Browse Articles

Broadband measurement of Feibelman’s quantum surface response functions

Feibelman d -parameter, a mesoscopic complement to the local bulk permittivity, describes quantum optical surface responses for interfaces, including nonlocality, spill-in and -out, and surface-enabled Landau damping. It has been incorporated into the macroscopic Maxwellian framework for convenient modeling and understanding of nanoscale electromagnetic phenomena, calling for the compilation of a d -parameter database for interfaces of interest in nano-optics. However, accurate first-principles calculations of d -parameters face computational challenges, whereas existing measurements of d -parameters are scarce and restricted to narrow spectral windows. We demonstrate a general broadband ellipsometric approach to measure d -parameters at a gold–air interface across the visible–ultraviolet regimes. Gold is found to spill-in and spill-out at different frequencies. We also observe gold’s Bennett mode, a surface-dipole resonance associated with a pole of the d -parameter, around 2.5 eV. Our measurements give rise to and are further validated by the passivity and Kramers–Kronig causality analysis of d -parameters. Our work advances the understanding of quantum surface response and may enable applications like enhanced electron field emission.

High-frequency monitoring enables machine learning–based forecasting of acute child malnutrition for early warning

The number of acutely food insecure people worldwide has doubled since 2017, increasing demand for early warning systems (EWS) that can predict food emergencies. Advances in computational methods, and the growing availability of near-real time remote sensing data, suggest that big data approaches might help meet this need. But such models have thus far exhibited low predictive skill with respect to subpopulation-level acute malnutrition indicators. We explore whether updating training data with high frequency monitoring of the predictand can help improve machine learning models’ predictive performance with respect to child acute malnutrition by directly learning the dynamic determinants of rapidly evolving acute malnutrition crises. We combine supervised machine learning methods and remotely sensed feature sets with time series child anthropometric data from EWS’ sentinel sites to generate accurate forecasts of acute malnutrition at operationally meaningful time horizons. These advances can enhance intertemporal and geographic targeting of humanitarian response to impending food emergencies that otherwise have unacceptably high case fatality rates.

This tiny device spins blood clots away

Programmable seconds-to-days-long delayed snapping in jumping metashells

Shape-shifting structures can transform and recover their shapes in response to external stimuli, but they often lack programmable, clock-like control over spatiotemporal deformation and motion, especially after stimuli are removed. Achieving autonomous, time-regulated spatiotemporal motion remains a grand challenge. Here, we present an autonomous delayed-jumping metashell that integrates viscoelastic materials with monostable architected structures to address this limitation. The metashell with tunable prestored elastic energy features an internal time clock enabling programmable autonomous delayed snapping and jumping after actuation removal. The delay spans from seconds to 2.4 d, with jumping heights decreasing from over 9 to 0.5 body heights. We demonstrate its utility in autonomous explosive seed dispersal devices, achieving wide-area omnidirectional distribution with high survival rates. This strategy paves the way for creating autonomous spatiotemporal shape-shifting structures with broad applications in robotics, morphing matter, ecology, and intelligent systems.

Daily briefing: Evidence-backed strategies for talking about vaccine hesitancy

Dynamic relocation of PKA regulatory subunits during sperm capacitation: Linking PKA to the CatSper signaling complex

To fertilize an oocyte, mammalian spermatozoa must undergo a maturation step known as capacitation that takes place after ejaculation. Protein kinase A (PKA) plays a fundamental role in capacitation in all mammalian species. Before capacitation, PKA is maintained in an inactive state where the catalytic subunits are bound to a dimer of inhibitory regulatory subunits. A key element in the regulation of PKA lies in its intracellular compartmentalization achieved by docking at A-kinase anchoring proteins (AKAP). Despite the crucial role of the modulation of local PKA activity in fertilization, its localization and mechanism of compartmentalization are not well understood. Here, we approach this problem using quantitative laser scanning microscopy and superresolution imaging to dissect the interactions and relocalization of PKA subunits during capacitation. We find that in the resting state, both catalytic and regulatory subunits colocalize close to the axoneme. Upon capacitation, the PKA regulatory subunits, but not the catalytic subunits, relocate to a quadrilateral structure along the flagellum principal piece, in the vicinity of AKAP4 and the CatSper channel signaling complex. Furthermore, this quadrilateral localization of PKA regulatory subunits disappears in sperm from CatSper1 knockout mice. The sharp difference between the localization of PKA regulatory subunits in capacitated vs. noncapacitated sperm cells demonstrates its suitability as a biomarker for identifying capacitation, an enduring problem in the study of sperm physiology.

Increased excitatory synapse size in hippocampal place cells compared to silent cells

Neuronal activity in the hippocampus creates a cognitive map of space that is essential for navigation. In any given environment, a fraction of hippocampal pyramidal cells (PCs) is active at specific locations (place cells), others are sparsely active without spatial tuning, and a significant proportion of the PCs is entirely silent. The mechanisms underlying the vastly different activities of PCs in the rodent hippocampal CA1 area are unknown. Here, we measured the in vivo activity of CA1 PCs using two-photon [Ca 2+ ] imaging in head-restrained mice during navigation in a virtual corridor and then performed in vitro patch-clamp recording to probe their intrinsic electrical properties and anatomical investigation to characterize their input synapses. The active and passive electrical properties of PCs were similar between PCs with different prior in vivo activities. Perisomatic inhibitory synapse density was also comparable among PCs. The average dendritic spine density and spine head area did not correlate with the mean in vivo activity of PCs, but the size of the spines of place cells was significantly larger compared to that of silent cells. Our results are consistent with excitatory synaptic plasticity as a major mechanism underlying spatially tuned activity of place cells in hippocampal networks.

Simpson’s gender-equality paradox

Several cross-country examinations have found larger gender differences in Western countries. More recently, it has been argued, from an evolutionary standpoint, that equality may paradoxically increase gender differences, because it provides more freedom for men and women to pursue innate preferences. However, this paradox has primarily been examined with this cross-country methodology, opening up for other cultural differences to drive the results. For instance, measures developed in Protestant and Germanic-speaking countries, may not work the same in other cultural clusters of countries, and may not have the same statistical qualities there (e.g., in terms of reliability). Here, we reanalyze the results from multiple studies on the gender-equality paradox with country-level data available. We find that gender differences covary more strongly with cultural regions and data quality than gender equality, and that any variable higher in the West appears to achieve similar correlations as gender equality. Also, controlling for cultural regions consistently and strongly attenuates the association with gender equality, including to become statistically nonsignificant, or to switch direction. In other words, the baseline associations differ between and within cultural clusters (a Simpson’s paradox), suggesting there is no simple causal relation between gender equality and expressed gender differences. Similarly, controlling for data quality indicators strongly attenuates the paradox. Finally, we show that, with and without controls, there is no consistent paradoxical association across many of the largest cross-cultural studies on gender differences, including newly analyzed data. The same is true for other country development variables considered in the gender-equality paradox literature.

Targeting of hyperlipid-producing senescent synovial fibroblasts to ameliorate cartilage degeneration

Osteoarthritis (OA) is one of the most common causes of physical disability among older people and its incidence increases with age. Removal of the senescent cells (SNCs) delays OA pathologies, but little is known about the heterogeneity of SNCs and their roles in OA pathogenesis. Here, we identify a subpopulation of senescent synovial cells and proposed a molecular mechanism governing pathogenic synovium-cartilage crosstalk in OA progression. Using single-cell RNA sequencing and synovial organoids, we demonstrate that RCAN1 + IL1α + senescent synovial fibroblasts, predominantly located in the lining layer of human OA synovium, exhibit proinflammatory phenotype, mitochondrial dysfunction, and promote cartilage degeneration. Mechanistically, RCAN1 stabilizes ATF4 mRNA and mediates saturated fatty acids (SFA) secretion from synovial fibroblasts, which could promote chondrocyte senescence and cartilage matrix degradation. Synovium-targeted delivery of anti-RCAN1 siRNA significantly ameliorated posttraumatic OA development in mice, reducing of SNC accumulation in synovium and increasing cartilage regeneration. Coculture experiments with human OA cartilage explants and synovial organoids confirm that RCAN1 silencing in synovial fibroblasts suppressess chondrocyte senescence and cartilage degradation. Our findings reveal a prodegenerative interaction between RCAN1 + IL1α + senescent synovial fibroblasts and chondrocytes mediated by secreted lipid in OA progression. Targeted RCAN1 knockdown in senescent synovium could be a new treatment strategy for restoring the joint homeostasis.

Water-rich incipient melt of the deep upper mantle indicates locally preserved low-velocity zones above the 410 km discontinuity

Seismic low-velocity layers (LVLs), frequently attributed to hydrous-silicate melts, are detected globally but exhibit lateral discontinuities. Geophysical and laboratory studies of water content in the mantle transition zone (MTZ) and upper mantle solubility limits suggest these layers likely form through global dehydration melting near the 410 km discontinuity (D410). A key hypothesis posits that melts form globally but are preserved only where melt stability permits retention. However, challenges in quenching melts into glass or fine-grained crystals at mantle pressures have precluded precise determination of melt composition, fueling debates over the mechanisms governing LVLs’ sporadic distribution. Here, we developed a fast-quenching high-pressure cell assembly to synthesize hydrous glasses or fine-grained quench crystals at pressures >10 GPa, enabling high-precision analysis of incipient melt composition. Experiments at 13 GPa reveal that the 410 melt contains 43 mol% H 2 O, 9.2 mol% CaO, 30.5 mol% (Mg, Fe)O, 0.2 mol% Al 2 O 3 , and 17 mol% SiO 2 . The melt’s high water content necessitates Fe enrichment to achieve neutral buoyancy, which can only be sourced from Fe-rich heterogeneities (Fe # = 100Fe/(Mg+Fe) in mole; Fe # >18) within the MTZ. In contrast, melts derived from normal MTZ material (Fe # <18) remain buoyant and migrate upward, precluding stable layer formation. We conclude that global dehydration melting generates hydrous melts, but only Fe-rich heterogeneities enable melt retention, reconciling the coexistence of widespread LVL detections and their lateral discontinuities.

Physics of notochord tube expansion in ascidians

Interaction of cells and the surrounding lumen drives the formation of tubular system that plays the transport and exchange functions within an organism. The physical and biological mechanisms of lumen expansion have been explored. However, how cells communicate and coordinate with the surrounding lumen, leading to continuous tube expansion to a defined geometry, is crucial but remains elusive. In this study, we utilized the ascidian notochord tube as a model to address the underlying mechanisms. We first quantitatively measured and calculated the geometric parameters and found that tube expansion experienced three distinct phases. During the growth processes, we identified and experimentally demonstrated that both Rho GTPase Cdc42 signaling-mediated cell cortex distribution and the stability of tight junctions (TJs) were essential for lumen opening and tube expansion. Based on these experimental data, a conservation-laws-based tube expansion theory was developed, considering critical cell communication pathways, including secretory activity through vesicles, asymmetric cortex tension driven anisotropic lumen geometry, as well as the TJs gate barrier function. Moreover, by estimating the critical tube expansion parameters from experimental observation, we successfully predicted tube growth kinetics under different conditions through the combination of computational and experimental approaches, highlighting the coupling between actomyosin-based active mechanics and hydraulic processes. Taken together, our findings identify the critical cellular regulatory factors that drive the biological tube expansion and maintain its stability.

Sequential drug release system: Targeting the tumor ECM for enhanced chemotherapy efficacy

The dense extracellular matrix (ECM) of stroma-rich solid tumors acts as a significant barrier to effective chemotherapy by hindering drug penetration. In this study, a supramolecular hydrogel was successfully developed, enabling the codelivery and sequential release of hydrophilic and lipophilic drugs designed to target the ECM. The hydrogel is easy to prepare, has self-healing properties and excellent biocompatibility. Upon administration, the hydrogel first releases pirfenidone to inhibit collagen production, weakening the ECM, followed by the release of paclitaxel, which improves tumor penetration. The effectiveness of this sequential drug delivery system was validated in both oral squamous cell carcinoma and pancreatic cancer models, a classic example of a tumor with abundant ECM. In vitro experiments showed controlled sequential release profiles, whereas in vivo experiments using cell-derived and patient-derived xenograft models revealed that the hydrogel was more effective at tumor suppression compared to traditional methods. Single administration of the hydrogel led to long-term localized drug release, maintaining higher concentrations of chemotherapeutic agents in the tumor tissue and effectively reducing the tumor volume. This study provided a promising strategy to enhance chemotherapy in ECM-dense tumors, offering an efficient and minimally invasive method for localized, sustained-release cancer therapy.

Shared disbelief and shared belief: Belief and disbelief as drivers of interpersonal neural synchronization during narrative processing

Despite living in an era where the mere concept of truth is increasingly contested, the cognitive processes underlying the processing of information we believe or disbelieve remain largely unexplored. In this fMRI study, we investigated how belief modulates narrative processing through belief context—the initial information indicating the speaker’s credibility—and actual belief—the truth value ultimately assigned by the listener. Across two experiments, participants listened to narratives preceded by contexts explicitly stating whether the speaker was lying or telling the truth. Then, after listening to the narratives, they were asked to rate their actual belief. To investigate the effects of (dis)belief on narrative processing, we analyzed neural synchronization using inter-subject-correlation analysis and inter-subject representational similarity analysis. In both experiments, we successfully differentiated (dis)belief contexts by modeling neural synchronization patterns, despite an actual “belief-bias” at the behavioral level. This indicates a unique neural pattern related to each belief context. Furthermore, our results revealed a dissociation between belief and disbelief in both contextual and actual (dis)belief. Per each narrative, belief and disbelief were associated with increased synchrony within the default mode network, but in distinguishable parcels. These findings highlight the influence of (dis)belief on narrative processing at both behavioral and neural levels. Behaviorally, the observed belief-bias supports the notion of belief as a cognitive default. Neurally, we suggest that belief and disbelief can be understood as fostering qualitatively distinct processing or interpretation of the same narrative, which are then reflected in shared neural responses among individuals who hold similar belief states.

Creb5 controls its own expression and directly induces the joint interzone regulatory program

Prior studies have indicated that the transcription factor Creb5 is expressed in the joint interzone, which contains the progenitors for all synovial joint tissues in both mouse and human embryos. In the absence of Creb5 function, most synovial joint interzones fail to form and the cartilage templates in the long bones remain fused. This earlier work did not clarify whether Creb5 initiates a cascade of signaling molecules, such as growth and differentiation factor 5 (Gdf5) and Wnt-family members, that in turn induce the formation of the joint interzone, or instead directly activates the expression of joint interzone markers. In the present study, an integrative analysis of the transcriptome, chromatin accessibility, and Creb5-occupancy in joint progenitors revealed that Creb5 directly binds to both its own two promoters and to the regulatory regions of Gdf5 and Sfrp2 , each of whose expression in the joint interzone is Creb5-dependent. Functional enhancer analysis indicated that Creb5 binding sites in either the two Creb5 promoters, or in Gdf5 and Sfrp2 regulatory elements are necessary for these sequences to drive transgene expression in the developing synovial joints. While Creb5 directly drives Gdf5 and Sfrp2 expression in the inner joint interzone, Creb5 activates Barx1 expression specifically in the outer joint interzone. Our findings indicate that Creb5 initiates a regulatory network that both promotes the formation of synovial joints, and subsequently activates distinct transcriptional targets in the inner versus the outer regions of the joint interzone, thus regionalizing gene expression in the developing joint.

Jund orchestrates <i>cis</i> -regulatory element dynamics to facilitate endothelial-to-hematopoietic transition

The tightly controlled spatiotemporal expression of developmental genes depends on the concerted action of cis -regulatory elements (CREs) and transcription factors (TFs) to ensure cell fate decisions. Endothelial-to-hematopoietic transition (EHT) is a cell fate transition process by which endothelial cells acquire hematopoietic identity and become hemogenic endothelial cells (HECs) and then hematopoietic stem and progenitor cells, but the underlying CRE network dynamics and its regulation by TFs remain unclear. In this study, we characterized the dynamics of CRE activation and TF occupancy during zebrafish EHT, and found that the enhancer–promoter collaboration forms the basis for EHT. Moreover, a ubiquitously expressed TF AP-1 collaborates with diverse lineage-specific TFs to remodel enhancer landscape. Deletion of AP-1 family member Jund impaired hematopoietic specification, resulting from the enhanced endothelial identity in the HEC. Mechanistically, Jund and hematopoietic TF Hoxa9a collectively repress the activity of an endothelial-related dll4 enhancer through tight control of the active histone modification H3K27ac. Our study provides insights into the cooperative function among ubiquitous TFs and cell type–specific TFs in orchestrating cell fate transition.

Assembly of a functional neuronal circuit in embryos of an ancestral metazoan is influenced by temperature and the microbiome

Understanding how neural populations emerge to give rise to behavior is a major goal in neuroscience. Here, we explore the self-assembly of neural circuits in Hydra , an organism with a simple nervous system but no centralized information processing, to enhance the understanding of nervous system evolution. We define self-assembly as spontaneous organization of neurons into functional circuits without requiring a prespecified structural template. In this context, the N4 neuronal circuit, which we have previously found to be particularly important in the feeding of the animal, develops in embryos through activity-driven self-assembly, a process in which intrinsic calcium activity drives connectivity and synchronization among spatially distributed neurons over time. Gap junctions and vesicle-mediated communication between neuronal and non-neuronal cells drive rapid assembly, with the embryo’s prospective oral region exhibiting the highest neuronal density. An artificial electrical circuit–based model as a biophysically inspired simulation demonstrates dynamic increases in synchronization over time, along with predictions for selective dynamic adaptions of connections. Environmental factors, like temperature and an absent microbiome, modify neural architecture, suggesting the existence of a certain adaptability during neural development. We propose that these fundamental features originated in the last common bilaterian ancestor, supporting the hypothesis that the basic architecture of the nervous system is universal. Since in the natural habitat of Hydra both temperature fluctuations and changes in the microbiome can occur, our work not only illuminates a fundamental developmental process but also may guide environmental and evolutionary studies by explaining how organisms adapt to environmental variations.

The tumor suppressor RASSF8: A WAVE interaction partner controlling migration and cohesion of invasive border cells in <i>Drosophila</i>

Collective cell migration is a key driver of tissue morphogenesis and cancer invasion. Here, we identified the tumor suppressor Ras association domain-containing protein 8 (RASSF8) as a WAVE interactor required for border cell migration. RASSF8 colocalizes with F-actin and cell adhesion molecules at border cell– border cell contacts. Loss of RASSF8 function results in border cell cohesion defects, a phenotype associated with changes in the localization of the Echinoid (Ed) and Coracle (Cora). Cell-type-specific RNA interference (RNAi) experiments suggest that cohesion defects are caused by changes in localization of Ed rather than E-cadherin. Gain-of-function experiments further revealed reciprocal functional interactions between RASSF8 and WAVE controlling collective border cell movement. Thus, we propose a dual function of RASSF8 in coordinating border cell cluster behavior. RASSF8 is thought to regulate the collective movement of border cells by restricting WAVE function, while it controls the epithelial cluster integrity by regulating cell–cell adhesion and septate junction molecules such as Ed and Cora.

Macropinosomes are a site of HIV-1 entry into primary CD4 ⁺ T cells

HIV-1 has been observed to enter target cells at both the plasma membrane and endosomes. However, which pathways mediate its entry into primary CD4 + T cells, the major targets of this virus, remains unclear. Here, we show that HIV-1 can enter primary CD4 + T cells through macropinocytosis, a form of endocytosis. We found that HIV-1 can enter primary CD4 + T cells at both the plasma membrane and internal compartments, while entry into common T cell lines occurred primarily at the plasma membrane. Inhibition of macropinocytosis suppressed HIV-1 internalization into and subsequent fusion with primary CD4 + T cells regardless of the viral coreceptor usage. Microscopic analysis of viral contents exposed to the cytosol confirmed that HIV-1 fusion occurs at the macropinosomal membrane. Finally, the inhibition of macropinocytosis blocked HIV-1 infection of primary CD4 + T cells. Altogether, this study identifies macropinocytosis as one pathway for HIV-1 entry into primary CD4 + T cells.

Assembly and activation of the death-inducing signaling complex

The death-inducing signaling complex (DISC), comprising Fas, Fas-associated death domain (FADD), and caspase-8, initiates extrinsic apoptosis. Using cryogenic electron microscopy (cryo-EM), we show that Fas and FADD death domains (DDs) form an asymmetric 7:5 oligomer, which promotes FADD death effector domain (DED) filament formation. Structural analysis reveals that FADD DED filaments closely resemble caspase-8 tandem DED filaments, suggesting that FADD DED serves as a nucleation scaffold for caspase-8 assembly. These findings provide a mechanistic framework for how DISC assembly initiates apoptosis and amplifies signaling via higher-order oligomerization.

Amortized template matching of molecular conformations from cryoelectron microscopy images using simulation-based inference

Characterizing the conformational ensemble of biomolecular systems is key to understand their functions. Cryoelectron microscopy (cryo-EM) captures two-dimensional snapshots of biomolecular ensembles, giving in principle access to thermodynamics. However, these images are very noisy and show projections of the molecule in unknown orientations, making it very difficult to identify the biomolecule’s conformation in each individual image. Here, we introduce cryo-EM simulation-based inference (cryoSBI) to infer the conformations of biomolecules and the uncertainties associated with the inference from individual cryo-EM images. CryoSBI builds on simulation-based inference, a merger of physics-based simulations and probabilistic deep learning, allowing us to use Bayesian inference even when likelihoods are too expensive to calculate. We begin with an ensemble of conformations, templates from experiments, and molecular modeling, serving as structural hypotheses. We train a neural network approximating the Bayesian posterior using simulated images from these templates and then use it to accurately infer the conformation of the biomolecule from each experimental image. Training is only done once on simulations, and after that, it takes just a few milliseconds to make inference on an image, making cryoSBI suitable for arbitrarily large datasets and direct analysis on micrographs. CryoSBI eliminates the need to estimate particle pose and imaging parameters, significantly enhancing the computational speed compared to explicit likelihood methods. Importantly, we obtain interpretable machine learning models by integrating physics-based approaches with deep neural networks, ensuring that our results are transparent and reliable. We illustrate and benchmark cryoSBI on synthetic data and showcase its promise on experimental single-particle cryo-EM data.