Song L, Kharel A, Xie P
… +6 more, Fan J, Baker A, Zhang Y, Zhang Y, Cui W, Zhang B
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378284
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Although A2AR is a key immunoregulatory receptor that suppresses CD8 T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8 T cell differentiation and...Although A2AR is a key immunoregulatory receptor that suppresses CD8 T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8 T cell differentiation and cell-fate decisions during chronic viral infection and cancer remains poorly understood. Using A2AR-eGFP reporter mice, we show that A2AR expression is rapidly induced by TCR stimulation and persists under chronic antigen exposure and hypoxia, with sustained expression strongly associated with terminal exhaustion via the canonical Gα-cAMP-PKA pathway. Paradoxically, A2AR loss does not alleviate exhaustion but instead accelerates differentiation toward the terminally exhausted state. Single-cell multiomics profiling revealed that A2AR deficiency activates CD122 (IL-2Rβ)-dependent signaling, driving T cell exhaustion. Genetic deletion of CD122 in A2AR-deficient CD8 T cells reduced terminal exhaustion, identifying CD122 signaling as a key mediator of A2AR loss-driven exhaustion. Intriguingly, both sustained A2AR expression and A2AR loss converge to promote T cell exhaustion differentiation through distinct mechanisms. These findings uncover a paradoxical role of A2AR in shaping CD8 T cell fate choices during chronic infection and cancer.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378283
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The brain possesses the remarkable ability to suppress undesirable signals generated by our own actions to ensure accurate perception, like the suppression of retinal motion signals during rapid eye movements, known as s...The brain possesses the remarkable ability to suppress undesirable signals generated by our own actions to ensure accurate perception, like the suppression of retinal motion signals during rapid eye movements, known as saccadic suppression. Attention, often referred to as the "mind's eye," undergoes rapid and frequent shifts, often occurring in the absence of explicit motor actions. Is visual processing similarly suppressed during attention shifts? In this study, we employed pupillometry and magnetoencephalography (MEG) to assess visual sensitivity across different attentional states. Our results revealed a reduced or suppressed visual sensitivity during attention shifts through an attentional oscillation paradigm. Such suppression was not due to microsaccades and was absent during rhythmic attentional sampling without spatial shift. MEG data further indicated that the suppression was more pronounced in parietal channels, manifesting at a relatively late stage (150 to 200 ms) of visual processing and suggesting a distinct neural mechanism compared to saccadic suppression. Our findings indicate that suppression mechanisms operate not only when there are spurious signals generated due to the movements of the sensors, but also during transitional states in the allocation of cognitive resources within representational space, thereby supporting stability of visual processing.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378282
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The NLRP3 inflammasome is central to host defense and sterile inflammation and forms condensates at the microtubule-organizing center (also known as the centrosome), although the mechanisms regulating this process remain...The NLRP3 inflammasome is central to host defense and sterile inflammation and forms condensates at the microtubule-organizing center (also known as the centrosome), although the mechanisms regulating this process remain unclear. Here we define a functional relationship among microtubule transport, the centrosomal kinase NEK7, priming, and NLRP3 abundance. We show that microtubule-dependent transport is required for NEK7-dependent NLRP3 activation and promotes NEK7 to the pericentriolar material (PCM). Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. Elevated NLRP3 expression compensates for limited PCM abundance, rendering K efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. By contrast, NLRP3 overexpression only partially bypasses NEK7 dependence in response to the K efflux-independent stimulus imiquimod, likely due to its activation of a non-trans-Golgi network pool of NLRP3 that is quantitatively limited. Together, these findings define a conserved spatial mechanism in which microtubule transport, NEK7 localization, priming, and NLRP3 abundance integrate at the PCM to establish the activation threshold and magnitude of NLRP3 inflammasome signaling across species and stimuli.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378281
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Understanding the reasons behind human choices under risk is a central goal of decision scientists, but traditional methods relying on behavioral data are limited by strict invariance assumptions. We introduce a scalable...Understanding the reasons behind human choices under risk is a central goal of decision scientists, but traditional methods relying on behavioral data are limited by strict invariance assumptions. We introduce a scalable analytical framework using large language models (LLMs) to analyze verbal reports and identify articulated reasons for choice between monetary lotteries. A validated LLM accurately identified predefined decision reasons in participants' free-text reports, aligning with their actual choices in 95% of trials. Our analysis reveals that the reasons behind people's decisions vary systematically and are driven more by the structure of the choice problem than by individual differences. Crucially, reasons identified from verbal reports yield more parsimonious and informative representations of decision processes compared to those inferred from choices alone; furthermore, problem-specific reason profiles achieve out-of-sample prediction accuracy that is competitive with established computational models. This work demonstrates that verbal reports are a rich data source and our analytical framework can unlock their potential, delivering results that challenge the field's foundational invariance assumptions and pave the way for more context-sensitive and interpretable models of human decision making.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378280
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Softer means stickier for solid adhesives, because material compliance facilitates close contact between nonconformal surfaces. Recent discoveries have revealed that soft materials can exhibit a rich array of new physics...Softer means stickier for solid adhesives, because material compliance facilitates close contact between nonconformal surfaces. Recent discoveries have revealed that soft materials can exhibit a rich array of new physics arising from competing effects of continuum elasticity, fluid-like surface mechanics, and internal poroelastic flows, all of which can directly impact interfacial interactions. In this work, we investigate this complex interplay across several orders of magnitude of elastic stiffness by measuring the complete adhesive contact geometry between compliant silicone gel microspheres and flat, rigid substrates. We observe a continuous elastocapillary transition in adhesion mechanics, revealed by both the breadth of data and the detailed contact geometries. Importantly, soft gel spheres exhibit a remarkably broad range of near-equilibrium contact morphologies and their contact line deformation is always mediated by a fluid contact zone that phase separates from the gel. To explain this, we develop a model incorporating elastocapillary and poroelastic mechanics that predicts the complete range of adhesive behavior and elucidates energetic tradeoffs. The data and model together reveal a shallow energy landscape that may contribute to the robustness of everyday adhesives.
An Y, Zhang B, Li W
… +5 more, Li L, Xu Y, Zhang C, Ritchie RO, Ding J
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378279
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Refractory high-entropy alloys (RHEAs) are ideal for extreme-temperature structural applications, but strengthening single-phase body-centered cubic (BCC) RHEAs typically compromises ductility, and systematic optimizatio...Refractory high-entropy alloys (RHEAs) are ideal for extreme-temperature structural applications, but strengthening single-phase body-centered cubic (BCC) RHEAs typically compromises ductility, and systematic optimization across their vast compositional space remains challenging. In this work, we introduce a "high-entropy + dilute" design strategy that integrates concentrated high-entropy matrices with targeted dilute microalloying. We further refine this concept into an opposite-eigenstrain solute-pairing rule, in which solutes with opposite-sign local volumetric strains are combined to cooperatively amplify lattice distortion. Specifically, adding 1.5 at.% substitutional Re (local contraction) and 0.3 at.% interstitial B (local expansion) cooperatively amplifies local lattice distortion by approximately 20%, while maintaining a chemically homogeneous single-phase solid solution. This strategy raises the room-temperature yield strength by more than 34% while maintaining ductility, with the strength advantage sustained across an unusually wide temperature range from 77 to 1,373 K. Mechanistically, the amplified lattice distortion simultaneously modifies kink-pair-mediated screw glide and strengthens solute pinning of edge segments, thereby reducing screw-edge mobility mismatch and promoting coordinated dislocation multiplication and storage. These findings establish opposite-eigenstrain solute pairing as a mechanistically grounded microalloying strategy for strengthening single-phase BCC RHEAs across extreme temperatures.
Alian A, McCullough J, Moss FR
… +9 more, Talledge N, Mohammed A, Gerstner CD, Dalluge JA, Paine EL, Davulcu O, Chang CL, Frost A, Sundquist WI
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378278
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Different inositol phospholipids (PIPs) distribute to distinct subcellular organelles, creating an addressing system that dictates the sites of action of PIP-binding proteins, including components of the Endosomal Sortin...Different inositol phospholipids (PIPs) distribute to distinct subcellular organelles, creating an addressing system that dictates the sites of action of PIP-binding proteins, including components of the Endosomal Sorting Complexes Required for Transport (ESCRT). The ESCRT machinery is recruited to remodel many different cellular membranes through combinatorial binding interactions made by the early-acting ESCRT-I and ESCRT-II complexes with PIPs, ubiquitin modifications, and membrane-specific adaptors. Membrane remodeling, constriction, and fission are then mediated by membrane-associated filaments formed by subunits of the late-acting ESCRT-III complexes, together with their associated VPS4 AAA ATPases. Here, we describe two different classes of helical ESCRT-III filaments that can surround and tubulate membranes containing PIP lipids. Cryo-EM reconstructions revealed that protofilaments comprising closed IST1 subunits formed 8-stranded nanotubes that encase membrane monolayers. The nanotube coordinates exposed PI(4,5)P or PI(3,5)P headgroups within a basic pocket formed at the junction of three IST1 subunits, and our structures reveal how the pocket can accommodate either PIP isomer with minimal adjustment. In contrast, protofilaments comprising open CHMP1A subunits formed one start helices that encase membrane bilayers and bind exposed PI(4,5)P headgroups across a basic surface that spans adjacent subunits of the CHMP1A protofilament. These two different structures extend the known plasticity of ESCRT-III polymers, reveal how PIP lipids can promote ESCRT-III filament assembly and membrane remodeling, and define the molecular contacts that underlie specific ESCRT-III/PIP interactions.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378277
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We challenge a recently popular view that a negative interest-growth rate gap ([Formula: see text]) offers a "free lunch" for debt-financed government spending by formulating a model in which [Formula: see text] and [For...We challenge a recently popular view that a negative interest-growth rate gap ([Formula: see text]) offers a "free lunch" for debt-financed government spending by formulating a model in which [Formula: see text] and [Formula: see text] are endogenous variables shaped by fiscal policy through its effects on equilibrium multiplicity and capital allocation. Observing [Formula: see text] can signal that sustained government deficits have generated multiple steady states, and the economy has converged to a stable low-efficiency equilibrium. With its heterogeneous entrepreneurs, the model's real interest rate serves as a screening device for investment efficiency. Causation runs from the fiscal regime to equilibrium selection and outcomes: Fiscal surpluses eliminate equilibrium multiplicity and anchor expectations that sustain a unique, high-productivity equilibrium, thereby rationalizing Alexander Hamilton's characterization of "debt as a blessing." Persistent deficits can push the economy into a "misallocation trap" characterized by scarce safe assets, low interest rates, survival of inefficient firms, depressed aggregate productivity, and self-validating low growth. Thus, costs of debt-financed fiscal deficits consist not only of deferred taxes, but also of permanently lower national productive capacity.
Hartman KS, Lopez BY, Gonzalez JH
… +3 more, Goetz ME, Cleveland A, Muroyama A
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378276
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Stomata, microscopic pores that regulate gas exchange in plants, are patterned according to conserved pathways that regulate their physiology. Here, we identify a mode of stomatal patterning that depends on previously un...Stomata, microscopic pores that regulate gas exchange in plants, are patterned according to conserved pathways that regulate their physiology. Here, we identify a mode of stomatal patterning that depends on previously unrecognized regulation of the final symmetric cell division (SCD) that creates paired guard cells. SCDs are aligned by tensile stress at both the subcellular and supracellular scales, creating a globally polarized stomatal field that tracks the major axes of tissue growth. By identifying KATANIN 1 as a critical regulator of symmetric division orientation, we show that stress-based division orientation is required to prepattern stomatal morphology and pore creation. We find that expansion of neighboring cells nonautonomously controls symmetric division orientation, linking stomatal alignment to overall leaf shape. Finally, we show that polarized stomatal fields are widespread across plant genera and their species-specific alignment patterns are consistent with the force-based mechanism we identify in . This force-responsive pathway provides a unifying model that explains long-standing observations of stomatal organization across species.
Maxson R, Smoyer CJ, Hampton MF
… +7 more, Shen Y, Wiese K, Yee C, Singh A, Funtila A, McKenney RJ, Ori-McKenney KM
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378275
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The microtubule-associated protein tau is implicated in neurodegenerative diseases, but its physiological roles remain poorly understood. Here, we find that panneuronal expression of human tau (HsTau) in coupled with in...The microtubule-associated protein tau is implicated in neurodegenerative diseases, but its physiological roles remain poorly understood. Here, we find that panneuronal expression of human tau (HsTau) in coupled with injury triggers elevated aggression in male flies, which was not observed in flies expressing nonphosphorylatable tau. These behavioral manifestations result from activation of dopaminergic circuits without neurodegeneration. Using in vitro reconstitution assays, we find that phosphorylated HsTau maintains microtubule binding but loses its ability to suppress catastrophes, thereby promoting microtubule dynamicity. In contrast, unphosphorylated HsTau as well as fly tau (DmTau) stabilize microtubules by reducing catastrophe frequency. Our findings challenge the canonical view of tau as a simple microtubule stabilizer and instead position it as a dynamic regulator of microtubule function and neuronal excitability. These results reveal how acute tau phosphorylation can alter neural circuit function and behavior prior to neurodegeneration, providing insights into tau's physiological and pathological roles.
Defos du Rau P, Godeau U, Carenton N
… +11 more, Dias J, Wachoum AS, Trolliet B, Baddour K, Chaibo A, Morin GP, Portier B, Suet M, Tormos T, Mondain-Monval JY, Deschamps C
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378274
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Lake Chad is both one of the largest transboundary wetlands in Africa and a major biodiversity hotspot. As such, Lake Chad would require sound and long-term biodiversity monitoring, but it is also a war zone. Using sever...Lake Chad is both one of the largest transboundary wetlands in Africa and a major biodiversity hotspot. As such, Lake Chad would require sound and long-term biodiversity monitoring, but it is also a war zone. Using several mitigation measures, we succeeded in surveying a major part of it in 2022 to estimate the abundance of wildlife. This study marked the first comprehensive population estimates for some species. Compared to previous total count approaches, we introduced an aerial distance sampling methodology to improve survey safety, repeatability, estimate uncertainty, and reduce detection bias. Due to strong security concerns, a portion of the lake was inaccessible. To overcome this limitation and estimate temporal trends, density surface modeling was applied to estimate species abundance over the entire lake. Locations of conflict events emerged as sites of higher densities for several species, suggesting a "refuge effect," a rare positive outcome of conflict zones on wildlife. Indeed, we also noted the persistence of endangered large mammal populations, possibly due to reduced anthropogenic pressure from displaced communities. Results indicated that Lake Chad hosts approximately 2.48 million waterbirds, to our knowledge the most important known wetland bird concentration in Africa. Updated population estimates revealed that some species may have experienced positive trends. However, a few species, including transcontinental ones, showed signs of reduced abundance. The study urges actions to protect this ecosystem of major importance for global biodiversity, recommending the establishment of a protected area and World Heritage status for Lake Chad.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42378273
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Limb dominance is a human behavioral characteristic with many cultural, practical, scientific, and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains un...Limb dominance is a human behavioral characteristic with many cultural, practical, scientific, and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains unanswered. Is it because of an intrinsic hemispheric advantage or instead is it the result of life-long practice with the dominant side? We tested these alternatives using two tasks either cross sectionally or after training. The first was 3D reaching with either an inertial challenge or the need to use a stick-like tool. The second required participants to write with their dominant and nondominant elbows. We applied a geometric analysis to quantify movement-trajectory shape. We show that 1) tool-use unmasks markedly inferior control in the nondominant arm, and this is because tools impose the need to generate unfamiliarly shaped movement trajectories; and 2) there is no general dominant limb motor control advantage, only task-specific experience or practice riding on top of an initial preference. These results reframe dominance as predominantly about learned control of tool kinematics rather than baseline asymmetry in control of limb dynamics.