, especially ‘center-ON’ neurons, exhibited heightened activity during behaviors classically associated with anxiety-like states, suggesting their involvement in aversive behavioral regulation. Conversely, mPFC→NAc neurons were more active during exploratory and approach-related behaviors, implicating them in the processing of positively valenced behavioral states. Notably, mPFC→NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in processing social preference. Additionally, repeated win/loss outcomes in the tube test produced distinct hierarchy-dependent behavioral changes and elevated corticosterone levels in loser mice, supporting the biological relevance of these behaviorally defined states. Together, these findings reveal pathway-specific representations of affect-related behavioral states in mPFC circuits and provide a framework for understanding how prefrontal outputs organize adaptive behavior across environmental contexts.

Correction: The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution

Thu, 06 Aug 2026 00:00:00 +0000

The cistrome response to hypoxia in human umbilical vein endothelial cells

bass@bio.fsu.edu (Ayush Singh) — Thu, 06 Aug 2026 00:00:00 +0000

Hypoxic stress triggers transcriptional signaling mainly through hypoxia-inducible transcription factors (HIFs), which bind hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (~1%) of known HREs are occupied by HIFs during hypoxia, suggesting the involvement of additional hypoxia-responsive factors. To address this gap, we utilized MNase-defined cistrome Occupancy Analysis sequencing (MOA-seq), with the term cistrome referring to all genomic regions where transcription factors and other trans-acting regulators are bound to cis-acting elements across the genome for a particular cell type or treatment. This MNase-based assay enables genome-wide, high-resolution (<30 bp) identification of transcription factor (TF) occupancy footprints embedded within larger regions, most of which were previously annotated as open or accessible chromatin. Applying this in situ cistrome mapping to fixed nuclei from endothelial cells under normoxia or hypoxia (1, 3, or 24 hr) revealed thousands of hypoxia-responsive genomic sites with dynamic TF footprints. The affected genes were enriched in canonical hypoxia-induced pathways, such as angiogenesis. Motif analysis identified over 100 candidate TFs potentially mediating these multifaceted genomic responses. By grouping hypoxia-modified occupancy signals across the hypoxia exposure times, we clustered differentially occupied MOA sites into defined 10 distinct TF kinetic clusters, half of which were associated with HIF1A. HIF1A-proximal binding sites suggested co-activators, while non-HIF1A clusters pointed to additional TFs that may have HIF1A-independent roles. This analysis provides insight into how multiple TF networks coordinate hypoxia responses and highlights the power of cistrome profiling to deepen our understanding of the complex genomic response to low oxygen conditions.

Pathogen-phage geomapping to overcome resistance

camilla.do@bcm.edu (Anthony W Maresso) — Thu, 06 Aug 2026 00:00:00 +0000

The rise of antibiotic resistance has renewed interest in bacteriophages as therapeutic alternatives. However, coevolution of phage and bacteria will naturally give rise to phage-resistant pathogens, complicating phage therapy efforts. A critical bottleneck in the production of phage therapeutics is the discovery of virulent phages against resistant pathogens. Conventional methods for discovery are time-consuming, biased, and laborious, limiting the potential for identifying suitable phage candidates. To overcome these limitations, we combined small-volume environmental sampling with 16 S rRNA sequencing to identify reservoirs where bacterial hosts co-exist with their phage predators. This strategy, which we term geographical phage mapping (geΦmapping), pinpoints ecological ‘hotspots’ for targeted phage hunting. We further developed a portable phage hunting device (ΦHD) that generates highly enriched phage concentrates directly from these reservoirs. By integrating geΦmapping with high-throughput enrichment, we constructed the RΦ library, a diverse collection of novel phages. We captured and isolated 36 new phages targeting extremely resistant organisms across various ESKAPE pathogens when conventional phage hunting and experimental evolution approaches failed.

LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics

Beccano-KellyD@cardiff.ac.uk (Adriano Lama) — Thu, 06 Aug 2026 00:00:00 +0000

Parkinson’s disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate literature meta-analysis and multi-omics with biochemical, imaging, and electrophysiological measurements in Lrrk2 mouse models and human iPSC-derived neurons lacking LRRK2. We demonstrate that brain-derived neurotrophic factor (BDNF) activates LRRK2 in differentiated SH-SY5Y cells and primary mouse neurons, reshaping the LRRK2 interactome toward a network of actin cytoskeleton-related proteins. Gene-ontology analyses of both literature-curated LRRK2 interactors and phospho-proteome from striatal tissues with elevated LRRK2 activity highlight synapse-actin remodeling as major affected pathways. We further observed that loss of LRRK2 impairs BDNF signaling and alters postsynaptic density architecture. Young Lrrk2 knockout mice display structural alterations in dendritic protrusions, a phenotype that normalizes with age. In human iPSC-derived neurons, LRRK2 knockout affects maturation and BDNF-dependent regulation of spontaneous synaptic activity. Taken together, our study discloses a critical role of LRRK2 in BDNF-dependent synaptic modulation and identifies the synaptic actin cytoskeleton as a convergent site of LRRK2-associated pathophysiological processes in PD.

Nanoscopy reveals heparan sulfate clusters as docking sites for SARS-CoV-2 attachment and entry

jyewdell@nih.gov (Albert J Jin) — Thu, 06 Aug 2026 00:00:00 +0000

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely considered the receptor for cell-surface attachment and subsequent cell entry. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment, and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ~6–137 HS molecules projecting 60–410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm², act as docking sites for viral attachment. Blocking HS binding with the clinically used HS-binding agent pixantrone strongly inhibited an authentic pathogen, the SARS-CoV-2 Omicron JN.1 subvariant, from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia

medhavi@iisc.ac.in (Akshar Rao) — Thu, 06 Aug 2026 00:00:00 +0000

Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival and growth of HRas^V12 mutants in human mammary and bronchial epithelia, producing contrasting outcomes in the two tissues. In mammary epithelium, isolated mutants are extruded – typical of epithelial defense against cancer – while mutant groups become spatially confined in kinetically arrested, jammed clusters, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the mutants, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in the two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that interfacial tension at mutant-wild-type boundaries dictates whether mutants are eliminated, restrained, or expanded. Additionally, modulating the heterotypic interfacial tension alters mutant cluster fates. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how interfacial mechanics between mutants and wild-type populations regulate tumor initiation and progression.

Endometrial cells with high ALDH activity contribute to uterine development and regeneration

dmonsiva@bcm.edu (Anna Catherine Unser) — Thu, 06 Aug 2026 00:00:00 +0000

Adult stem cells are thought to drive the regenerative potential of the endometrium and contribute to the pathogenesis of endometriosis; however, their identity and defining features remain to be characterized. Here, we used in vivo and in vitro approaches to demonstrate that cells with high aldehyde dehydrogenase 1 activity (ALDH^HI cells) were long-lived progenitors in the endometrium with a higher organoid formation capacity, long-term passaging potential, and stemness gene signatures. Using lineage tracing with an Aldh1a1^creERT2/+; Rosa26^LSL-tdTomato reporter mouse, Aldh1a1⁺ epithelial cells expanded during postnatal development, Aldh1a1⁺ stromal cells expanded during estrous cycling, and both populations of Aldh1a1⁺ cells were present during postpartum repair. In response to ovariectomy or exogenous estradiol, we found that ALDH1A1⁺ cells localized to glandular crypts of the endometrium or throughout the luminal epithelium, respectively, indicating that their spatial localization is hormone-sensitive. Functionally, we found that selective ablation of ALDH1A1⁺ cells in Aldh1a1^creERT2/+; Rosa26^LSL-DTR mice decreased endometrial gland number and FOXA2 expression. These findings were recapitulated in the human endometrium, where endometrial epithelial organoids with high ALDH activity (ALDH^HI cells) showed a higher organoid formation capacity than ALDH^LO cells and displayed unique transcriptomes with fewer luminal-like ciliated cells. Overall, our studies indicate that ALDH1A1⁺ cells are hormone-sensitive adult stem cells in the endometrium with regenerative potential that are critical for endometrial development and function.