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RelB NF-κB tunes Notch2 signaling to promote IL-23-secreting solitary isolated lymphoid tissue–resident DCs critical for gut immunity

While preserving tolerance toward commensals, dendritic cells (DCs) also orchestrate response against pathogens. The noncanonical RelB NF-κB pathway in DCs curbs tolerogenic Tregs in the intestine. Whether RelB-dependent DC regulations also impact intestinal immunity remains less clear. Here, we show that genetic ablation of RelB in DCs compromises IL-23-dependent immune response in the intestine, imparting vulnerability in Relb ΔCD11c mice to infection with Citrobacter rodentium , an enteropathogen. Our mechanistic studies revealed that RelB supported the expression of RBP-J from a κB site-driven promoter, tuning Notch2 response in DCs. This RelB-mediated Notch2 control specified a solitary isolated lymphoid tissue–resident DC subset, which served as a dominant source of IL-23 in infected mice. Indeed, we found that IL-23 supplementation readily rescued the immune deficiency of Relb ΔCD11c mice, improving bacterial clearance. In sum, we illustrate a previously unrecognized crosstalk between RelB and Notch2 underpinning IL-23-secreting DCs critical for gut immunity.

Profile of Morris Moscovitch

Morris Moscovitch’s five-decade career has reshaped scientists’ understanding of how the brain stores and retrieves memories. His Multiple Trace Theory challenged the view that the hippocampus serves only as temporary storage, showing instead that richly detailed episodic memories remain dependent on the hippocampus indefinitely. Moscovitch demonstrated that the hippocampus contributes not just to remembering but to imagination, problem-solving, and social cognition. His recent work reveals that people detect episodic richness in others’ memories and use this signal to guide social preferences. Through collaborative research spanning hemispheric specialization and face recognition, Moscovitch has revealed memory as central to human cognition.

Comparative archaeology reveals recurrent but nondeterministic pathways through complexification

The amount of variation observed among early complex societies has challenged efforts to understand their social dynamics. We advocate for a comparative approach that directly investigates the forces producing this variation. By holistically ranking 63 trajectories of societal change along five axes of differentiation, we characterize their development from a multidimensional perspective. Our analysis reveals that the majority of these trajectories align with one of six recurrent pathways through “complexification,” identified from broadly similar courses of development shared across multiple trajectories. These patterns provide a framework for understanding the conditions under which different forms of complexity emerged—or failed to do so. Particular attention is paid to the ways in which social and demographic forces interact along these pathways. Crucially, these forces interact probabilistically rather than deterministically, producing widespread tendencies rather than inevitable outcomes. Focusing future research on mediating and confounding variables, expanding the sample of trajectories available for analysis, identifying additional complexification pathways and the social forces at work in them, and leveraging the explanatory potential of trajectories that do not align well with any developmental pattern, will further enrich our understanding of the complexification process.

An expanded apolipoprotein D family provides spider mites with dual-layer protection against dietary oxidative stress

Plant defense has driven the evolution of species-dependent adaptive strategies in many herbivores, but the molecular mechanisms of adaptation in most arthropods remain largely unknown. The two-spotted spider mite ( Tetranychus urticae ) is a generalist herbivore that feeds by sucking the contents of mesophyll cells, a feeding strategy distinct from that of phloem-feeding insects. Here, we show the unexpected differential expression of apolipoprotein D ( ApoD ) genes during feeding when mites are transferred to different host plant species, as well as extreme gene family expansion (64 ApoD paralogs, the largest reported in any organism). We find that ApoD proteins protect mites against reactive oxygen species (ROS) during feeding, and we identify a dual-layer mechanism by which ApoD proteins counteract plant ROS defenses during ingestion and digestion. First, the salivary protein TuApoD2 is secreted during the ingestion of mesophyll cell contents, where it interacts with glycolate oxidase 2 (GOX2) to inhibit H 2 O 2 generation. After ingestion, TuApoD33 in the gut cells also interacts with GOX2 to maintain the inhibition of H 2 O 2 generation. These findings suggest that the evolutionary expansion of the ApoD gene family is a key component of the molecular arms race between herbivorous mites and host plants.

Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission

Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.

Depletion-induced interactions modulate nanoscale protein diffusion in polymeric crowder solutions

Macromolecular crowding plays a crucial role in modulating protein dynamics in cellular and in vitro environments. Polymeric crowders such as dextran and Ficoll are known to induce entropic forces, including depletion interactions, that promote structural organization, yet their nanoscale consequences for protein dynamics remain poorly understood. Here, we employ megahertz X-ray photon correlation spectroscopy (MHz-XPCS) at the European X-ray Free Electron Laser (XFEL) to probe the dynamics of the protein ferritin in solutions containing sucrose, dextran, and Ficoll. We find pronounced changes in collective protein dynamics in polymeric crowders, revealing depletion-driven short-range attractions that, combined with long-range repulsions, give rise to intermediate-range organization. These mesoscale correlations undergo collective relaxation on microsecond to millisecond timescales, as directly resolved by XPCS through the decay of ferritin density fluctuations. The magnitude of this depends sensitively on crowder molecular weight and type. Normalizing the crowder concentration by c * reveals scaling behavior of ferritin self-diffusion with a crossover near 2 c *, marking a transition from depletion-enhanced mobility to viscosity-dominated slowing. Our results demonstrate that bulk properties alone are insufficient to describe protein dynamics in crowded solutions, highlighting the need to include polymer-specific interactions and depletion theory in models of crowded environments.

Developmental changes in memory structure and precision alter the use of retrieved episodes during decisions for reward

Most widely studied option evaluation strategies rely on knowledge accumulated across repeated experiences. But how should options be evaluated in unfamiliar environments, in which knowledge is sparse? In these situations, how do decision makers make efficient use of limited past experience to guide their choices? One possible strategy is episodic sampling, in which a decision maker retrieves a small number of past decisions from memory to estimate the value of present options. By virtue of their age, children and adolescents have less experience than adults, making episodic sampling a particularly useful strategy for them. At the same time, the effectiveness of episodic sampling derives from memory’s precision and context sensitivity—properties that continue to develop into adolescence and young adulthood. This tension raises a key question: are developmental differences in episodic memory associated with differences in episodic sampling? To address this question, 106 participants, ages 8 to 25, completed a 2-d choice task that dissociated the influence of a single episodic memory from the influence of multiple episodes sharing a common context. At all ages, single episodes biased choices. But, only adults were sensitive to the broader evoked context. Further clarifying the relationship between episodic memory and decision making, differences in memory precision predicted differences in episodic sampling, even after taking into account age, while episodic sampling, in turn, accounted for individual differences in forward planning. Together, these findings suggest that episodic memory guides decision making throughout development, but the character of its influence evolves as memory becomes more precise and richly structured.

The floral illusion: A parasitic beetle mimics the scent of flowers to attract bees

Animals are not known to biosynthesize floral chemical signals to manipulate pollinators, although such mimicry could profoundly shape plant–pollinator interactions. Larvae of the poisonous European blister beetle Meloe proscarabaeus parasitize multiple solitary bee species, yet the mechanism enabling host attraction has remained unresolved. Here we show that these larvae lure bees by emitting a bouquet of volatile compounds that closely resembles floral scent. Chemical analyses reveal a complex blend of monoterpenoids derived from ( S )-linalool, a ubiquitous floral volatile. Behavioral assays demonstrate that these compounds function as floral-scent mimics, eliciting attraction in bees and acting as allomones (i.e., interspecific chemical signals that benefit the emitter while disadvantaging the receiver). Transcriptomic and functional analyses identify cytochrome P450 enzymes that oxidize ( S )-linalool, suggesting that larvae biosynthesize these plant-like volatiles de novo. Together, these findings broaden the scope of interkingdom chemical mimicry and uncover a striking form of sensory deception in which an insect chemically assumes the signal identity of a flower, revealing that animals can evolve biosynthetic pathways to exploit plant–pollinator communication.

Long-horizon associative learning as a unifying framework for statistical learning across scales

Sensory inputs are rich with temporal patterns that unfold across multiple timescales. Uncovering these regularities is essential for anticipating future events and navigating the environment efficiently. Numerous models have been proposed to account for learning at specific temporal scales; however, they are often designed in isolation and rely on narrowly tuned statistical measures, limiting their generalizability to other paradigms. In contrast, humans typically learn without prior knowledge of the underlying structure or the relevant timescale at which regularities occur. Here, we present a unifying account of statistical learning that spans a wide range of temporal dependencies, from adjacent and nonadjacent transitions to complex network structures. This model, long-horizon associative learning, offers a biologically grounded implementation of the successor representation, or equivalently, the free energy minimization model. Reanalyzing data from 11 previously published studies, we show that a single neural mechanism captures both local statistical regularities and higher-order structural properties. This mechanism rests on graded temporal overlap of associative traces and is governed by a single free parameter (β). This initial domain-general associative learning process, emerging from the graded structure of associations, may later scaffold to higher-level operations such as grouping, categorization, rule abstraction, and memory formation. Overall, this framework offers a conceptual synthesis that bridges disparate strands of the statistical learning literature and reframes apparent paradigm-specific effects as different expressions of a common underlying computation.

An antibody–drug conjugate active against antibiotic-resistant <i> <i>Neisseria</i> gonorrhoeae </i>

Neisseria gonorrhoeae is the causative agent of gonorrhea, a sexually transmitted infection which is rising in incidence, with increasing drug-resistant strains posing a significant public health threat. To address the urgent need for novel therapies, we developed an antibody–drug conjugate (ADC) that targets this important human pathogen. We utilized Tridecaptin A 1, a potent antimicrobial peptide (AMP) against Gram-negative bacteria that exhibits significant toxicity against human cells, limiting its development for clinical use. By conjugating the Tridecaptin A 1 analogue, Oct-TriA 1 to a monoclonal antibody (mAb) that specifically targets gonococcal MtrE, the outer membrane component of a drug efflux pump that is upregulated in resistant strains, we aim to selectively deliver the AMP to the gonococcus. However, Oct-TriA 1 was not bactericidal when directly conjugated to mAb. To circumvent this, we exploited an immune evasion mechanism employed by the gonococcus by introducing a linker between Oct-TriA 1 and the mAb which is specifically cleaved by the IgA protease (IgAP) secreted by the gonococcus; the IgAP inactivates human IgA. This ADC has no detectable toxicity for relevant human cells, kills the gonococcus in an MtrE- and IgAP-dependent manner, and is active against a strain which is resistant to first line agents. This modular ADC platform could be extended to other bacterial pathogens which employ proteases to evade immune killing, offering a strategy in the fight against antimicrobial resistance.

Balanced polymorphism in a floral transcription factor underlies the ancient rhythm of daily sex alternation in avocado

In avocado and certain wild relatives in Lauraceae, a highly synchronized daily rhythm of floral sex timing promotes cross-pollination between two hermaphroditic flowering types. A-type plants present female-phase flowers in the morning and male-phase flowers in the afternoon, while B-types show the complementary pattern—a form of heterodichogamy. We mapped this dimorphism to a pair of dominant and recessive haplotypes at SDMYB , which belongs to a subgroup of R2R3 MYB transcription factors established as key regulators of floral maturation with links to circadian hormone signaling. Rhythmic diel SDMYB expression is associated with biphasic floral anthesis, and the dominant allele, which contains nonsynonymous changes in conserved functional domains, exhibits a cis -regulated phase delay, corresponding to the delayed second anthesis of A-type flowers. The SDMYB haplotypes form an ancient trans-species polymorphism, maintained by negative frequency-dependent balancing selection over 42 My, and they segregate in at least 26 nonavocado species, including in a genus where this mating system has not been reported. Although exceptionally old, the polymorphism is absent in other magnoliids with highly similar mating systems, suggesting daily forms of heterodichogamy can convergently evolve when rhythmic floral movements are coupled with the temporal separation of sexes.

Structures of the sodium-coupled phosphate importer SLC34A2 reveal a distinct architecture and gating mechanism

Dysregulation of inorganic phosphate (Pi) homeostasis contributes to metabolic disease, cancer, pathological calcification, and kidney disease. Systemic phosphate balance is regulated by SLC34 transporters that mediate renal Pi retention (SLC34A1/A3) and intestinal dietary Pi absorption (SLC34A2). SLC34s couple Pi uptake to the symport of sodium (Na + ) down its electrochemical gradient. Mutations or altered expression of SLC34 proteins are linked to disorders such as chronic kidney disease, where hyperphosphatemia is a major complication, and the lung disease pulmonary alveolar microlithiasis, caused by inactivating SLC34A2 mutations. SLC34A2 is also overexpressed in most ovarian and uterine tumors, making it an attractive target for antibody–drug conjugates. We present cryoelectron microscopy structures of SLC34A2 when the transporter is empty, bound to Na + ions only, fully loaded with Na + ions and Pi, and bound to an inhibitor phosphonoformic acid, revealing its distinct architecture, substrate and ion binding sites, the role of Na + , and multiple transporter states. Pi binds at a highly symmetric, membrane-embedded pocket positioned approximately mid-membrane and is coordinated by its signature four residue QSSS repeat motifs. Na + shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state. Integrated with functional analyses, these structures reveal that SLC34 transporters operate through an atypical alternating access cycle defined by coordinated elevator movements of an auxiliary gate domain. This work lays a foundational framework for understanding Pi regulation and opens avenues for therapeutic strategies targeting disorders linked to phosphate imbalance.

Parenthood decisions in uncertain times: Experimental evidence from four countries

Fertility rates are declining across much of the globe, yet the forces driving this decline have become increasingly complex, and classic theories have become less adequate to explain recent trends. While economic and gender-related explanations have long dominated fertility research, emerging global uncertainties, such as climate change, democratic backsliding, economic crises, and regional conflicts, may also shape how individuals evaluate childbearing. In addition to the more classical factors, this cross-national study examines how macrolevel uncertainties influence perceptions of fertility intentions in Italy, Argentina, the United States, and Germany. These countries offer distinct fertility trajectories and face unique combinations of sociopolitical and environmental challenges. Using a conjoint experiment, we examine how individuals evaluate, across hypothetical scenarios, their intention of having a child under varying household, policy, and macrolevel conditions. Across all four countries, material security remains central: household income is the strongest predictor of fertility intentions, with homeownership and childcare playing smaller roles. At the same time, perceptions of macrolevel stability, including expectations about climate conditions, economic prospects, democratic functioning, and peace, exert substantial and meaningful effects, comparable to homeownership and childcare provision but more pronounced than those associated with gender-role arrangements. Cross-country differences show that macroeconomic stability and climate change are most consequential in Argentina, while in the United States respondents are less responsive to geopolitical conflict. These findings show that individuals evaluate childbearing not only through their immediate circumstances, but also through expectations about broader societal futures, highlighting the importance of incorporating macrolevel uncertainty when explaining contemporary fertility decline.

Treating language contact as normal: Coalescent-theoretic modeling of the prehistory of the Bantu language family

The Bantu language family of sub-Saharan Africa is among the largest in the world by the number of languages, by geographical extent, and by the number of speakers. The expansion of the Bantu languages is an important example of large-scale language-family expansions in the history of humankind. To learn the early prehistory of the Bantu language family, one needs to disentangle the signal of the original splits and diversification from that of the subsequent language contact, known to be strong in the Bantu languages. We introduce a coalescent-theoretic model to computationally study the prehistory of the Bantu family. Our model treats language contact as a norm rather than a rare exception, in contrast to earlier computational work. Applying Approximate Bayesian Computation, we show the rates of both language change and language contact to have been so high within the Bantu family that the signal of the original diversification has been largely erased in the currently available Bantu lexical data.

Adaptive molecular convergence is pervasive across deep time and largely decoupled from phenotypic convergence

Reuse of homologous genes during the evolution of similar traits or ecological transitions is often taken as evidence that evolution is repeatable at the molecular level. To study gene reuse, biologists frequently select specific convergent phenotypes and search for signatures of natural selection in genomes associated with those phenotypes. However, the causes and frequency of genome-scale molecular convergence remain unresolved, especially over deep timescales. We use phylotranscriptomics and analyses of sequence evolution to show that adaptive molecular convergence—defined as excess convergence of nonsynonymous substitutions between homologs, consistent with positive selection—is widespread across Medusozoa. Molecular convergence declines slightly over time but persists among lineages separated by over 600 My, consistently exceeding null expectations based on random overlap. Moreover, lineages sharing repeatedly evolved phenotypes (eyes, medusa loss, and upright colonies) do not exhibit elevated molecular convergence relative to other comparisons. Instead, convergence occurs idiosyncratically among species pairs and is broadly concentrated in genes associated with environment-facing functions, including metabolism, immunity, and xenobiotic processing. Our results suggest that selection often drives similar protein substitutions in disparate lineages, but that the selective causes of molecular convergence reflect multifaceted, lineage-specific interactions between organisms and their environments.

Pair living emerged early in placental mammals

It is widely assumed that the first placental mammals were solitary. Here, we tested this assumption and which ecological and life history factors are related to mammalian social organization. We compiled a comprehensive database by reviewing over 14,000 primary peer-reviewed publications on the social organization of the 5,390 extant placental mammal species. We found empirical data for 726 species across 1,473 populations: 353 populations were primarily solitary, 250 populations pair living, and 870 populations group living. Notably, 367 species (51%) and 583 populations (40%) exhibited intraspecific variation in social organization. Using a Bayesian phylogenetic framework that incorporates intraspecific variation, we show that the ancestral placental mammal was mainly but not exclusively solitary, displaying intraspecific variation. Pair living was estimated to account for approximately 26% of ancestral social organization. Phylogeny explained most of the variation between species, while life history and ecology were less important. Our analysis found that the ecology and life history of extant solitary and pair-living mammals is very similar and different from those of group-living mammals. Our results revise prevailing theories of mammalian social evolution, revealing that pair living emerged early, shifting the focus of studying mammalian social evolution from the origins of pair living to the origins of group living.

Science for America’s next 250 years

Proteolytic activation of c-MYC facilitated by DOT1L

c-MYC is a key regulator of growth and metabolism. Functional and molecular cooperation between the H3K79 methyltransferase DOT1L and c-MYC has been reported in several human cancer types, but the nature of their interaction remains undefined. We demonstrate that DOT1L and MYC [Myc and Mondo-like (MML-1) in Caenorhabditis elegans ] coregulate genes in the nematode model and mammalian cancer cells. Moreover, both c-MYC and MML-1 exhibit cleavage products facilitated by DOT1L function. Surprisingly, we found a similarity between a conserved sequence in DOT1 proteins and the DDI-family protease catalytic motif. We characterize a c-MYC sequence preceding the DNA-binding domain as a site of nuclear proteolytic cleavage, demonstrate its importance for transcription activation by c-MYC, and propose that c-MYC is activated by a protease, as previously reported for Nuclear factor erythroid 2-related factor (NRF) and SREBP transcription factors. Our results suggest that DOT1L may activate c-MYC and other transcription factors in the nucleus by acting as a protease.

Psychological inoculation against climate doom

Individuals encounter “climate doom,” extreme portrayals of climate change, on social media. While climate doom may be intended to motivate action, it may also be perceived as manipulative or elicit hopelessness. Yet, no research has examined whether psychological inoculation helps to improve recognition of climate doom or influences engagement with it on social media. In this preregistered study ( n = 521), we tested whether inoculation improves discernment of climate doom and influences engagement with it by collecting behavioral data using a social media simulator. We find that inoculation substantially improves discernment of climate doom and that this is due to increased perceived manipulation of doom messaging specifically ( d = 0.68). There was no interaction between the inoculation condition and political leaning and while higher perceived manipulation of doom content predicted lower behavioral intentions, inoculation did not moderate this relationship. Inoculation increased engagement, particularly disliking and flagging of doom content, and decreased sharing. Overall, our results should lead climate communicators to reconsider doom messaging as a mobilization strategy and demonstrate that inoculation is an effective tool for increasing recognition of, and critical engagement with, climate doom across the political spectrum.

Hypermutability of integrated sequences of viral origin in a chlorarachniophyte

Mutations provide the raw material for evolution, but mutation rates are not uniform across genomes. Using a mutation accumulation experiment in the marine phytoplankton Bigelowiella natans , we found extreme local variation in mutation rate: over 1,000-fold differences across its nuclear genome. While the baseline single-nucleotide mutation rate is approximately 3.5 × 10 –10 per site per generation, a common value for unicellular species, two genomic regions derived from integrated viruses exhibit strikingly elevated rates of about 6 × 10 –7 . These two regions show a distinctive mutational signature with almost exclusively T/A→C/G transitions, a pattern also found in other non-eukaryote-derived sequences in B. natans , contrary to the usual GC to AT mutation bias. Notably, hypermutation occurs only on TpA dinucleotides, and only in a subset of experimental lines, suggesting a regulated process rather than random genomic instability. We propose that B. natans targets invading DNA through localized hypermutation, reminiscent of deamination-based antiviral defense systems in animals. This prompts the idea of genome editing as a recurring immune strategy in eukaryotes.