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Neuron-derived mitochondrial DNA (mtDNA) activates microglia via the Z-DNA binding protein 1 (ZBP1)-mediated pathway in mild traumatic brain injury
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality, with closed-head mild TBI (mTBI) accounting for nearly 90% of all cases. Early pathological events include microglial activation and neuronal mitochondrial dysfunction; however, their interconnection in mTBI remains poorly understood. Using a clinically relevant closed-head weight-drop mouse model, we identified mitochondrial DNA (mtDNA)-specific damage and increased expression of innate inflammatory markers (IL-1α/β, IL-6, TNFα, and CXCL1) in the cerebral cortex during the acute mTBI phase. Mechanistically, neurons subjected to in vitro injury model of mTBI exhibited early mtDNA-specific damage followed by mtDNA release via extracellular vesicles (EVs) together with the neuronal and exosomal markers. The released neuronal mtDNA induced a robust microglial activation mediated by binding to the cytoplasmic DNA/RNA sensor Z-DNA–binding protein 1 (ZBP1), triggering activation of the ZBP1–TBK1–IRF3 pathway resulted IL-6 and TNFα expression. An early, enhanced amounts of mtDNA, neuronal and exosomal markers were measured in EVs circulating in the blood of mice subjected to mTBI. ZBP1 knockout (KO) mice displayed suppressed microglial—but not astrocytic—activation in the cortex during the acute mTBI phase. We also measured accumulation of mtDNA-specific damage in the hippocampus during the postacute mTBI phase. The absence of microglial activation in ZBP1 KO mice exacerbated hippocampal-related memory deficits in the postacute mTBI phase. Collectively, our findings identify mtDNA–ZBP1 signaling as a key mechanism regulating microglial activation in mTBI.
Functional role of small extrachromosomal circular DNA in colorectal cancer
Extrachromosomal circular DNA (eccDNA) are molecules that originate from chromosomal DNA but exist independently. While large eccDNA (ecDNA) contributes to tumorigenesis, the role of smaller eccDNA (<100,000 base pairs) in cancer remains unclear. Our analysis of 25 colorectal cancer (CRC) tumors and normal adjacent tissues revealed that eccDNA is significantly more abundant in tumor tissues, correlating strongly with chromosomal amplifications. The presence of whole intact genes on 1.29% of eccDNA was nonrandom. We identified 84 genes that recurred across tumors of multiple patients when present on eccDNA, with 19% of genes being cancer-associated. eccDNA-borne genes were often accompanied by increased expression, and their contribution to expression was much larger than that from linear amplifications and the larger ecDNA. The cytokine gene CXCL5 exemplified this phenomenon, showing substantial copy-number increase and upregulation when present on eccDNA. Functional validation in cell lines showed that CXCL5 eccDNA enhanced transcriptional output and immune cell recruitment function. The recurrence and overexpression of CRC-related genes on eccDNA indicate their selection in tumors, suggest that eccDNA can serve as an additional mechanism for dynamically influencing gene expression and is capable of conferring cancer phenotypes on cells. Analysis of chromatin landscapes revealed that eccDNA preferentially forms at sites of open chromatin and active transcription, with architectural boundaries marked by CTCF protein. Clinically, higher eccDNA levels correlated with poorer relapse-free survival in a small patient cohort. These findings suggest that circular DNA elements across the entire size spectrum participate in cancer evolution and warrant further investigation in larger cohorts.
Cultural tightness and social cohesion under coevolving beliefs, behaviors, and preferences
Successful collective action on issues from climate change to the maintenance of democracy depends on societal properties such as cultural tightness and social cohesion. How these properties evolve is not well understood because they emerge from a complex interplay between beliefs and behaviors that are usually modeled separately. Here, we address this challenge by developing a game-theoretic framework incorporating norm-utility models to study the coevolutionary dynamics of cooperative behavior, expressed belief, and norm-utility preferences. We show that the introduction of evolving beliefs and preferences into the Snowdrift game and Prisoner’s Dilemma leads to a proliferation of evolutionary stable equilibria, each with different societal properties. In particular, we find that reduced material benefits from cooperation can be associated with an expected increase in cultural tightness (the degree to which norms are strong and shared, so that individuals behave in accordance with widely held beliefs) and an expected reduction in social homogeneity and cohesion (the extent to which individuals belong to a single well-defined group with similar beliefs, behaviors, and preferences). Loss of social homogeneity occurs via a process of evolutionary branching, in which a population fragments into two distinct social groups with strikingly different characteristics. The groups that emerge differ not only in their willingness to cooperate, but also in their expressed beliefs about cooperation and in their preferences for conformity and coherence of their behaviors and expressed beliefs. These results have implications for our understanding of the resilience of cooperation and collective action in times of crisis.
Fitting coarse-grained models to macroscopic experimental data via automatic differentiation
Developing physics-based models for molecular simulation requires fitting many unknown parameters to diverse experimental datasets. Traditionally, this process is piecemeal and difficult to reproduce, leading to a fragmented landscape of models. Here, we establish a systematic framework for fitting coarse-grained molecular models to macroscopic experimental data by leveraging recently developed methods for computing low-variance gradient estimates with automatic differentiation. Using a widely validated DNA force field as an exemplar, we develop methods for optimizing structural, mechanical, and thermodynamic properties across a range of simulation techniques, including enhanced sampling and external forcing, spanning micro- and millisecond timescales. We highlight how automatic differentiation enables efficient sensitivity analyses that yield insights into the model parameters governing physical behaviors. We then demonstrate the broad applicability of these techniques by optimizing diverse biomolecular systems, including RNA and DNA–protein hybrid models. We show how conflict-free gradient methods from multitask learning can be adapted to impose multiple constraints simultaneously without compromising accuracy. This approach provides a foundation for transparent, reproducible, community-driven force field development, accelerating progress in molecular modeling.
The biased adenosine-rich content of the HIV-1 genome serves as a molecular signature that facilitates efficient packaging
The HIV-1 genome [genomic RNA (gRNA)] has an unusually biased nucleotide content and is rich in adenosines. Selective packaging of the gRNA is thought to be driven by specific binding of the nucleocapsid (NC) domain of the viral Gag protein to the packaging signal (Ψ) in the host cell cytosol. However, deletion of regions within Ψ reduces—but does not completely abolish—genome packaging. To probe whether another feature of the gRNA may contribute to the selective gRNA packaging process, we replaced NC with heterologous RNA-binding domains (RBDs) with distinct RNA-binding properties. Surprisingly, despite disparate RNA binding specificities, all Gag-RBD chimeras successfully recruited the gRNA to the plasma membrane, suggesting that the initial gRNA recognition in the cytosol is not rate limiting. Notwithstanding, many chimeras exhibiting G/C binding specificity were arrested at the assembly stage. Only the Gag-SRSF5 chimera, which multimerized efficiently on adenosine-rich sequences on the gRNA, assembled efficiently and packaged gRNA at near wild-type levels. Importantly, rationally designed mutations that altered the A/G-rich binding specificity of Gag-SRSF5 decreased genome encapsidation efficiency. Furthermore, many Gag chimeras displayed potent dominant negative activities, highlighting NC functions as a targetable step in virus replication. Together, our findings reveal an unexpected aspect of the HIV-1 gRNA, its biased nucleotide content, as a key driver of selective genome packaging.
Correction for Wang et al., Oligomeric assembly of the gatekeeper InvE orchestrates hierarchical type III protein secretion in <i>Salmonella</i> Typhimurium
Free information disrupts even Bayesian crowds
A core tenet underpinning the conception of contemporary information networks, such as social media platforms, is that users should not be constrained in the amount of information they can freely and willingly exchange with one another about a given topic. By means of a computational agent-based model, we show how even in groups of truth-seeking and cooperative agents with perfect information-processing abilities, unconstrained information exchange may lead to detrimental effects on the correctness of the group’s beliefs. If unconstrained information exchange can be detrimental even among such idealized agents, it is prudent to assume it can also be so in practice. We therefore argue that constraints on information flow should be carefully considered in the design of communication networks with substantial societal impact, such as social media platforms.
Hierarchical genotype networks and incipient ecological speciation in Qβ phage quasispecies
Understanding how viral mutant spectra organize and explore genotype space is essential for elucidating the mechanisms that drive molecular evolution. Here, we use deep-sequencing data of an amplicon in the A2 protein of the RNA bacteriophage Q β to reconstruct genotype networks comprising tens of thousands of haplotypes. The study of populations evolved under different temperature regimes reveals robust and reproducible patterns that arise from the interplay between fundamental geometrical motifs of sequence spaces and population dynamics. Mutant swarms exhibit a self-similar, hierarchical organization in which sequences cluster around highly connected, abundant cores that continuously regenerate diversity during evolution. The immediate neighborhood of these cores is rapidly rebuilt and extensively sampled, while a few mutations away sampling becomes dynamical and sparse. This population structure emerges from a dynamic, out-of-equilibrium balance between replication and mutational exploration and suggests that Q β populations do not rely primarily on neutral networks to navigate genotype space or to generate diversity. Combining genotype networks from populations adapted to different temperatures reveals early evolutionary divergence, with partially overlapping yet distinct populations that remain connected through short mutational paths. Even at the time scale of these experiments, evolutionary trajectories remain multiple, preventing the backward reconstruction of unique trajectories once mutations have been fixed. Together, this analysis provides a detailed view of the fine-scale processes shaping the evolution of heterogeneous viral populations and establishes genotype networks as a powerful framework for visualizing and interpreting the organization and diversification of viral quasispecies.
Correction for Lim et al., Longitudinal transformation of mitochondrial metabolism during neurogenesis
Correction for Elsler et al., Global nutritional equity of fishmeal and aquaculture trade flows
Lone black holes promise fresh insights into the fates of massive stars
ClpP2 modulates ClpXP assembly to promote multiple pathogenic phenotypes in <i> <i>Pseudomonas aeruginosa</i> </i>
In the opportunistic pathogen Pseudomonas aeruginosa ( Pa ), ClpXP proteases selectively degrade key transcriptional regulators (TRs), enabling dynamic control over phenotypes that promote pathogenesis and virulence. Here, we report that a natural Pa variant activates multiple pathogenic phenotypes by modulating ClpXP assembly dynamics through a spontaneous hypomorphic mutation in the canonical peptidase subunit ClpP1 (ClpP1 P6L ) and its synergistic activation by the atypical peptidase subunit ClpP2. Genetics, cell-based reporter assays, and biochemical analyses reveal that ClpP1 P6L impairs ClpXP-complex formation, but that this defect is partially suppressed upon heterooligomerization with ClpP2. Consequently, ClpX, ClpP1 P6L , and ClpP2 combine to catalyze sufficient proteolysis to trigger mucoid conversion, a virulence-associated phenotype characterized by alginate overproduction. Further, ClpP1 P6L also triggers premature rhl quorum sensing, thereby upregulating the expression of additional virulence factors. These findings demonstrate that by encoding two ClpP paralogs (ClpP1 and ClpP2), Pa can adaptively modulate ClpXP assembly dynamics to adjust proteolysis and expand its phenotypic versatility. We propose that organisms that encode multiple ClpP subunits can exert finer control over regulated substrate degradation and thereby optimize their display of pathogenic traits that support opportunistic infections.
Mining cancer genomes for copy number alterations identifies glycosylation enzymes as oncogenic drivers
Altered cell-surface glycans are established cancer biomarkers, yet no oncogenes have been identified within glycan biosynthesis machinery. This represents a critical gap, as defining a gene as a true oncogene, rather than merely a component of an oncogenic pathway, reveals targetable dependencies that can improve clinical decisions. To date, no gain-of-function mutations have been detected in glycogenes, and the search for such mutations is largely saturated. To address this gap, we developed a bioinformatic–experimental pipeline to identify copy number alteration (CNA)-based driver genes, overcoming noise from passenger genes. The approach recovered known oncogenes and tumor suppressors, while revealing novel candidates, including glyco-oncogenes. Focusing on the glycosphingolipid (GSL) biosynthetic pathway, we validated B4GALT5 as a bona fide glyco-oncogene whose genomic amplification drives proliferation, oncogene addiction, and poor prognosis, effects that can be reversed by targeted pathway inhibition. Mechanistic studies show that B4GALT5 promotes cancer cell survival via integrin-Src signaling under anchorage-independent conditions. Collectively, these findings establish glycosylation enzymes as a druggable oncogene class and provide a resource of high-confidence CNA-based cancer regulatory genes.
Microheterogeneous singlet oxygen generation at air–water interfaces
Singlet oxygen ( 1 O 2 ) is a short-lived, highly reactive oxidant driving natural element cycles, yet its spatial distribution in complex multiphase systems remains poorly understood. Here, we show that irradiation of organic carbon (OC)-containing aqueous microdroplets leads to pronounced interfacial enrichment of 1 O 2 , driven by the surface accumulation of photosensitizing OC. Combining fluorescence imaging with a reaction–diffusion kinetic model, we resolve steep 1 O 2 gradients across the air–water boundary: In a 1 µm-radius droplet, 1 O 2 levels drop by 90% within 10 µm from the interface into the gaseous phase, and within 230 nm from the interface into the aqueous phase. Tailored peptide probes reveal that molecules residing at the interface undergo substantially faster 1 O 2 -mediated transformation than their bulk counterparts. These findings identify the air–water interface as a privileged site for 1 O 2 photochemistry that strongly accelerates redox processes in aerosols, sea spray, and the ocean–atmosphere boundary.
Clade C MERS-CoV camel strains vary in protease utilization during viral entry
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a lethal pathogen with pandemic potential. Clade A and B MERS-CoV viruses have caused outbreaks in the Middle East since 2012 when they initially spilled over from camels to humans. Clade C viruses, however, are only found in camels across Africa and the spillover potential of these viruses seems to be lower than for clade A/B strains but remains to be fully understood. Here, we report that clade C spikes are less well-cleaved at the S1/S2 boundary than clade A or B viral spikes and that most clade C spikes induce reduced syncytium formation. Additionally, we demonstrate that several East African clade C strains are less able to utilize the TMPRSS2-mediated pathway for viral entry in both cell lines and primary nasal epithelial cultures. We map the molecular basis of this reduced TMPRSS2 usage to the N-terminal domain and subdomain 2 of East African clade C MERS-CoV. We suggest that reduced usage of the TMPRSS2-mediated entry pathway may underlie the reduced replication of East African clade C strains in humans, while the reduced replication of West African strains remains to be further investigated. Altered protease usage may contribute to differential tropism of East African clade C strains and indicate geographically distinct selection pressures on spike between MERS-CoV strains circulating in camels.
Dynamic switching of cell–substrate contact sites allows gliding diatoms to modulate the curvature of their paths
The directed motility of unicellular organisms is critical for their survival and ecological success, yet the mechanisms that enable rigid-walled diatoms to dynamically reorient and alter the shape of their trajectories remain poorly understood. Here, we investigate the gliding motility of Craspedostauros australis , a raphid pennate diatom that moves rapidly across submerged surfaces using an intracellular actomyosin motility complex and the secretion of adhesive extracellular polymeric substances (EPS) strands through slit-like openings termed raphes. Using high-precision single-cell tracking, scanning electron microscopy (SEM), interference reflection microscopy (IRM), and mathematical modeling, we reveal how diatoms achieve diverse path curvatures by dynamically modulating the location of raphe–substrate contact and switching between one- and two-raphe branch contact gliding. Our results indicate that local curvature variations along the raphes dictate trajectory shapes, with one-raphe branch contact gliding producing highly curved paths, while two-raphe branch contact gliding results in paths of lower curvature. IRM imaging further confirms that transitions between these gliding modes underlie abrupt changes in path curvature and cell reorientation. This dynamic raphe-switching mechanism is conserved across cell sizes and correctly predicts the increased path curvatures observed in smaller cells according to their more pronounced local raphe curvature. By quantitatively linking raphe geometry, cell–substrate attachment dynamics and motility patterns, our study provides insights into the motility mechanism that allows diatoms to adapt their movement to complex environments.
Distinct laminar origins of sensory-evoked high-gamma and low-frequency ECoG signals revealed by optogenetics
Electrocorticography (ECoG) provides a high-spatiotemporal-resolution measure of cortical activity (cortical surface electrical potentials, CSEPs) in humans and animals. The CSEP high-gamma band (Hγ, 65 to 170 Hz) correlates with neuronal firing rates at the columnar spatial scale and is widely used as a biomarker of local activity. Whether Hγ reports all stages of columnar processing, intermediate processing in L2/3 (close to the ECoG electrode), or the main columnar output in L5, is unknown. We disentangled the laminar origins of Hγ and other ECoG bands by optogenetically suppressing L2/3 or L5 pyramidal cells during micro-ECoG recording in the mouse somatosensory cortex. Whisker deflections evoked transient, topographically localized CSEPs. L5 optogenetic suppression most strongly reduced 65 to 450 Hz (Hγ-uHγ) bands in sensory-evoked ECoG signals, whereas L2/3 suppression most strongly reduced 4 to 27 Hz (θ-β) bands. Thus, different CSEP frequency bands reflect layer-specific activity and are biomarkers of distinct stages of sensory-evoked columnar processing.
Prokaryotic bias in surface ocean particles
While the ocean’s photosynthetic production of organic matter rivals that on land, a combination of heterotrophy and sinking prevents significant accumulation of particulate organic matter (POM) in open ocean surface waters. The origins and fates of POM in ocean surface waters are unclear, in part due to the dominance of nonliving, altered material. From the natural nitrogen isotopic composition of chlorophyll and its degradation products, we estimate the fraction of particles from eukaryotic vs. prokaryotic phytoplankton. In subtropical gyres and along the eastern North Pacific margin, the eukaryotic-to-prokaryotic ratio in particles matches that of living phytoplankton. However, in the North Atlantic outside its subtropical gyre, particles have a lower eukaryotic-to-prokaryotic ratio than do the living phytoplankton. This discrepancy at least partly arises from preferential sinking of eukaryotic biomass, consistent with the canonical but disputed paradigm that cyanobacteria disproportionately fulfill the energetic demands of the upper ocean microbial community while eukaryotes drive export production. The prokaryotic bias in surface ocean particles may also result from slow decomposition of specific components of prokaryotic biomass, a possible bottleneck in the ocean’s microbial loop. The different fates of organic matter produced by eukaryotic and prokaryotic phytoplankton affect the productivity of the surface ocean, carbon export to the interior, and the signals recorded in deep-sea sediments.
High-quality surrounding landscapes mitigate avian extirpations from forest remnants
The species–area relationship (SAR) has long been used to predict extirpation rates from habitat loss, but these rates depend not only on habitat area but also on the surrounding landscape and species’ habitat specialization. We collated global data from forest islands created by river damming and forest fragments resulting from clear-cut deforestation to examine the effects of matrix type (aquatic or terrestrial) and tree cover on avian SARs. Unlike oceanic islands, which are often millions of years old, anthropogenic forest islands provide a contemporary analog to forest fragments to understand matrix effects on SARs and serve as a baseline for worst-case scenarios of forest fragmentation. Our database comprises 50 datasets from 45 studies conducted in tropical and subtropical regions, totaling 1,954 bird species detected through 39,197 incidence records from 336 forest islands and 669 forest fragments. We found that bird extirpation rates were lower in fragments than on islands, especially for forest-dependent species compared to all species. Species losses were further reduced by increasing tree cover around forest remnants at local landscape scales of 300 m, highlighting the importance of small-scale conservation strategies. Moreover, even small forest fragments with greater nearby tree cover held high conservation value, emphasizing the crucial role of the surrounding landscape in mitigating avian extirpations from forest remnants. Beyond protecting forest remnants themselves, area-based conservation efforts would therefore be greatly enhanced by improving matrix quality and expanding tree cover in otherwise hostile landscapes.