Ibrahimi M, Jahanbakhsh E, Tzika AC
… +1 more, Milinkovitch MC
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391406
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The spatial patterning of mammalian hair follicle precursors in embryonic skin is most commonly studied in the laboratory mouse (), where new follicles form equidistantly from preexisting ones in successive waves. This s...The spatial patterning of mammalian hair follicle precursors in embryonic skin is most commonly studied in the laboratory mouse (), where new follicles form equidistantly from preexisting ones in successive waves. This simple geometric rule has been effectively described as emerging from an expansion-induction process. However, such a description is incompatible with more recent developmental data indicating instead that scale, feather, and hair placodes self-organize through reaction-diffusion-chemotaxis cell interactions involving epidermal and dermal signaling. Here, we suggest that the chemotactic component of this framework suffices to describe the dynamics of placode insertion in two mammalian species that exhibit drastically different patterns. More specifically, we investigate a continuum dynamical model capturing interactions between motile dermal mesenchymal cells and an epidermal chemoattractant, embedded in a two-dimensional, isotropically expanding domain representing the growing embryonic skin. Through numerical simulations, mathematical analysis, and comparison to experimental developmental data, we first show that the chemotaxis model gives rise to the effective geometric rule that initially justified the development of the expansion-induction model in the laboratory mouse. Second, we show that the strikingly regular hair placode pattern in the spiny mouse ()-with long-range order, specific orientation and anisotropies-is not generated by an expansion-induction mechanism, but is recapitulated by an anisotropic chemotaxis model combined with experimentally observed anisotropic growth. Overall, our findings reveal that variation in the chemotactic component of the corresponding self-organizational system might be a key determinant of interspecific differences in hair placode patterning dynamics and resulting spatial organizations.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391405
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Superconducting phases with exotic symmetries that differ from the underlying crystalline lattice are at the focus of superconductivity research. Yet, despite intense interest, detecting the order parameter symmetry and...Superconducting phases with exotic symmetries that differ from the underlying crystalline lattice are at the focus of superconductivity research. Yet, despite intense interest, detecting the order parameter symmetry and topology remains a major challenge. Real-space imaging near atomic impurities with scanning tunneling microscopy (STM) has been highly successful in revealing nodes of the superconducting gap, in particular in cuprate superconductors, however the order parameter phase winding has so far remained inaccessible by STM techniques. We demonstrate that STM can access this phase information by exploiting Young-type quasiparticle interference patterns generated by pairs of impurities acting as beam splitters. Superconducting order parameter tomography (SOPT), a technique proposed here, utilizes the response of real-space interference patterns of Bogoliubov quasiparticles to the controlled rotation of impurity configurations, allowing us to reconstruct the momentum space structure of the gap function [Formula: see text]. As a concrete example, we consider Strontium Ruthenate, whose superconducting order remains a subject of ongoing debate, and demonstrate how SOPT can distinguish between competing order parameter candidates. The Young's interference fringes, nodal directions, and rotating beams, detected by SOPT, encode information about both the nodes and phase winding of the superconducting order parameter. This method provides a broadly applicable route to identifying unconventional and topological superconductivity and establishes particle-hole interference as a new imaging modality for superconducting order.
Garcia MA, Farrell-Sherman A, Aydin B
… +22 more, Zhuo J, Fray EJ, Zinsser AM, Lai J, Sowers K, Li H, Lopez BM, Abeyta-Lopez A, Chu T, Lubbeck D, Chae M, Bachmann N, Varriale J, Westfall DH, Hoh R, Dalhuisen T, Simonetti FR, Peluso MJ, Deeks SG, Siliciano RF, Cohn LB, Siliciano JD
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391404
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HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interru...HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption without confounding interventions to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4 T-cells. We found no evidence of recombination among rebound sequences. Instead, resistance to autologous neutralizing antibodies (aNAbs) was a critical determinant of viral rebound. Increased suppression of viral outgrowth by contemporaneous IgG isolated from plasma was correlated with longer time to rebound. Using inhibitory potential (), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency with respect to contemporaneous aNAbs. Contemporaneous IgG antibodies inhibited different reservoir variants with a wide range of values (0.4 to 8.2 logs), whereas rebound viruses were minimally inhibited (0.5 to 2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency over time on antiretroviral therapy (ART) allows previously neutralized variants to gain rebound potential, consistent with the finding that rebound can come from variants deposited in the reservoir at different pre-ART time points. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints, including those exerted by aNAbs.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391403
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During an outbreak, infectious disease can spread among populations through host movement, potentially fueling local outbreaks with their own epidemiological dynamics. However, it is difficult to know how often infection...During an outbreak, infectious disease can spread among populations through host movement, potentially fueling local outbreaks with their own epidemiological dynamics. However, it is difficult to know how often infections between populations are transmitted by diseased travelers infecting healthy residents when abroad, rather than by diseased residents infecting healthy travelers, who later return home with the new pathogen. In this paper, we introduce a phylogeographic model where pathogens spread through visitor dynamics, whereby hosts visit other populations through short trips before returning home. To do so, we used the stationary properties of an epidemiological compartment model with visitor dynamics to construct an approximation that is statistically accurate and computationally tractable for phylogenetic modeling. In addition, we derive mathematical properties for the approximating model that provide a sufficient condition under which the approximation remains accurate. We applied our model to empirical infection data and travel statistics from the European SARS-CoV-2 pandemic. Inference under our model suggests that, in the early stages of the outbreak, SARS-CoV-2 was more often "pulled" into the home countries of returning travelers than "pushed" into foreign countries by visitors from abroad. Estimates of host movement-related parameter values under our visitor model suggest that alternative migration models, with trips of indefinite length, may underestimate the magnitude of outbreaks caused by visitors. This study emphasizes the importance of carefully incorporating host movement dynamics into such models.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391402
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Stable mounting is a central requirement for skin-interfaced wearable biomedical devices, because accurate and long-term measurements with clinical utility typically demand intimate contact with the skin, whereas practic...Stable mounting is a central requirement for skin-interfaced wearable biomedical devices, because accurate and long-term measurements with clinical utility typically demand intimate contact with the skin, whereas practical use also requires gentle removal to minimize skin irritation and damage. Existing mounting strategies often struggle to satisfy these competing requirements simultaneously, especially under prolonged wear or in the presence of sweat and moisture. Suction-based mounting has recently emerged as a promising alternative because it can provide strong, reversible, and adhesive-free attachment, yet its underlying mechanics remain insufficiently understood. Here, we establish analytical models for the deformation and force of suction cups in a fully explicit form, covering both the cone suction cup and an optimized ring suction cup design. Unlike previous approaches that rely on indirect quantities such as the pressure difference and contact radius, which are not available before experiments and therefore cannot serve as controllable design variables, the present framework yields direct relations between suction performance and geometry parameters, material properties, and loading conditions, including the maximum push down displacement and the subsequent pull up displacement. The resulting formulas agree closely with accurate numerical solutions and lead to compact scaling laws that clearly identify how geometry and material parameters govern suction performance. These results provide a quantitative and physically transparent foundation for the design of suction-based mounting strategies in wearable devices.
Jarman OD, Bohra N, Claus P
… +2 more, Paczia N, Erb TJ
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391401
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Energy-conserving mechanisms are essential in supporting cellular life. Yet in synthetic biology, it remains a challenge to reconstruct such processes from the bottom-up and integrate them with other biological functions...Energy-conserving mechanisms are essential in supporting cellular life. Yet in synthetic biology, it remains a challenge to reconstruct such processes from the bottom-up and integrate them with other biological functions to create complex systems with life-like properties. Recent efforts to build higher-order cell-free metabolic networks have suffered from the fact that their central oxidation reactions are not coupled to energy conservation, causing kinetic and thermodynamic limitations. Here, we developed an artificial respiratory chain that we tailored to sustain rapid electron transfer in a CO-fixing 16-enzyme catalytic cycle (crotonyl-CoA/ethylmalonyl-CoA/hydroxybutyryl-CoA), while also exploiting the concurrent electron flow for adenosine triphosphate synthesis. We demonstrate how such artificial respiratory chains can be further diversified to accept multiple electron entries and coupled to other biological functionalities, such as cell-free transcription-translation networks. Altogether, our work highlights the opportunities and challenges of directly integrating energy conservation mechanisms when building toward self-sustaining/self-energizing artificial life-like systems.
Yadav KK, Bhandari M, Mahsoub HM
… +7 more, Park YB, Le HV, Choi JM, Brown HM, Rajashekara G, Kenney SP, Meng XJ
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391400
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Hepatitis E virus (HEV), a leading cause of viral hepatitis globally, is associated with adverse outcomes during pregnancy. Despite its clinical significance, the mechanisms driving enhanced HEV replication during pregna...Hepatitis E virus (HEV), a leading cause of viral hepatitis globally, is associated with adverse outcomes during pregnancy. Despite its clinical significance, the mechanisms driving enhanced HEV replication during pregnancy remain poorly understood. In this study, we uncover a lipid-mediated pathway that facilitates HEV replication, with potential implications for pregnancy-associated pathogenesis. Lipidomic profiling reveals a marked upregulation of oleic acid during HEV infection in both human liver cells and in HEV-3ra-infected pregnant rabbits. We showed that oleic acid significantly enhances HEV replication, possibly through interaction with a predicted fatty acid-binding domain (FABD) located within the papain-like cysteine protease region of the HEV ORF1 polyprotein. We further demonstrated that phosphatidylethanolamine (PE) levels are elevated during HEV-3ra infection in pregnant rabbits, and that inhibition of PE biosynthesis by CRISPR/Cas9-mediated knockdown and silencing of phosphatidylserine decarboxylase/phosphoethanolamine cytidylyltransferase genes that are responsible for PE synthesis resulted in decreased HEV replication, indicating that PE is important for HEV replication. Additionally, we found that placental lactogen hormone, which is elevated during late pregnancy, stimulated fatty acid accumulation and potentiated HEV replication, therefore providing a potential explanation for pregnancy-associated adverse outcomes. Collectively, our findings reveal an important role of host lipid metabolism in HEV replication and offer mechanistic insights into lipid-dependent enhancement of HEV replication and a potential role of lipid reprogramming in HEV pathogenesis. The results may inform potential future anti-HEV therapeutic strategies targeting lipid pathways.
Martins C, Booth H, Salat-Canela C
… +2 more, Hadjivasiliou Z, Vještica A
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391399
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Differences between partner gametes, which evolved repeatedly in eukaryotes, can contribute to the evolution of the sexes, sexual selection, and non-Mendelian inheritance. Yet, the empirical evidence for how functional a...Differences between partner gametes, which evolved repeatedly in eukaryotes, can contribute to the evolution of the sexes, sexual selection, and non-Mendelian inheritance. Yet, the empirical evidence for how functional asymmetries arise between initially equivalent gametes is limited. Here, we combine theoretical and experimental approaches in the fission yeast to show how selective pressures acting concurrently on gametes and zygotes drive the evolution of gamete differences. We find that despite being morphologically identical, P- and M-type partner gametes invest asymmetrically in zygotic development by contributing different amounts of conserved meiotic cohesins. P-gametes preferentially produce the Rec8 cohesin that increases zygotic fitness but reduces gamete viability, revealing a trade-off between reproductive success and gamete survival. We demonstrate that this asymmetry is mediated by partner-specific communication and model its evolutionary dynamics using empirically determined parameters. Our results support classical theoretical predictions for the evolution of gamete differences and provide a mechanistic understanding of how molecular asymmetries between partners can originate from opposing selection pressures acting in species that lack morphologically distinct gametes.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391398
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Computational protein design using machine learning models has advanced rapidly since the introduction of AlphaFold2. There is now a suite of tools that enable in silico design of proteins with desired structures and pro...Computational protein design using machine learning models has advanced rapidly since the introduction of AlphaFold2. There is now a suite of tools that enable in silico design of proteins with desired structures and properties. Most design workflows require fitting a designed backbone with a sequence that stabilizes it, and many machine learning sequence design models have been proposed. These models are trained to recover the native sequence paired with a known structure, a task known as native sequence recovery (NSR). Here, we demonstrate the limitations of optimizing a sequence design model only for NSR. We show that NSR is often misaligned with more important metrics of model performance: the compatibility of the generated sequence with the desired fold and the ability of the model to predict the energetic effects of mutations. We introduce PottsMPNN, which is trained to generate a Potts energy function consisting of single-residue and residue-pair terms from a protein backbone, and we demonstrate that learning a Potts model reduces NSR but improves sequence generation and energy prediction. We also trained PottsMPNN with noised backbone structures and multiple sequence alignments. In tests on held-out data, NSR decreased, but the quality of the designed sequences and energy predictions improved. By demonstrating the limitations of optimizing for NSR and the effectiveness of strategies that avoid NSR overoptimization, our work advances sequence design and highlights future directions for the broader protein design field.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391397
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Spatial context modifies visual perception by enhancing novel and salient features over spatially redundant features in the underlying neural code of the primary visual cortex (V1). Although multiple intracortical pathwa...Spatial context modifies visual perception by enhancing novel and salient features over spatially redundant features in the underlying neural code of the primary visual cortex (V1). Although multiple intracortical pathways contribute to contextual modulation, their specific contributions to different types of contextual modulation are not fully understood. Leveraging the distinct laminar connectivity patterns of feedforward, feedback, and lateral pathways, we used ultra-high-resolution fMRI (7T T*-weighted, 0.6 mm isotropic resolution) to infer their relative contributions to contextual modulation in V1 by analyzing blood-oxygenation-level-dependent (BOLD) signal across cortical depth. Participants viewed sine-wave grating disks embedded in large surround gratings. Segmentation cues were introduced or removed by manipulating the relative phase and orientation of the surround gratings, yielding three contextual conditions and a surround-only condition to measure the effects of context in the absence of feedforward input. Our analysis isolated the effects of orientation-tuned surround suppression (OTSS) from orientation-independent border-induced modulation (BIM). The results show that BOLD laminar profiles differ by modulation type: OTSS was absent from deep layers, whereas BIM was more broadly distributed. We also find that voxels at all depths are driven by spatial context in the absence of feedforward input, which accords with the finding of contextually driven neural responses in mammalian V1. These laminar differences likely reflect different proportional contributions of feedback from higher-order visual areas and long-range lateral connections within V1. Our findings help to explicate the contributions of recurrent processing to visual contextual modulation and its impacts on laminar-dependent BOLD fMRI.
Liu N, Han G, Zhang F
… +5 more, Gu Q, Liu Y, Jia J, Zhu X, Chen M
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391396
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Non-small-cell lung cancer (NSCLC), the predominant type of lung cancer, is characterized by high invasiveness and significant mortality. Despite its clinical impact, the molecular mechanisms driving its pathogenesis and...Non-small-cell lung cancer (NSCLC), the predominant type of lung cancer, is characterized by high invasiveness and significant mortality. Despite its clinical impact, the molecular mechanisms driving its pathogenesis and progression remain poorly understood. This study demonstrates that TMED9 is overexpressed in NSCLC and showed using multiple independent sample sets that its expression level is significantly associated with poor patient prognosis. Gain- and loss-of-function experiments revealed that TMED9 promotes proliferation, invasion, and migration of NSCLC cells in vitro and significantly accelerates tumor growth and metastasis in vivo. Mechanistically, TMED9 interacts with ATG9A and recruits USP5 to facilitate the deubiquitination and stabilization of ATG9A, thereby activating autophagy and driving malignant progression. Notably, genetic depletion of TMED9 enhances the sensitivity of NSCLC cells to osimertinib. Collectively, these findings identify the TMED9-USP5-ATG9A signaling axis as a critical driver of NSCLC malignancy, highlighting TMED9 as a promising therapeutic target.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391395
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Recent data suggest that many membrane proteins spontaneously organize into spatial patterns through weak noncovalent interactions. These weak interactions are protein type-specific and underlie the formation of higher-o...Recent data suggest that many membrane proteins spontaneously organize into spatial patterns through weak noncovalent interactions. These weak interactions are protein type-specific and underlie the formation of higher-order transient structures (HOTS), which can function as 10 to 100 nanometer-sized, transient hubs of membrane signaling. We describe the necessary conditions for HOTS assembly to occur, its thermodynamic relationship to biomolecular condensate formation, and potential roles of HOTS in biology stemming from their unique physical properties. Currently, a quantitative understanding of HOTS is limited to membrane proteins, but many observations suggest that HOTS may also be abundant in three-dimensional cellular compartments.
Morfoisse T, Becuwe S, Palu M
… +3 more, Potier-Watkins C, Dehaene-Lambertz G, Dehaene S
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42391394
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The neural mechanisms by which the developing brain acquires higher mathematical concepts from elementary intuitions remain poorly understood. Through a large-scale longitudinal functional MRI study of children from pres...The neural mechanisms by which the developing brain acquires higher mathematical concepts from elementary intuitions remain poorly understood. Through a large-scale longitudinal functional MRI study of children from preschool through first and second grade, we tracked how neural responses to mathematical and nonmathematical statements change in the first 2 y of formal schooling, and we used these data to evaluate several theories of developmental change. Before school, when listening to math statements, children already engaged an adult-like cortical network, with partial specialization for geometry. Over the first 2 y of school, we observed an overall increase in math-related activation, a small recruitment of additional neural territory, reduced activation for facts that get better known, and a small overall increase in the dimensionality of representational space. fMRI responses to individual sentences suggest that these mechanisms, particularly in left inferior frontal gyrus and bilateral intraparietal sulcus, all contribute to children's growing mastery of mathematical concepts.
Yang W, Li R, Feng M
… +12 more, Chen Z, Guo W, Zhang Y, Peng H, Yao Y, Hu Z, Qin F, De Smet I, Bai M, Ni Z, Sun Q, Xin M
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384700
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Heat stress poses a severe threat to global crop yields and food security. Here, we demonstrate that TaSnRK1α1, the α-catalytic subunit of sucrose non-fermenting-1-related kinase 1, serves as a pivotal regulator that con...Heat stress poses a severe threat to global crop yields and food security. Here, we demonstrate that TaSnRK1α1, the α-catalytic subunit of sucrose non-fermenting-1-related kinase 1, serves as a pivotal regulator that confers thermotolerance and enhances grain weight in wheat ( L.). The findings reveal that TaMYB55 directly binds to the promoter to activate its expression, which positively contributes to heat tolerance in wheat. An A-to-G substitution in the promoter enhances the binding affinity of TaMYB55, which cosegregates with wheat thermotolerant phenotypes. In addition, we show that TaSnRK1α1 interacts with and phosphorylates the transcription factor TabZIP9, which subsequently promotes TabZIP9 degradation. Genetic analyses confirm that TaSnRK1α1 functions upstream of TabZIP9, and loss or gain-of-function of significantly alters thermotolerance in wheat by modulating reactive oxygen species homeostasis and scavenging capacity. Together, our findings shed light on the importance of the TaMYB55-TaSnRK1α1-TabZIP9 signaling module in the regulation of heat tolerance, providing practical strategies for engineering climate-tolerant crops.
Lima HS, Pereira RM, Moriconi L
… +2 more, Sreenivasan KR, Tsallis C
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384699
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Recent investigations of turbulent circulation fluctuations have uncovered substantial insights into the statistical organization of flow structures and revealed unexpected geometric features of turbulent intermittency....Recent investigations of turbulent circulation fluctuations have uncovered substantial insights into the statistical organization of flow structures and revealed unexpected geometric features of turbulent intermittency. Of particular interest here is the observation that circulation probability distribution functions admit a superstatistical representation, namely a description based on "ensembles of Boltzmann"Gibbs ensembles." A fundamental phenomenological ingredient of this approach, which serves as a natural starting point for modeling, relies on the strong correlation between the dissipation field and the spatial distribution of elementary circulation-carrying structures, i.e., small-scale vortices. Within the language of superstatistics, this corresponds to characterizing circulation statistics through an appropriate choice of conditioned (Boltzmann-like) distributions and mixing distributions. We show that the superstatistical class of [Formula: see text]-exponentials, known to have broad applicability in a wide range of multiscale and nonequilibrium systems, provides an accurate description of the observed circulation statistics in homogeneous and isotropic turbulence. This finding opens avenues for exploring the statistical structure of the turbulent cascade in the context of nonextensive statistical mechanics, rooted in the concept of nonadditive entropies.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384698
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Cobamides are essential nutrients for most organisms but are only biosynthesized by a limited number of taxa through aerobic and anaerobic pathways. Although the origin of these widespread shared cofactors changed ecosys...Cobamides are essential nutrients for most organisms but are only biosynthesized by a limited number of taxa through aerobic and anaerobic pathways. Although the origin of these widespread shared cofactors changed ecosystems and the metabolisms of living organisms, little evolutionary information is available about the biosynthetic genes and the producers. Here, we established a timeframe for the emergence of cobamide biosynthesis genes and producers, using a series of Bayesian molecular clock analyses combined with phylogenetic reconciliation. We revealed the partial producers of tetrapyrrole precursor and corrin ring were earlier than the oldest cobamide producer, suggesting the possibility that cobamide-like compounds may have existed before the emergence of their de novo producers. We also found that the anaerobic de novo producers and corrin ring producers emerged first (, around 2458 Mya), and that the Great Oxidation Event postdated emergence of aerobic producers (, around 1784 Mya). These findings reveal the chronology of cobamide biosynthesis, which greatly changed global ecological frameworks and resulted in the current biosphere, and can guide the exploration of cross-feeding and the origin of diverse organisms on the planet.