eLife: latest articles

Adrenomedullin restores the human cortical interneurons migration defects induced by hypoxia

apasca@stanford.edu (Alyssa Puno) — Fri, 15 May 2026 00:00:00 +0000

Extremely preterm birth (at <28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human-induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript, we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development.

Stranded short nascent strand sequencing reveals the topology of DNA replication origins in Trypanosoma brucei

slavica.stanojcic@umontpellier.fr (Bridlin Barckmann) — Fri, 15 May 2026 00:00:00 +0000

The universal features that define genomic regions acting as replication origins remain unclear. In this study, we mapped a set of origins in Trypanosoma brucei using stranded short nascent strand sequencing methods. Our results showed that DNA replication predominantly initiates in intergenic regions between poly(dA)- and poly(dT)-enriched sequences. G4 structures were detected in the vicinity of some origins and were embedded in poly(dA)-enriched sequences in a strand-specific manner: G4s on the plus strand were located upstream while those on the minus strand were located downstream of the centre. The origins' centres were found to be areas of low nucleosome occupancy, surrounded by regions of high nucleosome occupancy. Furthermore, our results demonstrate that 90% of replication origins overlap with a minor proportion of the previously reported RNA: DNA hybrids. These findings shed new light on the sequence and structural features that define the topology of replication origins in T. brucei. To further characterise replication dynamics at the single-molecule level, we employed DNA combing analysis.

Bilateral equalization of synaptic output in olfactory glomeruli of Xenopus tadpoles

allobet@ub.edu (Artur Llobet) — Fri, 15 May 2026 00:00:00 +0000

Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using Xenopus tropicalis tadpoles, we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hr after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D₂ receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionarily conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism described here may represent a general property of the vertebrate olfactory system to establish an odor map.

Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing

kbeier@uci.edu (Cindy M Yamamoto) — Fri, 15 May 2026 00:00:00 +0000

Addictive drugs cause long-lasting changes in connectivity from inputs onto ventral tegmental area dopamine cells (VTA^DA) that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered. Here, we used a rabies virus (RABV)-based mapping strategy to quantify RABV-labeled inputs to VTA cells after a single exposure to one of a variety of misused drugs – cocaine, amphetamine, methamphetamine, morphine, and nicotine – and compared the relative global input labeling across conditions. We observed that all tested addictive drugs elicited similar input changes onto VTA^DA cells, in particular onto DA cells projecting to the lateral shell of the nucleus accumbens and amygdala. In addition, repeated administration of ketamine/xylazine to induce anesthesia induces a change in inputs to VTA^DA cells that is similar to but different from those elicited by a single exposure to addictive drugs, suggesting that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors. Furthermore, comparison of viral tracing data to an atlas of gene expression in the adult mouse brain showed that the basal expression patterns of several gene classes, especially calcium channels, were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced changes in RABV-labeled inputs to VTA^DA cells. Reducing expression levels of the voltage-gated calcium channel Cacna1e in cells in the nucleus accumbens lateral shell reduced RABV-mediated input labeling of these cells into VTA^DA cells. These results directly link genes controlling cellular excitability and the extent of input labeling by RABV.

The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells

sp.gravel@umontreal.ca (Ana Maria Duman) — Fri, 15 May 2026 00:00:00 +0000

Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR–Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD⁺/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.

Tumors mimic the niche to inhibit neighboring stem cell differentiation

swzhao@nankai.edu.cn (Chang Sun) — Fri, 15 May 2026 00:00:00 +0000

Although it is well established that stem cells maintain tissue homeostasis while tumors disrupt it, the mechanisms by which tumors influence the development of nearby stem cells remain poorly understood. Using Drosophila ovaries as a model system, here we discovered that bam or bgcn mutant germline tumors inhibit the differentiation of neighboring wild-type germline stem cells (GSCs). Mechanistically, these tumor cells mimic the stem cell niche by secreting the bone morphogenetic protein (BMP) ligands Dpp and Gbb, but at reduced levels, resulting in moderate BMP signaling activation in adjacent GSCs. Such BMP signaling activation is sufficient to repress bam transcription, thereby blocking GSC differentiation. To our knowledge, this is the first example that tumors can functionally mimic a stem cell niche to inhibit the differentiation of neighboring wild-type stem cells. Similar regulatory paradigms may operate in mammalian tissues, including humans, during tumorigenesis.

A meta-analysis suggests that TMS targeting the hippocampal network selectively improves episodic memory

joelvoss@uchicago.edu (Arantzazu San Agustin) — Thu, 14 May 2026 00:00:00 +0000

Episodic memory is critically dependent on the hippocampal network and is frequently impaired in many clinical disorders. Recent findings highlight Hippocampal Indirectly Targeted Stimulation (HITS) as a promising, network-guided non-invasive transcranial magnetic stimulation (TMS) procedure to enhance episodic memory performance. Here, we report the first comprehensive meta-analysis of HITS effects on episodic memory, encompassing both healthy individuals and clinical populations. HITS using parieto-occipital network targets robustly improved episodic memory, with effects selective for episodic memory versus other non-memory cognitive domains. Efficacy was significantly greater when memory performance was assessed using memory tasks sensitive to recollection, which is strongly linked to hippocampal network function, compared to recognition or other types of episodic memory tasks. Efficacy was also significantly greater when HITS was delivered before the memory tasks were administered versus in the period between study and test phases of tasks. No serious adverse events were reported. These findings establish HITS as a robust approach for episodic memory enhancement, suggesting potential for clinical translation in memory disorders. Selectivity of effects for episodic memory generally and for recollection-format tests in particular indicates cognitive and mechanistic specificity, supporting the potential for targeted and selective neuromodulation of hippocampal networks and their associated functions.

Subregional activity in the dentate gyrus is amplified during elevated cognitive demands

a-contractor@northwestern.edu (Anis Contractor) — Thu, 14 May 2026 00:00:00 +0000

Neural activity in the dentate gyrus (DG) supports the detection and discrimination of novelty, context, and patterns. Granule cell activation differs between the supra- and infrapyramidal blades across hippocampal-dependent tasks, yet how excitatory dynamics shape this blade-specific bias under varying cognitive demands remains unclear. Here, we combined an automated touchscreen pattern separation task in mice with temporally controlled tagging of active neurons to determine how increasing cognitive demand influences spatial activity patterns in the DG. As task difficulty increased, activation became progressively biased toward the suprapyramidal blade and was accompanied by structured distributions of active mature granule cells (mGCs) along both the radial and transverse axes. Selective inhibition of mGCs did not alter these spatial patterns, but profoundly impaired performance, as mice were no longer able to discriminate between closely spaced locations. In contrast, chemogenetic inhibition of adult-born dentate granule cells (abDGCs) beyond a critical maturation window impaired performance under high-demand conditions, increased overall mGC activity, and disrupted blade-specific organization even in animals that successfully completed the task. These findings demonstrate that high cognitive demand recruits spatially organized mGC activity and support a modulatory role for abDGCs in shaping dentate circuit dynamics.

Identification of the regulatory elements and protein substrates of lysine acetoacetylation

yzheng@uga.edu (Bhoj Kumar) — Thu, 14 May 2026 00:00:00 +0000

Short-chain fatty acylations establish connections between cell metabolism and regulatory pathways. Lysine acetoacetylation (Kacac) was recently identified as a new histone mark. However, regulatory elements, substrate proteins, and epigenetic functions of Kacac are not yet fully understood, hindering further in-depth understanding of acetoacetate-modulated (patho)physiological processes. Here, we created a chemo-immunological approach for reliable detection of Kacac, and demonstrated that acetoacetate serves as the primary precursor for histone Kacac. We report the enzymatic addition of the Kacac mark by the acyltransferases GCN5, p300, and PCAF, and its removal by the deacetylase HDAC3. Furthermore, we establish acetoacetyl-CoA synthetase as a key regulator of cellular Kacac levels. A comprehensive proteomic analysis has identified 139 Kacac sites on 85 human proteins. Bioinformatics analysis of Kacac substrates and RNA sequencing data reveal the broad impacts of Kacac on multifaceted cellular processes. These findings unveil pivotal regulatory mechanisms for the acetoacetate-mediated Kacac pathway, opening a new avenue for further investigation into ketone body functions in various pathophysiological states.

Effort produces after-effects costly for others but valued for self

zhengya1982@gmail.com (Rumeng Tang) — Thu, 14 May 2026 00:00:00 +0000

Engaging in prosocial behavior requires effort, yet people are often averse to exerting effort for others’ benefit. However, it remains unclear how effort exertion affects subsequent reward evaluation during prosocial acts. Here, we combined high-temporal-resolution electroencephalography with a paradigm that independently manipulated physical effort and monetary reward for self and others to elucidate the neural mechanisms underlying the reward after-effect of prosocial effort expenditure. We found dissociable reward after-effects for self-benefiting and other-benefiting effort. For self-benefiting rewards, the reward positivity (RewP) increased with effort demand, suggesting an effort-enhancement effect. In contrast, for other-benefiting rewards, the RewP decreased as effort increased, demonstrating an effort-discounting effect. Critically, this dissociation was contingent upon high reward magnitude and modulated by individual differences in effort discounting, yet remained distinct from performance evaluation. Our findings reveal distinct neural computations for self- and other-benefiting efforts, offering new insights into how prior effort expenditure shapes reward evaluation during prosocial behavior.

A context-free model of savings in motor learning

pgribble@uwo.ca (Jonathan A Michaels) — Wed, 13 May 2026 00:00:00 +0000

Learning to adapt voluntary movements to an external perturbation, whether mechanical or visual, is faster during a second encounter than during the first. The mechanisms underlying this phenomenon, known as savings, remain unclear. Recent studies propose that the high dimensionality of neural control enables the retention of learning traces that may facilitate savings. To test this idea, we used MotorNet, a framework for training recurrent neural networks (RNNs) to control biomechanical models of the human upper limb. RNNs were trained to perform reaching movements with a velocity-dependent force field (FF) and without (NF) in the sequence NF1 (baseline), FF1 (adaptation), NF2 (washout), and FF2 (re-adaptation). RNNs showed behaviural signatures of savings in the absence of any explicit contextual input signalling the presence or absence of the FF. Savings was more robust in RNNs with larger numbers of units. We identified a component of RNN activity associated with savings—a shift in preparatory activity that persisted even after washout. Displacing this preparatory activity in the direction of the shift enhanced savings, whereas perturbations in the opposite direction reduced or eliminated savings. These findings suggest a potential neural basis for motor memory retention underlying savings that is reliant on the high dimensionality of neural circuits for control, and is independent of cognitive or strategic learning.

Intravital calcium imaging of meningeal macrophages reveals niche-specific dynamics and aberrant responses to brain hyperexcitability

dlevy1@bidmc.harvard.edu (Anna Gutterman) — Wed, 13 May 2026 00:00:00 +0000

The meninges, which envelop and protect the brain, host a dense network of resident macrophages with diverse roles in regulating homeostasis and neuroinflammation. Despite their importance, we have a limited understanding of their behavior in vivo. Many dynamic cellular functions of macrophages involve intracellular Ca²⁺ signaling. However, virtually nothing is known about the spatiotemporal Ca²⁺ dynamics of meningeal macrophages in vivo. We developed a chronic intravital two-photon imaging approach and related computational analysis tools to interrogate meningeal macrophage Ca²⁺ dynamics, at subcellular resolution, in a novel Pf4-Cre:Ai162 conditional GCaMP6s reporter mouse model. Using imaging in awake mice, we characterized Ca²⁺ activity in meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD), an aberrant pro-inflammatory brain hyperexcitability event implicated in migraine, traumatic brain injury, and stroke. In homeostatic meninges, macrophages in the dural perivascular niche exhibited several Ca²⁺ dynamic features, including event duration and signal frequency spectrum, distinct from those localized to the interstitial, non-perivascular niche. Simultaneous tracking of macrophage Ca²⁺ dynamics and local vasomotion revealed a subset of dural perivascular macrophages whose activity was coupled to locomotion-driven diameter fluctuations of their associated vessels. Most perivascular and non-perivascular meningeal macrophages displayed propagating intracellular Ca²⁺ activity and synchronized intercellular Ca²⁺ elevations, potentially driven by extrinsic factors. In response to CSD, the majority of perivascular and non-perivascular meningeal macrophages showed a persistent decrease in Ca²⁺ activity, while a smaller subset displayed Ca²⁺ elevations. Mechanistically, calcitonin gene-related peptide receptor signaling mediated the increase but not the decrease in CSD-mediated Ca²⁺ signaling. Collectively, our results highlight a previously unknown diversity of Ca²⁺ dynamics in meningeal macrophages at steady state and in response to an aberrant brain hyperexcitability event linked to neuroinflammation.

Examining the role of lipids in hearing

Angela.Ballesteros@nih.gov (Angela Ballesteros) — Wed, 13 May 2026 00:00:00 +0000

The asymmetry of lipid membranes is tightly regulated in eukaryotic cells, and auditory hair cells are no exception.

Locus coeruleus modulation of prefrontal dynamics during attentional switching in mice

hongdian@ucr.edu (Hongdian Yang) — Wed, 13 May 2026 00:00:00 +0000

Behavioral flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies and internal demands, is fundamental to cognitive functions. Despite a large body of pharmacology and lesion studies, the precise neurophysiological mechanisms that underlie behavioral flexibility are still under active investigations. This work is aimed to determine the role of a brainstem-to-prefrontal cortex circuit in flexible rule switching. We trained mice to perform a set-shifting task in which they learned to switch attention to distinguish complex sensory cues. Using chemogenetic inhibition, we selectively targeted genetically defined locus coeruleus (LC) neurons or their input to the medial prefrontal cortex (mPFC). We revealed that suppressing either the LC or its mPFC projections severely impaired switching behavior, establishing the critical role of the LC-mPFC circuit in supporting attentional switching. To uncover the neurophysiological substrates of the behavioral deficits, we paired endoscopic calcium imaging of the mPFC with chemogenetic inhibition of the LC in task-performing mice. We found that mPFC prominently responded to attentional switching and that LC inhibition not only enhanced the engagement of mPFC neurons but also broadened single-neuron tuning in the task. At the population level, LC inhibition disrupted mPFC dynamic changes and impaired the encoding capacity for switching. Our results highlight the profound impact of the ascending LC input on modulating prefrontal dynamics and provide new insights into the cellular and circuit-level mechanisms that support behavioral flexibility.

Characterisation of cold-selective lamina I spinal projection neurons in the mouse

Andrew.Todd@glasgow.ac.uk (Aimi N Razlan) — Wed, 13 May 2026 00:00:00 +0000

Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.

Dissociable neural substrates of integration and segregation in exogenous attention

xhe@bournemouth.ac.uk (Ai-Su Li) — Wed, 13 May 2026 00:00:00 +0000

The integration-segregation theory proposes that early facilitation and later inhibition (i.e. inhibition of return [IOR]) in exogenous attention arises from the competition between cue-target event integration and segregation. Although widely supported behaviorally, the theory lacked direct neural evidence. Here, we used event-related functional magnetic resonance imaging (fMRI) in human participants with an optimized cue-target paradigm to test this account. Cued targets elicited stronger activation in the frontoparietal attention networks, including the bilateral frontal eye field (FEF), intraparietal sulcus (IPS), right temporoparietal junction (TPJ), and left dorsal anterior cingulate cortex (dACC), consistent with the notion of attentional demand of reactivating the cue-initiated representations for integration. In contrast, uncued targets engaged the medial temporal cortex, particularly the bilateral parahippocampal gyrus (PHG) and superior temporal gyrus (STG), reflecting the segregation processes associated with new object-file creation and novelty encoding. These dissociable activations provide the first direct neuroimaging evidence for the integration-segregation theory. Moreover, we observed neural interactions between IOR and cognitive conflict, suggesting a potential modulation of conflict processing by attentional orienting. Taken together, these findings provide new insights into exogenous attention by clarifying the neural underpinnings of integration and segregation and uncovering the interaction between spatial orienting and conflict processing.

Drosophila ryanodine receptor gene triggers functional and developmental muscle properties and could be used to assess the impact of human RYR1 mutations

christophe.jagla@uca.fr (Catherine Sarret) — Wed, 13 May 2026 00:00:00 +0000

The ryanodine receptor (RYR) genes encode evolutionarily conserved calcium release channels involved in a wide range of calcium-dependent biological processes. Here, we show that the sole Drosophila RYR gene (dRyR) functions in differentiated somatic and cardiac muscle as well as in developing embryonic myotubes. In the larval body wall muscles, dRyR protein localizes at the SR membranes, and dRyR knockdown adversely affects muscle contractility, suggesting its conserved role in calcium-triggered E-C coupling. After dRyR attenuation, sarcomere, and mitochondrial patterns are severely impaired, showing dRyR involvement in structural muscle properties. However, dRyR is also prominently expressed and functionally required in growing embryonic muscles. dRyR loss of function leads to myotube growth defects and thin myofiber phenotypes, while its overexpression induces myofiber splitting. Given the structural and functional conservation of dRyR, we used Drosophila to test the impact of one human RYR1 variant of unknown significance (VUS). Larvae carrying p.Met4881Ile RYR1 VUS showed impaired mobility and altered structural muscle properties reminiscent of those seen in dRyR knockdown, thus indicating it is likely pathogenic. Overall, we show that Drosophila dRyR plays a conserved role in setting muscle contractility and structural muscle features. Our findings underline the still under-investigated role of dRyR as a promyogenic factor and provide a first example of the impact assessment of a human RYR1 VUS in Drosophila.

Physiological febrile heat stress increases cytoadhesion through increased protein trafficking of Plasmodium falciparum surface proteins into the red blood cell

moritz.treeck@gimm.pt (David Anaguano) — Wed, 13 May 2026 00:00:00 +0000

Fever is a hallmark of malaria. Several studies have linked febrile temperatures to reduced parasite viability, but also to increased cytoadhesion, a key driver of pathology. However, different mechanisms have been proposed to cause changes in cytoadhesion and parasite sensitivity to heat. Here, we demonstrate that exposure of Plasmodium falciparum-infected red blood cells (iRBCs) to physiologically relevant febrile heat stress (39 °C), derived from patient data, enhances cytoadhesion through increased trafficking of the major virulence factor PfEMP1 to the iRBC surface. This phenomenon is not limited to PfEMP1 and common laboratory strains, as it extends to the surface nutrient channel PSAC in four clinical isolates of diverse geographic origin. The increased surface protein display occurs without changes in overall protein expression or parasite developmental progression. Using phosphoproteomics and proximity labelling, we find that elevated temperature also increases trafficking and phosphorylation of exported proteins into the RBC. Enhanced export is likely reliant on the presence of a transmembrane domain as shown by NanoLuc reporter assays. Collectively, our results indicate that febrile temperatures commonly experienced during infection can accelerate protein export, likely at the parasitophorous vacuole. This enhanced export following heat stress is relevant because increased cytoadhesion could influence disease severity through earlier iRBC sequestration and elevated bound parasite mass.

Modeling flexible behavior with remapping-based hippocampal sequence learning

yito@nips.ac.jp (Taro Toyoizumi) — Wed, 13 May 2026 00:00:00 +0000

Animals flexibly change their behavior depending on context. It is reported that the hippocampus is one of the most prominent regions for contextual behaviors, and its sequential activity shows context dependency. However, how such context-dependent sequential activity is established through reorganization of neuronal activity (remapping) remains unclear. To better understand the formation of hippocampal activity and its contribution to context-dependent flexible behavior, we present a novel biologically plausible reinforcement learning model. In this model, Context selector promotes the formation of context-dependent sequential activity and allows for flexible switching of behavior in multiple contexts. This model reproduces a variety of findings from neural activity, optogenetic inactivation, human fMRI, and clinical research. Furthermore, our model predicts that imbalances in the ratio between sensory and contextual representations in Context selector account for schizophrenia and autism spectrum disorder-like behaviors.

The long non-coding RNA Dreg1 is required for optimal ILC2 development

ajith.vasanthakumar@petermac.org (Adelynn Tang) — Wed, 13 May 2026 00:00:00 +0000

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells, and innate lymphoid cells (ILCs). As such, the levels and timing of Gata3 expression are critical for directing lineage fate decisions. The Gata3 locus has a complex and dynamic distal regulatory enhancer landscape. Recently, we identified a non-coding RNA, Dreg1, located immediately upstream of the classic +280 kb T/NK cell enhancer (Tce1). To test its function, we excised the Dreg1 locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK, and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCPs) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of Gata3 in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express Dreg1 and showed alterations in the epigenetic landscape of the Dreg1 locus. Finally, we discovered that potential homologues of Dreg1 harboured in a syntenic enhancer of GATA3 are also highly expressed in human ILC2. Taken together, we conclude that Dreg1 is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of Gata3 required for the optimal development of the ILC2 lineage.

An altered cell-specific subcellular distribution of translesion synthesis DNA polymerase kappa (POLK) in aging mouse neurons

amp7167@psu.edu (Anirban Paul) — Wed, 13 May 2026 00:00:00 +0000

Genomic stability is critical for cellular function; however, in the central nervous system, highly metabolically active differentiated neurons are challenged to maintain their genome over the organismal lifespan without replication. DNA damage in neurons increases with chronological age and accelerates in neurodegenerative disorders, resulting in cellular and systemic dysregulation. Distinct DNA damage response strategies have evolved with a host of polymerases. The Y-family translesion synthesis (TLS) polymerases are well known for bypassing and repairing damaged DNA in dividing cells. However, their expression, dynamics, and role, if any, in enduring postmitotic differentiated neurons of the brain are completely unknown. We show through systematic longitudinal studies for the first time that DNA polymerase kappa (POLK), a member of the Y-family polymerases, is highly expressed in mouse neurons. With chronological age, there is a progressive and significant reduction of nuclear POLK with a concomitant accumulation in the cytoplasm that is predictive of brain tissue age. The reduction of nuclear POLK in old brains is congruent with an increase in DNA damage markers. The nuclear POLK colocalizes with damaged sites and DNA repair proteins. The cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Nuclear POLK expression is significantly higher in GABAergic interneurons (INs) compared to excitatory pyramidal neurons and lowest in non-neurons, possibly reflective of the inherent biological differences such as firing rates and neuronal activity. INs associated with microglia have significantly higher levels of cytoplasmic POLK in old age. Finally, we show that neuronal activity itself can lead to an increase in nuclear POLK levels and a reduction of the cytoplasmic fraction. Our findings open a new avenue in understanding how different classes of postmitotic neurons deploy TLS polymerase(s) to maintain their genomic integrity over time, which will help design strategies for longevity, healthspan, and prevention of neurodegeneration.

Drift in individual behavioral phenotype as a strategy for unpredictable worlds

rtmaloney@coloradocollege.edu (Athena Q Ye) — Tue, 12 May 2026 00:00:00 +0000

Individuals, even with matched genetics and environment, show substantial phenotypic variability. This variability may be part of a bet-hedging strategy, where populations express a range of phenotypes to ensure survival in unpredictable environments. In addition, phenotypic variability between individuals (‘bet-hedging’), individuals also show variability in their phenotype across time, even absent external cues. There are few evolutionary theories that explain random shifts in phenotype across an animal's life, which we term drift in individual phenotype. We use individuality in locomotor handedness in Drosophila melanogaster to characterize both bet-hedging and drift. We use a continuous circling assay to show that handedness spontaneously changes over timescales ranging from seconds to the lifespan of a fly. We compare the amount of drift and bet-hedging across a number of different fly strains and show independent strain-specific differences in bet-hedging and drift. We show manipulation of serotonin changes the rate of drift, indicating a potential circuit substrate controlling drift. We then develop a theoretical framework for assessing the adaptive value of drift, demonstrating that drift may be adaptive for populations subject to selection pressures that fluctuate on timescales similar to the lifespan of an animal. We apply our model to real-world environmental signals and find patterns of fluctuations that favor random drift in behavioral phenotype, suggesting that drift may be adaptive under some real-world conditions. These results demonstrate that drift plays a role in driving variability in a population and may serve an adaptive role distinct from population-level bet-hedging.

Science under threat around the world

debat.humberto@inta.gob.ar (Humberto J Debat) — Tue, 12 May 2026 00:00:00 +0000

Politicians are reducing public funding for science and dismantling scientific institutions for ideological reasons in Argentina and the United States. It appeared as if something similar could happen in the Netherlands, but the collapse of a coalition government led to a reprieve. How should the scientific community respond to such crises?

Endogenous corazonin signaling modulates the post-mating switch in behavior and physiology in females of the brown planthopper and Drosophila

wusf@njau.edu.cn (Congfen Gao) — Tue, 12 May 2026 00:00:00 +0000

Mating in insects typically triggers a post-mating response (PMR) in females, characterized by reduced receptivity to re-mating and increased oviposition, which ensures numerous and viable offspring and male paternity. This PMR is induced by male seminal factors, such as sex peptide in Drosophila melanogaster, as well as intrinsic female signaling components. The latter signaling remains poorly understood in most insects, including the devastating rice pest, the brown planthopper (BPH) Nilaparvata lugens. Here, we show that the neuropeptide corazonin (CRZ) and its receptor (CrzR) are critical for the PMR in female BPHs. Peptide injection, RNAi knockdown, and CRISPR/Cas9 mutagenesis confirm that intact CRZ signaling reduces re-mating frequency and increases ovulation in mated BPH females. The CrzR is highly expressed in the female reproductive tract, and CrzR knockdown phenocopies CRZ diminishment. Importantly, female CRZ/CrzR signaling is required for male seminal factors, such as the peptide maccessin, to induce the PMR; with disrupted CrzR signaling, injection of seminal fluid or maccessin fails to reduce female receptivity. Notably, CRZ is not produced in male accessory glands (MAGs) of BPHs and thus not transferred during copulation. We furthermore demonstrate that also in D. melanogaster disrupted CRZ signaling increases female re-mating and reduces oviposition, while CRZ injection suppresses virgin receptivity and increases oviposition. Finally, we detected no CRZ in the MAG of D. melanogaster, supporting its role as an endogenous signal in the female PMR also in this species. In summary, our findings reveal a conserved role of endogenous CRZ signaling in regulating the female PMR and demonstrate that female CRZ signaling and male-derived signals cooperate to induce post-mating transitions in BPHs and D. melanogaster. CRZ is a paralog of the peptide gonadotropin-releasing hormone, known to regulate reproduction in vertebrates, including humans, suggesting evolutionary conservation of an ancient function.

Cortical motor activity modulates respiration and reduces apnoea in neonates

caroline.hartley@paediatrics.ox.ac.uk (Caroline Hartley) — Tue, 12 May 2026 00:00:00 +0000

Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea – the cessation of respiration – is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if there was any evidence for cortical coupling with respiration in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we investigated interactions between cortical and respiratory activity (known as cortico-respiratory coupling) using phase-amplitude coupling. We show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5±2.6 weeks postmenstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. Whilst our study was limited in spatial resolution, and determining causality is challenging, we believe these findings support the notion that the cortico-respiratory coupling observed here constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel insight into this common and potentially life-threatening neonatal pathology.

Functional imaging of nine distinct neuronal populations under a miniscope in freely behaving animals

mary.phillips@zeiss.com (Mary L Phillips) — Tue, 12 May 2026 00:00:00 +0000

Head-mounted miniscopes have enabled functional fluorescence imaging in freely moving animals. However, current technology is limited to recording at most two spectrally distinct fluorophores, severely restricting the number of identifiable cell types. Here, we introduce multiplexed neuronal imaging (Neuroplex), a pipeline combining miniscope Ca²⁺ recordings with in vivo multiplexed confocal spectral imaging to distinguish nine projection-defined neuronal subtypes through the same GRIN lens. By co-registering defined neurons with fluorophore-specific spectral fingerprints via linear unmixing, we link projection-defined identities to behaviorally relevant neuronal activity. This approach overcomes spectral constraints of miniscopes, enabling circuit-level dissection of behavior in single animals.

HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane

mmellado@cnb.csic.es (Adriana Quijada-Freire) — Tue, 12 May 2026 00:00:00 +0000

HIV-1 entry into susceptible cells requires the dynamic interaction of its envelope (Env) glycoprotein with the host cell receptor CD4 and a co-receptor, either CCR5 or CXCR4. While the core molecular mechanisms driving Env-receptor interactions and subsequent membrane fusion are well characterized, the precise nanoscale spatial reorganization of these co-receptors at the viral binding site remains poorly defined. In this study, we employed single-particle tracking total internal reflection fluorescence (SPT-TIRF) microscopy to quantitatively analyze nanoscale organizational changes of CXCR4 on the surface of human CD4⁺ T cells following binding by X4-tropic HIV-1. Our data reveal that both recombinant X4-gp120 and virus-like particles expressing physiological levels of X4 Env proteins (gp120 and gp41) promote CXCR4 clustering, a phenomenon linked to cell infection. Furthermore, these ligands induced oligomerization of CXCR4^R334X, a naturally occurring mutant associated with WHIM syndrome that supports HIV-1 infection, but fails to oligomerize in response to CXCL12. Our findings establish a link between CXCR4 clustering and HIV-1 infection, enhancing our understanding of the initial events in viral attachment and entry. These results further suggest that HIV-1 depends on a specific spatial arrangement of co-receptors, distinct from that induced by their natural chemokine ligands, highlighting the critical role of cell-surface receptor spatial organization in dictating cellular function.

Regime shift detection and neurocomputational substrates for under and overreactions to change

raccoon65.y@nycu.edu.tw (George Wu) — Mon, 11 May 2026 00:00:00 +0000

The world constantly changes, with the underlying state of the world shifting from one regime to another. The ability to detect a regime shift, such as the onset of a pandemic or the end of a recession, significantly impacts individual decisions, as well as governmental policies. However, determining whether a regime has changed is usually not obvious, as signals are noisy and reflective of the volatility of the environment. We designed an fMRI paradigm that examines a stylized regime-shift detection task. Human participants showed systematic overreaction and underreaction: Overreaction was most commonly seen when signals were noisy, but when environments were stable and change is possible but unlikely. By contrast, underreaction was observed when signals were precise but when environments were unstable and hence change was more likely. These behavioral signatures are consistent with the system-neglect computational hypothesis, which posits that sensitivity or lack thereof to system parameters (noise and volatility) is central to these behavioral biases. Guided by this computational framework, we found that individual subjects’ sensitivity to system parameters was represented by two distinct brain networks. Whereas a frontoparietal network selectively represented individuals’ sensitivity to signal noise but not environment volatility, the ventromedial prefrontal cortex (vmPFC) showed the opposite pattern. Further, these two networks were involved in different aspects of regime-shift computations: while vmPFC correlated with subjects’ beliefs about change, the frontoparietal network represented the strength of evidence in favor of regime shifts. Together, these results suggest that regime-shift detection recruits belief-updating and evidence-evaluation networks and that under- and overreactions arise from how sensitive these networks are to the system parameters.

Adult-neurogenesis allows for representational stability and flexibility in early olfactory system

Krishnan_Padmanabhan@urmc.rochester.edu (Krishnan Padmanabhan) — Mon, 11 May 2026 00:00:00 +0000

In the olfactory system, adult-neurogenesis results in the continuous reorganization of synaptic connections and network architecture throughout the animal’s life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information, and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level. By contrast, in the olfactory piriform cortex (PCx), both individual cell responses and overall population dynamics undergo progressive changes due to adult-neurogenesis. This leads to representational drift, a gradual alteration in stimulus-evoked activity patterns. Both processes are dynamic and depend on experience such that repeated exposure to specific odors reduces the drift due to adult-neurogenesis; thus, when the odor environment is stable over the course of adult-neurogenesis, it is spike-timing-dependent plasticity that leads representations to remain stable in the PCx; when those olfactory environments change, adult-neurogenesis allows cortical representations to track environmental change. Whereas perceptual stability and plasticity due to learning are often thought of as two distinct, often contradictory processes in neuronal coding, we find that adult-neurogenesis serves as a shared mechanism for both. In this regard, the quixotic presence of adult-neurogenesis in the mammalian olfactory bulb that has been the focus of considerable investigation in chemosensory neuroscience may be the mechanistic underpinning behind an array of complex computations.

Recombination shapes the diversification of the wtf meiotic drivers

gongzhen@nnu.edu.cn (Guan-Zhu Han) — Mon, 11 May 2026 00:00:00 +0000

Meiotic drivers are selfish genetic elements that distort fair segregation. The wtf genes are poison-antidote meiotic drivers that are experiencing rapid diversification in fission yeasts. However, gene duplication alone is insufficient to drive the diversification of wtf genes, given the poison encoded by a newly duplicated wtf gene can be detoxified by the antidote encoded by the original wtf gene. Here, we analyze the evolution of wtf genes across 21 strains of Schizosaccharomyces pombe. Knocking out each of 25 wtf genes in S. pombe strain 972h- separately does not attenuate the yeast growth, indicating that the wtf genes might be largely neutral to their carriers in asexual life cycle. Interestingly, wtf genes underwent recurrent and intricate recombination. As proof of principle, we generate a novel meiotic driver through artificial recombination between wtf drivers, and its encoded poison cannot be detoxified by the antidotes encoded by their parental wtf genes but can be detoxified by its own antidote. Therefore, we propose that recombination can generate new meiotic drivers and thus shape the diversification of the wtf drivers.

Cross-modal interaction of human alpha activity does not reflect inhibition of early sensory processing in a frequency-tagging study using EEG and MEG

marion.brickwedde@charite.de (Ali Mazaheri) — Mon, 11 May 2026 00:00:00 +0000

Selective attention involves prioritising relevant sensory input while suppressing irrelevant stimuli. It has been proposed that oscillatory alpha-band activity (~10 Hz) aids this process by functionally inhibiting early sensory regions. However, recent studies have challenged this notion. Our EEG and MEG studies aimed to investigate whether human alpha oscillations serve as a 'gatekeeper' for downstream signal transmission. We first observed these effects in an EEG study and then replicated them using MEG, which allowed us to localise the sources. We employed a cross-modal paradigm where visual cues indicated whether upcoming targets required visual or auditory discrimination. To assess inhibition, we utilised frequency-tagging, simultaneously flickering the fixation cross at 36 Hz and playing amplitude-modulated white noise at 40 Hz during the cue-to-target interval. Consistent with prior research, we observed an increase in posterior alpha activity following cues signalling auditory targets. However, remarkably, both visual and auditory frequency-tagged responses amplified in anticipation of auditory targets, correlating with alpha activity amplitude. Our findings suggest that when attention shifts to auditory processing, the visual stream remains responsive and is not hindered by occipital alpha activity. This implies that alpha modulation does not solely regulate 'gain control' in early visual areas but rather orchestrates signal transmission to later stages of the processing stream.

Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila

dujuan9981@cau.edu.cn (Juan Du) — Fri, 08 May 2026 00:00:00 +0000

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl5^1bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.

Neural representation of time across complementary reference frames

xuya@cbs.mpg.de (Léo Dutriaux) — Fri, 08 May 2026 00:00:00 +0000

Humans conceptualize time in terms of space, allowing flexible time construals from various perspectives. We can travel internally through a timeline to remember the past and imagine the future (i.e., mental time travel) or watch from an external standpoint to have a panoramic view of history (i.e., mental time watching). However, the neural mechanisms that support these flexible temporal construals remain unclear. To investigate this, we asked participants to learn a fictional religious ritual of 15 events. During fMRI scanning, they were guided to consider the event series from either an internal or external perspective in different tasks. Behavioral results confirmed the success of our manipulation, showing the expected symbolic distance effect in the internal-perspective task and the reverse effect in the external-perspective task. We found that the activation level in the posterior parietal cortex correlated positively with sequential distance in the external-perspective task but negatively in the internal-perspective task. In contrast, the activation level in the anterior hippocampus positively correlated with sequential distance regardless of the observer’s perspectives. These results suggest that the hippocampus stores the memory of the event sequences allocentrically in a perspective-agnostic manner. Conversely, the posterior parietal cortex retrieves event sequences egocentrically from the optimal perspective for the current task context. Such complementary allocentric and egocentric representations support both the stability of memory storage and the flexibility of time construals.

Prolonged oscillating preoptic area kisspeptin neuron activity underlies the preovulatory luteinizing hormone surge in mice

aeh36@cam.ac.uk (Allan Edward Herbison) — Thu, 07 May 2026 00:00:00 +0000

The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3V^KISS neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3V^KISS neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3V^KISS neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3V^KISS neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3V^KISS neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.

How membranes shape up for lipid transfer

tendo@cc.kyoto-su.ac.jp (Takashi Hirashima) — Thu, 07 May 2026 00:00:00 +0000

The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.

A novel 3D visualization method in mice identifies the periportal lamellar complex (PLC) as a key regulator of hepatic ductal and neuronal branching morphogenesis

chongchen@scu.edu.cn (Banglei Yin) — Thu, 07 May 2026 00:00:00 +0000

The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34⁺Sca-1⁺ endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.

HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content

sfrangos@uoguelph.ca (Cezar M Khursigara) — Wed, 06 May 2026 00:00:00 +0000

It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I–IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Natural xanthones as α-Mangostin induce vasorelaxation involving key gating residues in the S6 domain of BK channels

m.musinszki@physiologie.uni-kiel.de (Marianne A Musinszki) — Wed, 06 May 2026 00:00:00 +0000

Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from Garcinia mangostana as a potent modulator of several potassium channels, with large-conductance K⁺ (BK) channels as its primary target for vasorelaxation. Mangostin-activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1–Ca_v nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²⁺ sensitivity. Docking, competition, single-channel analysis, and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin’s vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.

Fully computational design of PAM-relaxed Staphylococcus aureus Cas9 with expanded targeting capability using UniDesign

jiex@umich.edu (Jie Xu) — Wed, 06 May 2026 00:00:00 +0000

CRISPR–Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. Staphylococcus aureus Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type enzyme through a fully computational point-mutation design workflow, UniDesign, without additional experimental optimization. As expected, KRH efficiently recognizes an expanded NNNRRT PAM and exhibits substantially enhanced editing efficiency at non-canonical PAM sites, with improvements of up to 116-fold over the wild type. KRH achieves genome- and base-editing efficiencies comparable to, or exceeding, those of the well-known evolution-derived KKH variant. Computational modeling by UniDesign provides a mechanistic explanation for the PAM relaxation observed in both KRH and KKH, with structural and energetic analyses revealing that KRH relaxes PAM specificity by fine-tuning the balance between sequence-specific interactions with PAM bases and nonspecific contacts with the DNA backbone. Beyond its practical utility, KRH demonstrates that computational design can identify a minimal set of mutations sufficient to remodel the PAM interface while preserving high nuclease activity. This approach recapitulates—and in some cases surpasses—the performance of evolution-derived variants, offering a scalable strategy for high-throughput Cas9 engineering. Overall, these results establish KRH as a blueprint for rationally engineered, PAM-relaxed nucleases and underscore the power of computational design to accelerate next-generation genome editing.

Dynamic architecture of mycobacterial outer membranes revealed by all-atom simulations

wonpil@lehigh.edu (Matthieu Chavent) — Wed, 06 May 2026 00:00:00 +0000

Tuberculosis remains a global health crisis due to the resilience of Mycobacterium tuberculosis (Mtb), largely attributed to its unique cell envelope. The impermeability and structural complexity of the outer membrane of this envelope, driven by mycolic acids and glycolipids, pose significant challenges for therapeutic intervention. Here, we present the first all-atom models of an Mtb outer membrane using molecular dynamics simulations. We demonstrate that α-mycolic acids adopt extended conformations to stabilize bilayers, with a phase transition near 338 K that underscores their thermal resilience. Lipids in the outer leaflet, such as PDIM and PAT, induce membrane heterogeneity, migrating to the interleaflet space and reducing lipid order. The simulated mycobacterial outer membrane has ordered inner leaflets and disordered outer leaflets, which contrasts with the outer membrane of Gram-negative bacteria. These findings reveal that PDIM- and PAT-driven lipid redistribution, reduced lipid order, and asymmetric fluidity gradients enable Mtb’s outer membrane to resist host-derived stresses and limit antibiotic penetration, thereby promoting bacterial survival. Our work provides a foundational framework for targeting the mycobacterial outer membrane in future drug development.

Canonical neurodevelopmental trajectories of structural and functional manifolds

Alicja.Monaghan@mrc-cbu.cam.ac.uk (Alicja Monaghan) — Wed, 06 May 2026 00:00:00 +0000

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N=390 with one observation, N=163 with two observations and N=57 with three) and functional (512 participants, N=340 with one observation, N=128 with two observations and N=44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, such as working memory, are robust predictors of coupling. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These gradients are established early in life, refined through development, and their coupling is predicted by working memory.

Continuous flash suppression of neural responses and population orientation coding in macaque V1

tangshm@pku.edu.cn (Cai-Xia Chen) — Wed, 06 May 2026 00:00:00 +0000

Continuous flash suppression (CFS), in which a dynamic masker presented to one eye suppresses awareness of a stimulus in the other eye, is widely used to study visual subconsciousness. Although some studies report preserved high-level processing under CFS, these effects have been increasingly questioned and may partly reflect residual low-level feature processing. A key unresolved issue is how strongly neuronal responses in V1, where inputs from the two eyes first converge, are affected by CFS, and how much the remaining signals can support downstream processing. Here, we used two-photon calcium imaging to record large populations of V1 neurons in awake, fixating macaques while presenting grating stimuli under CFS. CFS strongly suppressed V1 orientation responses in an ocular-dominance-dependent manner, nearly abolishing responses in neurons preferring the masker eye or both eyes, and significantly reducing responses in neurons preferring the grating eye. Modeling analyses further indicated that V1 population activity under CFS may still support coarse orientation classification but not accurate stimulus reconstruction. These results suggest that CFS substantially degrades orientation information in V1. The residual signals may support limited low-level processing but are likely insufficient for downstream higher-level visual and cognitive tasks.

Real-time transcriptomic profiling in distinct experimental conditions

buttamer@uni-mainz.de (Anna Wierczeiko) — Tue, 05 May 2026 00:00:00 +0000

Nanopore technology offers real-time sequencing opportunities, providing rapid access to sequenced data and allowing researchers to manage the sequencing process efficiently, resulting in cost-effective strategies. Here, we present focused case studies demonstrating the versatility of real-time transcriptomics analysis in rapid quality control for long-read RNA-seq. We illustrate its utility through four experimental setups: (1) transcriptome profiling of distinct human cellular populations, (2) identification of experimentally enriched transcripts, (3) transcriptional analysis of cells under heat shock conditions, and (4) identification of experimentally manipulated genes (knockout and overexpression) in several yeast strains. We show how to perform multiple layers of quality control as soon as sequencing has started, addressing both the quality of the experimental and sequencing traits. Real-time quality control measures assess sample/condition variability and determine the number of identified genes per sample/condition. Furthermore, real-time differential gene/transcript expression analysis can be conducted at various time points post-sequencing initiation (PSI), revealing dynamic changes in gene/transcript expression between two conditions. Using real-time analysis, which occurs in parallel to the sequencing run, we identified differentially expressed genes/transcripts as early as 1 hr PSI. These changes were consistently observed throughout the entire sequencing process. We discuss the new possibilities offered by real-time data analysis, which have the potential to serve as a valuable tool for rapid and cost-effective quality checks in specific experimental settings and can be potentially integrated into clinical applications in the future.

Hugin-AstA circuitry is a novel central energy sensor that directly regulates sweet sensation in Drosophila and mouse

lmwang83@cimrbj.ac.cn (Daihan Li) — Tue, 05 May 2026 00:00:00 +0000

Taste sensation plays a crucial role in shaping feeding behavior and is intricately influenced by internal states like hunger or satiety. Despite the identification of numerous neural substrates regulating feeding behavior, the central neural substrate that linked energy-sensing and taste sensation remained elusive. Here, we identified a novel neural circuitry that could directly sense internal energy state and modulate sweet sensation in the Drosophila brain. Specifically, a subset of neuropeptidergic neurons expressing hugin directly detected elevated levels of circulating glucose via glucose transporter Glut1 and ATP-sensitive potassium channels. Upon activation, these neurons released hugin peptide and activated downstream Allatostatin A (AstA)⁺ neurons via its cognate receptor PK2-R1. Subsequently, the activation of AstA⁺ neurons then directly inhibited sweet sensation via AstA peptide and its cognate receptor AstA-R1 expressed in sweet-sensing Gr5a⁺ neurons. We also showed that Neuromedin U (NMU), the mammalian homolog of fly hugin, served as an energy sensor to suppress sweet sensation. Therefore, these data identify hugin⁺ neuron as a glucose-responsive central energy-sensing module that modulates sweet sensation across species.

Auditory perception and neural representation of temporal features are altered by age but not by cochlear synaptopathy

georg.klump@uni-oldenburg.de (Christine Köppl) — Tue, 05 May 2026 00:00:00 +0000

Age-related hearing loss is a complex phenomenon. The earliest-onset degenerative event is the gradual loss of neural connections between the cochlea and auditory brainstem. To probe for perceptual deficits that might arise from this loss, cochlear synaptopathy was induced pharmacologically in young-adult gerbils, which were then tested in a challenging listening task for the perception of temporal fine structure. Treated gerbils behaved no differently than normal-hearing, young-adult animals. In contrast, old gerbils, which typically express many cochlear and central-neural pathologies, showed impaired perception. To probe for the underlying mechanisms, single-unit responses were obtained from the auditory nerve to the same test stimuli. Responses from old gerbils showed no impairment in temporal locking to the stimulus fine structure. However, responses were significantly more driven by slower temporal fluctuations of the stimulus envelope, suggesting that the central auditory system may be unable to extract the relevant information for discrimination from such altered inputs.

Human adherent cortical organoids in a multi-well format

sk2602@cumc.columbia.edu (Femke MS de Vrij) — Tue, 05 May 2026 00:00:00 +0000

In the growing diversity of human induced pluripotent stem cell (iPSC)-derived models of brain development, we present here a novel method that exhibits 3D cortical layer formation in a reproducible topography of minimal dimensions. The resulting adherent cortical organoids (ACOs) develop by self-organization after seeding frontal cortex-patterned iPSC-derived neural progenitor cells in 384-well plates during 8 weeks of differentiation. The organoids have stereotypical dimensions of 3 × 3 × 0.2 mm, contain multiple subtypes of neurons, astrocytes, and oligodendrocyte lineage cells, and are amenable to extended culture for at least 10 months. Longitudinal imaging revealed morphologically mature dendritic spines, axonal myelination, and robust neuronal activity. Moreover, ACOs compare favorably to existing free-floating brain organoid models on the basis of robust reproducibility in obtaining topographically standardized radial cortical structures and circumventing internal necrosis. Adherent human cortical organoids hold considerable potential for high-throughput drug discovery applications, neurotoxicological screening, and mechanistic pathophysiological studies of brain disorders.

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

david.papadopoli@mail.mcgill.ca (Daina Avizonis) — Tue, 05 May 2026 00:00:00 +0000

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

Collective epithelial migration mediated by the unbinding of hexatic defects

giomi@lorentz.leidenuniv.nl (Dimitrios Krommydas) — Tue, 05 May 2026 00:00:00 +0000

Collective cell migration in epithelia relies on cell intercalation: a local remodeling of the cellular network that allows neighboring cells to swap their positions. Unlike foams and passive cellular fluid, in epithelial intercalation, these rearrangements crucially depend on activity. During these processes, the local geometry of the network and the contractile forces generated therein conspire to produce a burst of remodeling events, which collectively give rise to a vortical flow at the mesoscopic length scale. In this article, we formulate a continuum theory of the mechanism driving this process, built upon recent advances toward understanding the hexatic (i.e., sixfold ordered) structure of epithelial layers. Using a combination of active hydrodynamics and cell-resolved numerical simulations, we demonstrate that cell intercalation takes place via the unbinding of topological defects, naturally initiated by fluctuations and whose late-times dynamics is governed by the interplay between passive attractive forces and active self-propulsion. Our approach sheds light on the structure of the cellular forces driving collective migration in epithelia and provides an explanation of the observed extensile activity of in vitro epithelial layers.

Investments in photoreceptors compete with investments in optics to determine eye design

SL104@cam.ac.uk (Francisco JH Heras) — Tue, 05 May 2026 00:00:00 +0000

Eyes provide opportunities to understand the function, design, development, and evolution of elaborate sense organs. We take a new cost–benefit approach to understanding eye design by considering that optics and photoreceptors compete for the resources invested in an integrated system. We investigate this competition theoretically and empirically using a new measure of cost, specific volume. This common currency for optics and photoreceptors relates investments to image quality via geometrical, optical, and physiological constraints. By covering the morphospace of an eye of given type and cost, we model how trading optics against photoreceptors changes information capacity. In apposition compound eyes and simple eyes, an optimum configuration maximises efficiency. Efficiency requires heavy investment in photoreceptors and depends on photoreceptor energy consumption. Optimum information capacities and efficiencies scale non-linearly with total investment. Diurnal insects’ apposition eyes follow trends that promote efficiency: photoreceptor arrays take 40–80% of total specific volume, photoreceptor length increases systematically with spatial resolution, and photoreceptors are exceptionally long. Thus, competition between optics and photoreceptors shapes eye design, and matching investments in optics and photoreceptors to improve efficiency is a design principle. Our new methodology can be developed to view the adaptive radiation of eyes through a cost–benefit lens.

Herbivorous insects independently evolved salivary effectors to regulate plant immunity by destabilizing the malectin-LRR RLP NtRLP4

lijunmin@nbu.edu.cn (Chuan-Xi Zhang) — Tue, 05 May 2026 00:00:00 +0000

Plants utilize receptor-like proteins and receptor-like kinases (RLPs/RLKs) to perceive and respond to a wide variety of invading pathogens and insect herbivores. While the strategies employed by microbial pathogens to suppress plant immunity have been well characterized, it remains unclear how herbivorous insects counteract receptor-mediated defenses. Here, we show that salivary effectors evolve independently in whiteflies and planthoppers to dampen RLP4-mediated plant immunity. RLP4, as a leucine-rich repeat RLP (LRR-RLP), confers plant resistance against herbivorous insects by forming the RLP4/SOBIR1 complexes. In the whitefly Bemisia tabaci, BtRDP, the Aleyrodidae-specific salivary sheath protein, interacts with RLP4 from multiple plant species and promotes its ubiquitin-dependent degradation. Overexpression of NtRLP4 in transgenic plants exerts a detrimental effect on B. tabaci by exploiting the crosstalk between the salicylic acid and jasmonic acid pathways. Conversely, overexpression of BtRDP or silencing of NtRLP4 effectively alleviates such negative effects. In planthopper Nilaparvata lugens, the Delphacidae-restricted salivary protein NlSP104 also targets and promotes the degradation of OsRLP4 from rice plants. These findings reveal convergent evolution of salivary proteins in insects and underscore the complex interactions between plants and herbivorous insects.