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Defect-modulated oxygen adsorption and Z-scheme charge transfer for highly selective H2O2 photosynthesis in pure water
Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated prepositioning
Antibodies that recognize the conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins typically show limited neutralization and have not been considered promising therapeutic agents. We previously developed a bispecific antibody (bsAb), iMab/D5_AR, directed toward both the gp41 N-heptad repeat (NHR) that is exposed within the HIV-1 PHI and toward CD4, the HIV-1 receptor on T cells. CD4-binding led to prepositioning of the bsAb at the site of viral fusion, enhancing its neutralization potency and achieving 95% breadth (IC80 < 5 μg/mL) against a panel of 119 pseudotyped, multiclade HIV-1 viruses. In the current study, we engineered a bsAb against NHR that also targets CCR5, one of two HIV-1 coreceptors on T cells. This optimized bsAb design further improves neutralization potency and achieves 100% neutralization breadth against the 119-member pseudotyped virus panel, including those resistant to CD4-binding iMab/D5_AR. Considering that nearly all initial HIV-1 infections occur via CCR5-tropic viruses, we expect our redesigned bsAb targeting CCR5 to be an effective prophylactic agent. These findings further support the rationale for pursuing the NHR as a therapeutic target for HIV-1 and lay the groundwork for a new class of engineered broadly neutralizing antibodies.
In vivo imaging of the barrier properties of the glia limitans during health and neuroinflammation
Abstract The glia limitans ensheathes the entire central nervous system (CNS) parenchyma towards the outer surfaces and the perivascular spaces and is formed by a subset of astrocytes strategically localized at these outer parenchymal borders. Barrier properties of the glia limitans during health and neuroinflammation are incompletely understood. By developing an aquaporin-4 (Aqp4)-mRuby3 knock-in reporter mouse that allows for in vivo imaging of the superficial and perivascular glia limitans, we here show that the glia limitans forms a barrier for soluble mediators, beads and immune cells. Combining the Aqp4-mRuby3 reporter strain with additional reporter alleles for vascular, leptomeningeal or myeloid cells ensures precise localization of immune cells to CNS border zones versus the CNS parenchyma allowing to assign functional roles in CNS immune surveillance versus neuropathology. Availability of the Aqp4-mRuby3 reporter mouse will further advance our understanding of the active role of the glia limitans in CNS immune privilege.
Biliverdin reductase A is a major determinant of protective NRF2 signaling
Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer’s disease. Thus, this noncanonical BVRA–NRF2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings position BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.
Ecdysone signaling-induced dumpless1 expression controls nurse cell dumping in Drosophila oogenesis
How to upgrade stolen organelles into permanent plastids: A comparative transcriptomic perspective
Tertiary plastids derived from diatoms in “dinotom” dinoflagellates offer a rare view of organellogenesis in action, while the genomic and metabolic processes underlying their conversion remain poorly understood. Here, we present a comparative transcriptomic analysis of two dinotoms at different plastidial levels: Durinskia capensis at the kleptoplastidy state, alongside its kleptoplastid-source diatom Nitzschia captiva , and its close relative Durinskia kwazulunatalensis at an early permanent state. We show that in both dinotoms, the diatom nucleus retains high transcriptional autonomy, but its expression profile is plastid biased, signaling early host influence. In contrast, only D. kwazulunatalensis exhibits striking signs of genomic reconfiguration in the diatom nucleus: intron insertions, increased guanine (G) and cytosine (C) content, and growing nucleotide similarity to host transcripts. These shifts suggest an incipient nucleomorph-like transformation. Metabolically, only D. kwazulunatalensis expresses a complete hexose phosphate export pathway, suggesting deeper metabolic integration, while both species retain simpler carbohydrate transport routes. Additionally, we propose that diatom karyokinesis might be controlled by a dual mechanism via suppression of key transcription factors at the G1-S checkpoint and nitrate availability. Together, our findings reveal a continuum of plastid integration degrees, from temporary organelle theft to genomic accommodation and metabolic codependence. Dinotoms thus serve not only as evolutionary artifacts but as living laboratories, illuminating how kleptoplastids inch toward permanence.
Engineering of mRNA vaccine platform with reduced lipids and enhanced efficacy
Living/controlled supramolecular protein polymerization
With the learning from living protein polymerization in nature, achieving living/controlled supramolecular assembly of biopolymers such as proteins in vitro is a longstanding challenge for material design. Herein, we provide a thiol-regulated interfacial protein aggregation (TRIPA) for unfolded protein systems with typical living polymerization features. By triggering globule proteins into the unfolded state through a reversible exchange reaction of disulfide bonds and sulfhydryl agents (R-SH), protein monomers are partially unfolded and assembled at the air–water/solid–water interface (AWI/SWI) through the entropy-driven adsorption and conformation transition. The process could be well repeated over time to form a two-dimensional (2D) nanofilm at the interface by following a pathway of monomer-oligomer-2D assembly. Similar to living polymerization, the film thickness exhibited a linear increase with the assembly conversion ratio of the monomers. With the stepwise addition of native protein into the reaction system, the thickness periodically increased in a linear manner. Such living/controlled supramolecular polymerization (LCSP) of protein at the interface leads to the synthesis of a nanofilm with well-defined flat morphology, ultrahigh modulus, and nano- to macroscale controlled thickness. The resultant protein nanofilm could then attach onto a variety of flexible and rigid material surfaces to produce a stable structural color coating. Compelling evidence in the present work thus underlines a demonstration of LCSP of biopolymers in vitro. It may hold a solid impact by opening a window for living/controlled polymerization of versatile biospecies such as proteins, saccharides, nucleic acids, and cells.
Mechanistic understanding of nitrate reduction as the dominant production pathway of nitrous oxide in marine oxygen minimum zones
The role of colony morphotype in shaping gene essentiality in <i>Mycobacteroides abscessus</i>
Changes in bacterial colony morphology are common during chronic human infections and are thought to provide a survival advantage. In the human pathogen Mycobacteroides abscessus (MAB), a unidirectional transition from a smooth (MAB S ) to rough (MAB R ) morphotype frequently occurs during chronic infection. This transition has profound clinical implications, as MAB R induces a heightened proinflammatory response, contributing to increased morbidity. To better understand this phenomenon, we used transposon insertion site sequencing (Tn-seq) to identify genes essential for the survival of MAB S and MAB R . Our analysis revealed distinct genetic requirements for growth in vitro, including several genes involved in responding to environmental stresses. Notably, some of these uniquely essential genes are therapeutic targets in mycobacteria. In a murine infection model, the divergence in essential gene profiles between MAB S and MAB R was even more pronounced, driven partly by the differing host immune responses elicited by each morphotype. These findings demonstrate that the transition from a smooth to rough morphotype not only impacts MAB’s survival strategies but also highlights the importance of considering morphotype-specific genetic and functional adaptations when developing therapeutic approaches. Our work underscores the critical need to incorporate morphotype conversion into the prioritization of drug targets, as targeting morphotype-specific vulnerabilities could improve treatment outcomes for infections caused by this pathogen.
High-dimensional strain unlocks fast polysulfide redox kinetics for lithium-sulfur batteries
Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway
The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2 −/− mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia–reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.
Accessing acyclic vicinal tetrasubstituted stereocenters via biomimetic Cu/squaramide cooperative catalysed asymmetric Mannich reactions
Cranial modularity drives phenotypic diversification and adaptive radiation of Antarctic icefishes
Modularity among traits is thought to drive morphological evolution and diversification, with more modular species often showing greater morphological disparity and faster evolutionary rates. However, recent studies suggest this pattern is not universal, as higher integration can sometimes be linked to faster rates of evolution. In adaptive radiation, modularity likely facilitates morphological divergence, but its specific role in trait diversification within these events remains uncertain. Antarctic icefishes (Perciformes: Notothenioidei) have undergone adaptive radiation in the frigid Southern Ocean, yet the role of modularity in their craniofacial evolution remains poorly understood. Emerging from a common ancestor 22 Mya, these fishes developed unique morpho-physiological adaptations, such as antifreeze glycoproteins, that contributed to their evolutionary success, but the contribution of cranial modularity to their diversification is still unexplored. Here, we analyze skull shape across 172 perciform species using micro-CT scanning and geometric morphometrics to investigate the tempo and mode of skull evolution in 80 notothenioids versus 92 perciform relatives. Notothenioids exhibit considerable cranial shape diversity, with skull shapes ranging from short to long faces. Fast rates of skull shape evolution occurred in smaller subclades following the emergence of cranial elongation, a derived trait within notothenioids. They also exhibit elevated evolutionary modularity relative to their perciform relatives, with reduced covariation among skeletal elements over time, likely corresponding with Miocene cooling events and the formation of the Antarctic Circumpolar Current. We propose that greater phenotypic modularity in notothenioid skulls represents a pivotal innovation, facilitating their evolutionary response to new ecological opportunities in the Antarctic.
Experimental entanglement swapping through single-photon χ(2) nonlinearity
Abstract In photonic quantum information processing, quantum operations using nonlinear photon-photon interactions are vital for implementing two-qubit gates and enabling faithful entanglement swapping. However, due to the weak interaction between single photons, the all-photonic realization of such quantum operations has remained out of reach so far. Herein, we demonstrate an entanglement swapping using sum-frequency generation between single photons in a χ (2)-nonlinear optical waveguide. We show that a high signal-to-noise ratio (SNR), stable sum-frequency-generation-based entanglement heralder with an ultralow-dark-count superconducting single-photon detector can satisfy the unprecedented SNR requirement indispensable for the swapping protocol. Furthermore, the system clock is enhanced by utilizing ultrafast telecom entangled photon-pair sources that operate in the GHz range. Our results confirm a lower bound 0.770(76) for the swapped state’s fidelity, surpassing the classical limit of 0.5 successfully. Our findings highlight the strong potential of broadband all-single-photonic nonlinear interactions for further sophistication in long-distance quantum communication and photonic quantum computation.
Wild canids and felids differ in their reliance on reused travel routeways
Diverse factors, including environmental features and cognitive processes, can drive animals’ movements and space use, with far-reaching implications. For example, repeated use of individual-level travel routeways (directionally constrained but imperfectly aligned routes), which results in spatial concentration of activity, can shape encounter-based processes including predation, mate finding, and disease transmission. However, how much variation in routeway usage exists across species remains unknown. By analyzing GPS movement tracks for 1,239 range-resident mammalian carnivores—representing 16 canid and 18 felid species from six continents—we found strong evidence of a clade-level difference in species’ reliance on repeatedly used travel routeways. Across the global dataset, tracked canids had a 15% (±7 CI) greater density of routeways within their home ranges than did felids, rising to 33% (±16 CI) greater in landscapes shared with tracked felids. Moreover, comparisons within species across landscapes revealed broadly similar home range routeway densities despite habitat differences. On average, canids also reused their travel routeways more intensively than did felids, with hunting strategies and spatial contexts also contributing to the intensity of routeway usage. Collectively, our results suggest that key aspects of carnivore routeway-usage have an evolutionary component. Striking interspecific and clade-level differences in carnivores’ reliance on reused travel routeways within home ranges identify important ways in which the movement patterns of real-world predators depart from classical assumptions of predator-prey theory. Because such departures can drive key aspects of human-wildlife interactions and other encounter-based processes, continued investigations of the relationships between movement mechanisms and space use are critical.
Fast hierarchical processing of orthographic and semantic parafoveal information during natural reading
Abstract In reading, information from parafoveal words is extracted before direct fixation; however, it is debated whether this processing is restricted to orthographic features or also encompasses semantics. Moreover, the neuronal mechanisms supporting parafoveal processing remain poorly understood. We co-registered MEG and eye-tracking data in a natural reading paradigm to uncover the timing and brain regions involved in parafoveal processing. Representational similarity analysis revealed that parafoveal orthographic neighbours (e.g., “writer” vs. “waiter”) showed higher representational similarity than non-neighbours (e.g., “writer” vs. “police”), emerging ~68 ms after fixation onset on the preceding word (e.g., “clever”) in the visual word form area. Similarly, parafoveal semantic neighbours (e.g., “writer” vs. “author”) exhibited increased representational similarity at ~137 ms in the left inferior frontal gyrus. Importantly, the degree of orthographic and semantic parafoveal processing was correlated with individual reading speed. Our findings suggest fast hierarchical processing of parafoveal words across distinct brain regions, enhancing reading efficiency.
A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron–sulfur cluster and supercomplex formation
MEPAN ( M itochondrial E noyl CoA Reductase P rotein- A ssociated N eurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC–MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron–sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.