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Gut microbiome features associated with Bifidobacterium colonization predict personalized probiotic persistence patterns
Sluggish post-garnet transformation controls slab stagnation at the uppermost lower mantle
Abstract The behavior of subducted slabs in the deep mantle is crucial for understanding Earth’s evolution and mantle dynamics. Seismic observations reveal widespread slab stagnation at around 1000 km, yet no major phase transitions have been found at that depth, leaving the underlying mechanisms enigmatic. Here we show that sluggish kinetics of the post-garnet transformation could induce a critical density deficit within subducting slabs. This deficit sustains metastable garnet over tens of millions of years, effectively stalling slabs at the uppermost lower mantle. Our results reveal that slab stagnation at this depth is transient and inherently tied to delayed phase transformation kinetics, consistent with geophysical inferences. This offers an alternative explanation for slab stagnation in a pyrolitic mantle without requiring long-standing rheological or chemical explanations alone. These findings highlight a critical, yet underexplored, role of phase transformation kinetics in slab behavior and deep mantle dynamics.
Multiparty entanglement loops in quantum spin liquids
Charting the human brain’s lifelong functional organization
TBL1X/TBL1XR1 govern β-cell identity through a PAX6-containing gene regulatory network
Abstract A main mechanism of β-cell dysfunction in diabetes is loss of identity, controlled by transcription factors that induce identity gene expression and disallowed gene repression. How transcription factors facilitate simultaneous expression and repression is not fully understood, representing a knowledge gap in diabetes research. We identify the transcriptional co-factors transducin β-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1, together TBL/R1) as crucial regulators of β-cell identity and determinants of diabetes development and progression. β-cell specific TBL/R1 knockout in mice leads to progressive hypoinsulinemia and hyperglycemia. scRNA-sequencing reveals loss of β-cells, emergence of polyhormonal cells, and reduced β-cell maturity upon TBL/R1 knockout. Interactome screens and chromatin immunoprecipitation show TBL/R1 directly regulate insulin promoter activity through a PAX6-HDAC3 gene regulatory network, evident also in human models. TBL/R1 associates with diabetes in humans, thus our study uncovers an additional regulatory layer maintaining β-cell identity crucial for diabetes development and progression.
Temporal heterogeneity shapes diffusion dynamics in complex networks
Cation-inhibitor and metal–support synergy for efficient and durable hydrogen evolution in natural seawater
Physical mechanisms governing generalization and hallucination in deep learning for imaging through scattering media
Abstract Deep learning has revolutionized computational imaging, yet its real-world deployment remains constrained by two critical challenges: poor generalization under dynamic conditions and the emergence of hallucinatory artifacts. By leveraging a physics-guided framework based on scattering media, a model system where controlled variations in light transmission matrices ( $$T$$ T ) isolates these challenges, we unravel the mechanistic interplay between generalization limits and hallucination origins. We demonstrate that a network’s generalization capacity is fundamentally bounded by its ability to accommodate distinct inverse mappings ( $${T}^{-1}$$ T − 1 ), while hallucinations arise when this capacity is exceeded, resulting in unconstrained, non-physical predictions. We also identify residual ballistic light, if not negligible, as a stabilizing anchor, enabling robust predictions under scattering variability. Integrating experimental validation with wave-optics simulations, we establish a universal framework that links these phenomena, showing that strategic training on diverse physical mappings enhances generalization while suppressing hallucinations. This work bridges physics-driven interpretability with AI design, offering actionable strategies to develop reliable models for applications ranging from medical imaging through biological tissues to autonomous navigation in scattering environments.
Fault-mediated magma propagation and triggered seismicity revealed by the 2022 São Jorge Azores unrest
Abstract Understanding failed volcanic eruptions is key to mapping magma plumbing and forecasting hazards. Faults and fractures guide magma, but their mechanisms remain unclear due to the lack of precise earthquake locations and limited 3-D fault mapping in volcanic regions. The triple-junction setting of the Azores Archipelago, where volcanic systems and seismogenic faults coexist, offers a natural laboratory to study fault–magma interactions. We analysed ~18,000 earthquakes relocated to high precision using onshore and ocean-bottom seismometers, combined with geodetic data and seismic autocorrelation imaging, during a failed 2022 eruption on São Jorge Island. A magmatic dike ascended rapidly and mostly aseismically from the upper mantle, intruding a crustal fault before stalling ~1,600 m below the surface. Seismicity indicates that magma branching and lateral fluid escape along the fault triggered an intense, months-long swarm with rotated focal mechanisms. This study demonstrates the dual role of faults in facilitating and arresting magma ascent.
The role of hydration in the removal of glyphosate (GLY) and aminomethylphosphonic acid (AMPA) by nanofiltration membranes
Abstract Nanofiltration can remove glyphosate (GLY) and aminomethylphosphonic acid (AMPA) from water via steric, Donnan, and dielectric exclusions, although the significance of dielectric exclusion resulting from hydration has not been elucidated. This study investigates the properties of hydration and its role in GLY/AMPA removal. Results show that charge and dielectric exclusions are dominant in membranes with molecular weight cut-off (MWCO) > 150 Da. The contribution of dielectric exclusion is evident when GLY and AMPA in neutral forms are partially removed (50–80%) with >150 Da membranes at pH 2. When GLY/AMPA are negatively charged (pH from 4 to 12), GLY/AMPA removal increased from 50–80 to 90%, indicating the growing contribution of both charge and dielectric exclusions. The hydration layer can be shredded at higher applied pressures, decreasing removal from 86 to 28% (GLY) and 27 to 7% (AMPA). Both molecular dynamics and Fourier-transform infrared spectroscopy (FTIR) agree on the strong hydration of GLY/AMPA especially at pH 4–6. Understanding the role of hydration in the removal of small and charged organic micropollutants is important for tuning NF membranes for water purification.
Ketogenic diet exacerbates DSS-induced colitis through a β-hydroxybutyrate-Thomasclavelia spiroformis-γδ17 T cell axis in mice
Assessing the contribution of rare DNA states to cancer mutational signatures using sequence-specific conformational fingerprinting
Superstrong and supertough biomimetic nanocellulose composites with gradient bouligand architecture
Molecular mechanisms of native ligand selectivity in catecholamine G protein-coupled receptors
Abstract Activation of G protein-coupled receptors (GPCRs) by extracellular ligands is crucial for cellular communication and modulates numerous physiological processes. Despite sharing highly similar orthosteric binding sites, catecholamine GPCRs exhibit exquisite selectivity for their native agonists, even among nearly identical chemical messengers. However, the molecular basis and evolution of receptor selectivity remain poorly understood. To elucidate the structural mechanisms of GPCR selectivity, we focus on the prototypical human β 2 -adrenergic and D 1 dopaminergic receptors, which are important drug targets and respond to the catecholamines adrenaline/noradrenaline and dopamine, respectively. Guided by structural and sequence data, we identify a small set of residues responsible for ligand selectivity. By exchanging residues at four positions in the β-adrenergic receptors and seven in the D 1 -like dopaminergic receptors, we swap the pharmacological profiles of the two subfamilies. Unexpectedly, the switch in selectivity not only involves residues interacting with the ligand, but is also controlled by regions outside the orthosteric binding site. Cryo-electron microscopy structures and computational models of the mutant receptors identify distinct molecular mechanisms contributing to selectivity in a concerted manner. Our findings provide insights into GPCR evolution and highlight strategies for protein engineering and drug design.
Discovery of a novel envelope protein derived from simian retrovirus 2 for pseudotyping retroviral vectors used for production of CAR immune cells
Abstract In this study, we develop a simian retrovirus 2 pseudotyped retrovirus (SRV2 RV) for the generation of CAR-based immune cells. The SRV2 RV exhibits superior gene transduction efficiency in both T cells and NK cells compared to feline endogenous retrovirus (RD114) pseudotyped retrovirus (RD114 RV) or vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentivirus (VSV-G LV). Among the various SRV pseudotypes tested, only the SRV2 RV successfully transduces genes into immune cells. Unlike the SRV2 RV, however, lentivirus pseudotyped with the SRV2 envelope glycoprotein (ENV) fails to mediate gene transduction into T cells. CAR-T and NK cells generated using SRV2 RV demonstrate substantial anticancer activity both in vitro and in preclinical models. In conclusion, our findings highlight the SRV2 RV as a highly effective platform for producing CAR-based immune cells.
RNA-induced PRC2 inhibition depends on the sequence of bound RNA
Abstract Methyltransferase PRC2 (Polycomb Repressive Complex 2) deposits histone H3K27 trimethylation to establish and maintain epigenetic gene silencing. PRC2 is precisely regulated by accessory proteins, histone post-translational modifications, and, particularly, RNA. Research on PRC2-associated RNA has mostly focused on the tight-binding G-quadruplex (G4) RNAs, which inhibit PRC2 enzymatic activity in vitro and in cells, a mechanism explained by our recent cryo-EM structure showing G4 RNA-mediated PRC2 dimerization. However, PRC2 binds a wide variety of RNA sequences, and it remained unclear how diverse RNAs beyond G4 associate with and regulate PRC2. Here, we show that variations in RNA sequence elicit disparate effects on PRC2 function. A G-rich RNA lacking consecutive G’s and an atypical G4 structure called a pUG-fold mediate PRC2 dimerization nearly identical to that induced by G4 RNA. In contrast, pyrimidine-rich RNAs, including a motif identified by CLIP-seq in cells, do not induce PRC2 dimerization and instead bind PRC2 monomers with retention of methyltransferase activity. Only RNAs that dimerize PRC2 compete with nucleosome binding and inhibit PRC2 methyltransferase activity. Thus, PRC2 binds many different RNAs with similar affinity; however, the functional effect on enzymatic activity depends entirely on the sequence of the bound RNA, a conclusion potentially applicable to any RNA-binding protein with a large transcriptome.
Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22
Abstract Targeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. Relatively few E3s have been successfully utilized for TPD and the governing principles of functional ternary complex formation between the E3, degrader, and protein target remain elusive. FBXO22 has recently been harnessed for TPD applications by degraders that covalently modify its cysteine residues. Here, we reveal that the aldehyde derivative of UNC10088 promotes cooperative binding of FBXO22 to NSD2, a histone methyltransferase and oncogenic protein, leading to a cryo-EM structure of the SKP1-CUL1-F-box (SCF)-FBXO22 complex with NSD2. This structure revealed a conformational change in the FBXO22 loop surrounding C326, further exposing the cysteine for covalent recruitment. Additional medicinal chemistry efforts led to the discovery of benzaldehyde-based non-prodrug degraders that similarly engage C326 of FBXO22 and potently degrade NSD2. Unlike many degraders, our molecules recruit NSD2 to a different surface of FBXO22 than the known FBXO22 substrate BACH1, allowing for concurrent complex formation and structural determination of SCF FBXO22 bound to both the neosubstrate NSD2 and native substrate BACH1. Overall, we demonstrate the biochemical and structural basis for NSD2 degradation, revealing key principles for efficient and selective TPD by SCF FBXO22 .