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Macroscopic assembly of supramolecular coacervates for underwater adhesion
Archaic ancestry inference in imputed ancient human genomes
Abstract When modern humans expanded from Africa into Eurasia, they interbred with archaic hominins such as Neanderthals and Denisovans. This introgression shaped human evolution, yet most insights have been gained from present-day genomes, leaving little known about how archaic variants evolved after interbreeding. Ancient genomes offer a direct view of this process, but low coverage and poor quality have limited their use. Recent advances in genotype imputation offer a way to overcome these challenges by reconstructing missing information from reference panels and recovering evolutionary signals from low-coverage data. Here, we show that imputation enables accurate detection and quantification of archaic introgression in ancient genomes, improves local archaic ancestry inference, and that regions of archaic ancestry are imputed with especially high accuracy. We further demonstrate that imputed genomes can reconstruct the trajectories of introgressed haplotypes, distinguish populations across time and geography, and identify both known and additional candidates for adaptive introgression.
A chromatin-informed transcriptional regulatory framework to stratify patients and guide therapy selection in triple-negative breast cancer
Surfaceome CRISPR activation screening uncovers ligands regulating tumor sensitivity to NK cell killing
Leaf development regulates state transition capacity in trees
Abstract State transitions (ST) balance excitation energy between photosystem I and II. This process has been extensively studied in Arabidopsis but the regulation and physiological significance of ST in other angiosperms remain largely unknown. Here, we investigate ST in hybrid aspen and other tree species using physiological, biochemical, ultrastructural, and genetic approaches. We discover a pronounced canopy gradient in greenhouse-grown aspens, with young, upper leaves exhibiting substantially higher fluorescence-derived state-transition capacity (qT) than lower, older leaves. Seasonal monitoring of field-grown trees reveals a conserved developmental decline in qT across species. Reduced qT correlates with increased grana stacking and lower LHCII/PSII ratios, but not with LHCII phosphorylation, suggesting developmental remodeling of thylakoid architecture may influence the functional reorganization of PSII antenna connectivity during state transitions. Using the serine/threonine protein kinase (STN7) knockout mutant characterized outside Arabidopsis , we show that aspens lacking ST exhibit altered PSI/PSII ratios, reduced PSII operating efficiency in young leaves, and slower growth under greenhouse conditions with naturally variable light conditions but not under constant-light climate room condition. These findings indicate that ST is important for performance under dynamic light conditions, particularly in young leaves, and reveal a previously unrecognized developmental control of photosynthetic regulation.
MBNL depletion drives stem cell fusion and immature myonuclear states in myotonic dystrophy type 1
Abstract Myotonic dystrophy type 1 is caused by the expression of expanded CTG repeats in the DMPK gene and the resulting loss of function of MBNL protein. Affected skeletal muscle displays abundant centrally located nuclei despite limited immune-cell–associated fibre necrosis, complicating interpretation of muscle damage and remodelling mechanisms. Here we show that muscle stem cells are activated and fuse with existing muscle fibres in myotonic dystrophy type 1. Single-nucleus transcriptomics in patient’s muscle identifies increased activated muscle stem cells and distinct myonuclear populations exhibiting transitional transcriptional states, including muscle stem cell associated markers and elevated DMPK expression. Myofibre-specific MBNL knockdown mouse models demonstrate that muscle stem cell fusion contributes to central nucleation, whereas their deletion does not improve myotonia or muscle strength. Together, these findings indicate that loss of MBNL function in muscle drives myonuclear accretion through stem cell-mediated fusion, giving rise to myonuclei with immature states in myotonic dystrophy type 1.
Longer-lived mammals exhibit greater evolutionary conservatism and epigenetic modification at cancer-associated loci
Regional diversity of cranial skeletal stem cells governs bone morphogenetic protein-2 mediated bone regeneration
Abstract Skeletal stem cells (SSCs), originally identified in 2015, are increasingly understood to exhibit significant heterogeneity throughout the body. Cranial SSCs provide a unique model to investigate this diversity because cranial bones arise from both neural crest and mesoderm, unlike mesoderm-derived long bones. Here, we show that cranial SSCs possess anatomically defined transcriptomic and functional heterogeneity. Through comprehensive in vitro and in vivo functional assays combined with targeted gene expression analyses by qPCR, we demonstrate that cranial SSCs exhibit region-specific transcriptional signatures and lineage biases that influence their osteogenic and chondrogenic capacities. Temporal analysis further reveals that SSCs progressively outnumber progenitor cells with age, suggesting that the SSC-to-progenitor ratio may serve as an indicator of skeletal developmental and regenerative potential. Finally, we demonstrate that SSC heterogeneity critically influences bone regeneration in response to Bone Morphogenetic Protein-2 in vitro and in vivo, supporting the need for region-specific optimization of BMP-2-based regenerative therapies.
Room-temperature ferroelectrically switchable quantum geometry in few-layer WTe2 for complementary in-memory computing
Population-scale disease-associated tandem repeat analysis reveals locus and ancestry-specific insights
Glycoprotein-induced phase separation drives unconventional secretion of galectin-3
Abstract The mechanism of unconventional protein secretion remains an unresolved issue. Here, we describe an unconventional protein secretion pathway for galectin-3 that is mediated by phase separation and condensation. Using four lysosomal damage models, we observed a rapid, pronounced release of galectin-3 in large, non-exosomal particles. This secretion is driven by glycoprotein-induced galectin-3 phase separation and is independent of pyroptosis and secretory autophagy. During phase separation, the S-face of galectin-3 carbohydrate recognition domain binds glycoproteins that triggers galectin-3 N-terminal tail release and condensation. These condensates then recruit ALG-2 via the exposed N-terminal tail. ALG-2 directs the condensates to the endoplasmic reticulum–late endosome interface. After translocation into late endosomes, galectin-3 condensates are secreted into the extracellular milieu by SNARE-dependent vesicular transport. This mechanism of exporting phase-separated protein condensates may serve as a clean-up response to membrane damage.
Retraction Note: Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
Strategic timing for the decarbonization contributions by China’s photovoltaic manufacturers in global energy transition
Abstract Photovoltaic (PV) technology is central to clean electricity and the Sustainable Development Goals. However, China’s PV manufacturing industry, which accounts for nearly two-thirds of global capacity, is often criticized for its high carbon emissions. Existing studies typically assign emission responsibility to manufacturers while attributing decarbonization benefits to power generation, overlooking upstream producers’ contributions. Here we propose a Producer Decarbonization Contribution framework to quantify these long-overlooked contributions at national and global scales. We show that China’s PV manufacturers contribute 31.4%-73.8% of total PV decarbonization in China and 27.9%-45.4% globally. We further identify a strategic timing, defined as the point at which the PV’s decarbonization contributions reach their maximum, occurring around 2035 in China under the Announced Pledges Scenario and 2030 globally under the Net Zero Emissions Scenario proposed by the International Energy Agency. These findings suggest maintaining supportive policies for China before 2035, while adopting more stringent measures globally after 2030 to avoid overproduction. The proposed framework that enables adaptive industrial policy design can be extended to other renewable energy technologies.
Dilute electrolytes for suppressing metal anode corrosion during calendar aging and cycling in aqueous zinc batteries
Abstract While numerous improvements in cycling stability have been demonstrated for next-generation battery chemistries with metallic anodes, their calendar aging (e.g., capacity loss during idle periods of rest) performance painfully lags behind and remains a critical bottleneck hindering their practical deployment. In contrast to their commercial counterparts, metallic anodes exhibit substantial capacity loss during calendar aging. Despite several recent studies exploring the underlying reasons for calendar aging, few solutions have been proposed to mitigate this key issue. Here, we design a low concentration electrolyte (0.1 M ZnSO 4 ) that can reduce calendar aging losses in Zn metal chemistries by more than an order of magnitude (<1.5% capacity fade after 24 hours of aging) while still maintaining improved cycling stability (>3300 cycles at 4 C) with an average Coulombic efficiency of 99.8%. We find that solvated water molecules (rather than unsolvated water molecules) drive Zn corrosion, motivating our effort to minimize these reactive solvated water molecules through a holistic approach centered around concentration reduction, aided by isotopic solvent substitution and targeted additives. This strategy could be applicable to other battery chemistries and provides an approach that can address both calendar aging and cycling stability, both of which are necessary for practical applications.
Enhanced spin-to-charge conversion in epitaxial La0.67Sr0.33MnO3/NdNiO3 bilayers at the nickelate metal-insulator phase transition
Abstract Phase transition materials such as NdNiO 3 (NNO) when coupled with low damping ferromagnets such as La 0.67 Sr 0.33 MnO 3 (LSMO) hold the promise for developing new multi-functional material systems harnessing the interplay of charge, spin, and orbital degrees of freedom. In this study, we probe the evolution of spin-to-charge conversion in epitaxial all-oxide LSMO (12 nm)/NNO (4, 8, and 16 nm) bilayers. Using spin pumping ferromagnetic resonance, we track the spin-to-charge conversion within the NNO layer through the paramagnetic metal to antiferromagnetic insulator transition and observe a pronounced enhancement of the inverse spin Hall effect signal at the onset of this phase transition. We attribute this enhancement to the electronic and magnetic disorder in NNO at the first-order phase transition, thereby providing insights into the mechanism of spin transport through the phase transition. The tunability of spin-to-charge conversion in this low damping bilayer system offers a pathway for developing reconfigurable, energy-efficient spintronic devices.
Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven drug-resistance in GIST
Abstract Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.
Ribosomal architecture and rRNA modification landscape in the tick-borne parasite Babesia divergens
Abstract Babesia are tick-borne intracellular apicomplexan parasites that infect a wide range of wild and domestic animals (e.g., cattle), resulting in significant economic losses to the livestock industry. Humans are considered accidental hosts for a few Babesia species. Babesia microti and B. divergens are the most prevalent causes of human babesiosis that are showing a broadening geographic distribution. Due to the complex life cycle of Babesia species, their survival depends on the precise control of gene expression, which is primarily regulated by epigenetic, transcriptional, and post-transcriptional mechanisms. High-resolution structural information on key components of the translation machinery, such as ribosomes, could aid in the development of antiparasitic drugs. Here, we report cryogenic electron microscopy ribosome structures from B. divergens , showing associated tRNAs, an mRNA fragment, and RACK1, a signaling scaffold crucial to translation regulation. Density map analysis displays ribosome regions at high resolution, which, when combined with nanopore sequencing, enabled the comprehensive identification of rRNA modifications. The rRNA modifications localize not only to the reduced B. divergens rRNA expansion segments but also to functionally essential ribosomal sites.
α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson’s disease
Abstract The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson’s disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson’s disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson’s disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson’s disease.