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Cell competition overcomes host tissue resistance to unleash tumor growth in a <i>Drosophila</i> brain cancer model
Primary tumors of the central nervous system are extremely aggressive and often incurable. While tumor cells are known to interact with their microenvironment, the complexity and temporal dynamics of this interplay and its impacts on tumor progression remains to be fully understood. We addressed this question in a Drosophila model of cancer stem cell–driven tumor which originates during development and grows extensively within a network of cortex glia cells through adulthood. We revealed a biphasic interplay between tumor and cortex glia cells, characterized by morphological, molecular, and functional changes. In early stages, glial cells infiltrate the tumor, display a distinct transcriptional signature, and resist its growth, supported by the intrinsic neuroprotective activity of the c-Jun N-terminal kinase (JNK) signaling pathway. However, cancer stem cell–driven competition takes place, eliminating cortex glia by apoptosis and ultimately unleashing tumor growth. This second phase sees the breakdown of the glial meshwork and adhesions to neurons, along with the downregulation of the JNK pathway and a decline in essential cellular functions. Ultimately, the host tissue collapses, in turn curbing tumor growth. This study uncovers a dynamic and complex interplay between host tissue resistance and tumor-driven competition, which shapes tumor progression.
Ion–backbone accessibility enables unity doping efficiency in organic electrochemical transistors
Structural insights into the nairovirus nucleoprotein endonuclease activity
Nairoviruses are emerging tick-borne pathogens for which effective antiviral therapies are currently unavailable. Although nucleoproteins (NPs) are essential for viral genome encapsulation and have been extensively characterized at the structural level, whether they perform additional functions during viral replication remains unclear. Here, we investigated the NP of the representative nairovirus Tacheng tick virus 1 (TcTV1). We found that the TcTV1 NP binds to nucleic acids in a sequence-independent manner and assembles into tetramer-based ribonucleoprotein complexes upon nucleic acid binding. This assembly process is accompanied by a pronounced conformational rearrangement that facilitates NP polymerization. In addition to its role in RNA encapsulation, TcTV1 NP exhibits intrinsic endonuclease activity that does not require metal ions and preferentially cleaves unstructured single-stranded RNA, while structured RNA substrates are largely resistant to cleavage. Functional analysis indicates that the stalk domain of NP plays a central role in coordinating RNA binding, oligomerization, and access to the nuclease-active site, thereby influencing whether an RNA molecule is protected or degraded. Finally, we identified a small-molecule compound that interferes with both RNA binding and nuclease activity by targeting a conserved functional region of nairovirus NP. Together, these results reveal an expanded functional repertoire of nairovirus NPs and suggest that NP-mediated RNA discrimination may contribute to viral replication. Our findings also support the feasibility of targeting NP for the development of antiviral drugs against emerging nairoviruses.
TAF15 amyloids propagate via defined motifs in a prion-like fashion
Human and animal morbillivirus strains causing chronic neurological infections share key genotypic and phenotypic traits
Long-term persistent measles virus (MeV) infection of the central nervous system (CNS) can result in subacute sclerosing panencephalitis (SSPE), an invariably fatal late neurological complication of measles. Analogous SSPE-like chronic diseases have also been reported in adult dogs, cetaceans, and more recently harbor seals following infection by canine distemper virus (CDV), dolphin morbillivirus (DMV), and phocine distemper virus (PDV), respectively. Here, we characterize different animal morbilliviruses (CDV lynx , PDV 2001 , PDV 2014 , and DMV 232-18 ) that persisted in the CNS of their respective host species for several years after the initial infections. The CDV lynx and DMV 232-18 strains encode nonfunctional matrix proteins and hyperfusogenic fusion proteins which are hallmark features of SSPE MeV strains. The complex mutational profile apparent in the PDV 2001 strain also has parallels with MeV strains from SSPE cases. In contrast, the PDV 2014 strain encodes for a nonfunctional matrix protein but an unmodified F protein supporting the evolutionary precedence of M protein changes in facilitating long-term morbillivirus infections of the CNS. Consequently, our findings show that similar evolutionary pathways across different animal species drive morbilliviruses to evolve analogous mechanisms favoring virus persistence in the CNS and the development of chronic neurological disease. Such naturally occurring chronic animal morbillivirus infections of the CNS provide natural analogues for studying the evolutionary trajectory and molecular basis of the pathogenesis of SSPE in humans. This may pave the way for developing early diagnostics and intervention strategies.
Epigenetic signatures mark early peripheral human B lineage bifurcation and differential transcriptional profiles in mature populations
Abstract During human B cell maturation, immature transitional (T1) cells transit from bone marrow into the blood. At the subsequent immature T2 stage, a separation into IgM hi (T2M hi ) and IgM lo (T2M lo ) developmental trajectories has been proposed. Here, we isolate T1, T2M hi and T2M lo cells from human adult and cord blood for bulk and single-cell ATAC-seq, CUT&RUN, RNA-seq and CITE-seq to profile their transcriptomic and epigenetic differences. We identify accessible chromatin domains discriminating between T2M hi and T2M lo cells in peripheral B cell development, with signatures persisting during the differentiation of T2M lo to naïve B cells. Similarly, memory and marginal zone B cells retain epigenetic hallmarks of their T2M lo and T2M hi precursors, coupled with transcriptional diversity. Imaging mass cytometry with RNAscope of spleen, appendix and tonsil further validates the spatial relationships of expressed genes. Our study thus provides insights into B lineage T2 bifurcation and describes epigenetic signatures of B cell developmental pathways.
Endothelial Arf6 sustains electrical signaling and cerebral blood flow in mice through PIP <sub>2</sub> -dependent activation of Kir2.1 channels
Brain capillaries sense neural activity and direct blood flow to active regions—a process termed neurovascular coupling that underlies activity-dependent increases in local perfusion (functional hyperemia). A key contributor to functional hyperemic responses is the capillary endothelial cell (cEC) inward rectifier K + (Kir2.1) channel, which, when activated by neuronal activity–derived extracellular K + , initiates vasodilatory electrical signals that propagate through the vascular network. Kir2.1 channel function requires continual production of its lipid cofactor, phosphatidylinositol-4,5-bisphosphate (PIP 2 ), and is compromised in mouse models of cerebral small vessel (cSVD). Although decreased PIP 2 availability is a common feature of cSVDs, mechanisms underlying PIP 2 synthesis remain poorly understood. We hypothesized that Arf6, a small GTPase expressed in cECs that stimulates PIP 2 production, is critical for this process. Using patch-clamp electrophysiology, we demonstrate that inhibiting Arf6 activity progressively decreased cEC Kir2.1 channel activity. This deficit manifested as loss of capillary-to-arteriole electrical signaling in isolated vessels and diminished functional hyperemia in vivo. Exogenously provided PIP 2 restored Kir2.1 currents and functional hyperemia after Arf6 inhibition or genetic knockdown. Collectively, our data suggest that cEC Arf6 sustains Kir2.1 activity by maintaining PIP 2 levels and demonstrate that diminished PIP 2 synthesis is sufficient to impair functional hyperemia. Furthermore, we identify Arf6 as a mechanistic link between PIP 2 production and endothelial electrical signaling, highlighting Arf6 as a potential therapeutic target for restoring functional hyperemia.
Scaling‑free electro‑membrane crystallization enabled by electric field-assisted organic acid control
Mitonuclear discordance modulates mitochondrial ageing dynamics in natural <i>Drosophila</i> populations
Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
Early tidal despinning history recorded in the tectonics of Oz Terra, Charon
Abstract Records of early geologic and thermal evolution after planetary accretion are rarely preserved on icy moons in the Solar System. Charon’s ~ 4.0 Ga surface age suggests the potential preservation of landforms induced from early orbital evolution. Here we show that despinning-induced stress inferred from compressive tectonic features explains latitudinal variations in the orientations and types of tectonic features in Charon’s northern highland, Oz Terra. In addition to global extensional features, we identify north-trending arcuate ranges in Oz Terra, interpreted as compressional in origin. Using an elastic dislocation model, we infer the geometry and kinematics of two thrust faults by fitting the observed tectonically induced topography. The inferred geometry yields a lower bound of 30–36 km for the elastic ice shell thickness at the time. The thrusts accommodate ~ 1 % east-west compressive strain in the equatorial area. The corresponding flattening change suggests an initial rotation period of ~ 14.3 h for Charon. The modeled stress patterns also account for the east-west extensional features. Our work suggests that Charon’s surface presents an example that records the planetary despinning history, which predates the proposed global extension and cryovolcanism on Charon. The coevolution of despinning and global contraction favors a cold start for Charon, offering insights into the early thermal evolution of icy satellites in the outer Solar System.
Dendritic morphology and synaptic nonlinearities enhance functional complexity in human cortical neurons
Humans exhibit unique cognitive abilities within the animal kingdom, but the neural mechanisms driving these advanced capabilities remain poorly understood. Human cortical neurons differ from those of other species, such as rodents, in both their morphological and physiological characteristics. Could the distinct properties of human cortical neurons help explain the superior cognitive capabilities of humans? Understanding this relationship requires a measure to quantify how neuronal properties contribute to the functional complexity of single neurons; yet, such a standardized measure is currently missing. Here, we propose the Functional Complexity Index (FCI), a general, deep-learning-based framework for assessing the input–output complexity of neurons. By comparing the FCI of cortical pyramidal neurons across layers in rats and humans, we identified key morpho-electrical factors that underlie neuronal functional complexity. Human cortical pyramidal neurons are significantly more functionally complex than their rat counterparts, primarily due to differences in dendritic membrane area and branching patterns, as well as in the density and nonlinearity of NMDA-mediated synaptic receptors. These findings reveal the structural and biophysical basis for the enhanced functional properties of human cortical neurons, providing a key step toward understanding the underpinnings of our enhanced cognitive capabilities.
Lithographic patterning of conformal thin films on 3D structures using Scaffold-architected Lift-off masks
Abstract Micro- and nanoscale patterning of conformal thin-film coatings on the exterior surfaces of complex three-dimensional (3D) structures is essential for emerging applications such as soft robotics, photonics, and functional 3D-printed MEMS devices. However, existing methods struggle to deliver high-resolution patterning on complex 3D structures and often suffer from poor thickness control, and inadequate surface conformity of the thin-film coatings. Here we present a robust approach for patterning of conformal thin-film coatings on complex 3D structures, including on sloped surfaces with angles up to 90°, with multiscale dimensions from 100 μm to 100 nm, and even down to the sub-30 nm scale when mask shrinkage techniques are used. This patterning approach utilizes a lithographically defined 3D Scaffold-Architected Lift-Off (SALO) mask in the lift-off process. It is agnostic to the used thin-film deposition process and enables even lift-off patterning of atomic layer deposited (ALD) conformal coatings, a task infeasible for conventional shadowing-based lift-off processes. Our approach opens opportunities for manufacturing complex 3D structures at the micro- and nanoscale by enabling lithographic patterning on the exterior surfaces of arbitrary 3D structures.
Costunolide ameliorates autoimmune uveitis by targeting USP15 to suppress TNF-α-induced retinal endothelial inflammation
Autoimmune uveitis is a sight-threatening inflammatory disease, with the majority of entities driven by leukocyte infiltration into the retina. A critical early step in this process is the activation of retinal vascular endothelial cells (ECs), which up-regulate adhesion molecules that mediate T cell adhesion and subsequent extravasation. Here, we identify the small terpenoid compound costunolide (COS) as a potent suppressor of retinal endothelial inflammation and disease progression in experimental autoimmune uveitis (EAU). Quantitative proteomics of primary human retinal endothelial cells stimulated with TNF-α defined a proinflammatory endothelial signature and revealed induction of adhesion molecules. Screening of a focused library of 337 terpenoids uncovered COS as a top hit that markedly attenuated TNF-α-induced endothelial activation. In vivo, COS treatment significantly reduced clinical and histopathologic EAU scores, accompanied with reduced endothelial adhesion molecule expression and decreased T cell infiltration. Mechanistically, COS directly targeted deubiquitinase USP15, inhibiting USP15-dependent deubiquitination of TRAF1 and TNF signaling in retinal ECs. These findings establish COS as a candidate therapeutic agent for autoimmune uveitis and reveal a TNF-α–USP15–TRAF1 axis in retinal endothelium that can be pharmacologically exploited to limit pathogenic leukocyte trafficking.
Bacterial turbulence drives interfacial waves and shape dynamics in phase-separated droplets
Abstract Liquid-liquid phase separation is important across biology, physics, and materials science. Although usually studied at equilibrium, active components-such as motor proteins, enzymes, and synthetic microswimmers-are increasingly recognized as key players in reshaping phase separation dynamics. Yet how internally generated active stresses are transmitted to capillary interfaces to reshape three-dimensional droplet dynamics remains poorly understood. Here, we encapsulate dense suspensions of motile bacteria inside phase-separated aqueous droplets, creating a closed droplet whose interface is driven from within by bacterial turbulence. By varying bacterial density, we control the active stress at the droplet interface. At low bacterial density, we observe scale-dependent interfacial fluctuations that propagate as waves. In this low Reynolds number regime, these waves arise from an effective inertial response, generated when active bacterial stresses balance passive viscous damping of the interface. At higher bacterial density, droplets deform strongly-exceeding the Plateau-Rayleigh instability threshold-and even form bacteria-scale filaments-a morphology without a passive counterpart. Enhanced droplet motility and accelerated coarsening accompany these shape changes. Our work shows how active stresses can reshape the morphology and dynamics of multiphase systems, offering new insight into the physics of internally driven phase-separated fluids.
Divergent trait controls on soluble sugars and starch underlie global strategies of tree carbohydrate storage
Nonstructural carbohydrate (NSC) stores buffer tree metabolism, osmotic regulation, and defense, thereby mediating tolerance and survival under climate extremes. Yet, the functional and evolutionary determinants of interspecific variation in NSC remain elusive, limiting understanding and prediction of forest carbon allocation and mortality under global change. Here, we present a cross-species synthesis of NSC concentrations across multiple organs for 281 woody species from 102 mixed forest communities worldwide, where we quantified species-specific deviations from community means to disentangle intrinsic trait effects from environmental and methodological variation. We found phylogenetic signals in NSC deviations, with coniferous gymnosperms and evergreen species consistently maintaining lower stem soluble sugars and starch concentrations than co-occurring angiosperms and deciduous species, respectively. A global pattern emerged where greater stomatal sensitivity to leaf water potential was associated with declines in the relative concentrations of both sugars and starch. In contrast, xylem hydraulic safety traits showed weak and organ-dependent relationships with NSC concentrations. Sugars increased with photosynthetic capacity and declined with wood density, whereas starch showed the reverse pattern, which aligned with the distinct functional-metabolic roles of sugars and starch. By integrating trait-based ecology with a community-centered framework, our study provides global evidence that stomatal regulation, photosynthetic capacity, specific leaf area, and wood density jointly govern interspecific NSC variation, through contrasting effects on sugars and starch. These are among the most broadly measured traits globally, thus the emergent carbohydrate–trait relationships can have broad applications toward understanding and predicting forest growth and survival under climate change.
Osteocyte parvalbumin mediates mechanotransduction to attenuate osteoarthritis
A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer
The TMPRSS2:ERG gene fusion, present in approximately 50% of prostate cancers in patients of European ancestry, drives oncogenesis through aberrant overexpression of the ERG transcription factor. Despite its role as a truncal oncogenic driver, ERG has been considered undruggable due to the absence of enzymatic activity and apparent lack of ligandable pockets. Here, we demonstrate continued dependency on ERG in metastatic prostate cancer and identify a druggable pocket within its N-terminal Pointed (PNT) domain. Using an inducible shRNA system in TMPRSS2:ERG -positive VCaP cells, we show that ERG depletion causes profound growth inhibition. To therapeutically exploit this vulnerability, we conducted a domain-focused differential scanning fluorimetry screen targeting the ERG PNT domain, followed by structure–activity relationship optimization. This approach yielded PBITE-1 (PNT-Binding Inhibitor of the Transcription factor ERG), a small molecule that selectively binds the ERG PNT domain. NMR chemical-shift perturbation mapping and molecular docking revealed that PBITE-1 engages a discrete, solvent-exposed surface comprising two α-helices and an adjacent flexible loop, defining a ligand-binding pocket within the PNT domain. In cellular models, PBITE-1 directly engaged ERG, selectively inhibited proliferation and invasion, and induced apoptosis in ERG-driven prostate and hematologic malignancies. PBITE-1 potently suppressed growth of ERG-positive mouse and human-derived prostate cancer organoids. Furthermore, PBITE-1 treatment significantly induced tumor cell apoptosis in VCaP xenograft models. These findings establish the ERG PNT domain as ligandable and provide preclinical evidence that ERG is directly targetable by small molecules, enabling future development of ERG-directed inhibitors and targeted protein degraders.
Key link between iron and the size structure of three major mesoplanktonic groups in the upper ocean
Abstract In marine ecosystems, critical services like fish production, carbon export, or the delivery of nutrients through N 2 -fixation rely heavily on the size spectrum of pelagic organisms, particularly mesoplankton (200-20,000 µ m). However, the linkages between environmental factors and mesoplankton spectral biogeography remain largely unresolved, as so far only limited datasets exist to understand the large-scale shifts in mesoplankton size. Using global compilations of Rhizarian, colonial N 2 -fixer, and Crustacean images, we reveal the role of iron in shaping the size structure and related biogeography of these groups. Our findings underscore the importance of atmospheric sources of iron for N 2 -fixers and Rhizarians while total iron, accounting for organic and inorganic compounds, appeared to explain a high percentage of the variance in Crustacean size structure via apparent recycling. Using environmental explanatory variables, our models reached high R 2 (0.93, 0.88, and 0.79 respectively), providing robust predictions of mesoplankton size structure related to elemental cycling and ecosystem services. Our results suggest that without compensatory mechanisms, future increases in global temperatures could have negative effects on mesoplankton size, possibly limiting carbon export from the productive layers to sequestration depth, that might be offset by expected increases in iron inputs that benefit N 2 -fixers, Rhizarians, and eventually Crustaceans.
Sex- and experience-dependent regulation of synaptic protein turnover
Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism’s lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.