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Oriented diffusion tailors interfacial strain-polarization coupling for broadband electromagnetic absorption
Small-molecule binding and sensing with a designed protein family
Abstract The de novo design of small-molecule–binding proteins holds great promise as a potential tool to develop sensors on-demand for arbitrary small molecules. Here we combine deep learning and physics-based methods to generate a family of proteins with diverse and designable pocket geometries, which we employ to computationally design binders for six small-molecule targets. Biophysical characterization of the designed binders reveals nanomolar to low micromolar binding affinities and atomic-level design accuracy. Additionally, we use a cortisol binder to design a chemically induced dimerization (CID) system that enables the construction of a biosensor for cortisol detection. The approach described here demonstrates the potential of the NTF2 fold and deep learning-based protein design in sensor development, paving the way for future platforms to design binders and sensors for small molecules across analytical, environmental, and biomedical applications.
Zanubrutinib-rituximab followed by shortened chemoimmunotherapy as frontline treatment for mantle cell lymphoma (CHESS): a phase II trial
Neoantigen evolution and response to checkpoint inhibitor immunotherapy in colorectal cancer
Structural basis for pH-responsive amino acid transport via SLC7A4.
Abstract The transport of amino acids across cell membranes is essential for metabolism, neuronal signalling, and immune system function. The amino acid polyamine organocation (APC) superfamily controls amino acid transport via mechanisms including amino acid exchange, facilitative diffusion, and sodium- or proton-coupled transport. Although many mammalian APC members functioning as exchangers and sodium-coupled systems have been identified, the mechanisms underlying pH-regulated amino acid transport in mammalian cells remain unclear. Here, we show that the plasma membrane amino acid transporter SLC7A4 is regulated by low extracellular pH and functions as a leucine transporter in human cells. Using Cryo-EM structures of the plant homologue, CAT4, from Arabidopsis thaliana in outward-open apo and L-ornithine-bound states, as well as transport assays and molecular dynamics simulations based on homology models of the human transporter, we identify residues responsible for amino acid selectivity that supports an allosteric mechanism linking ligand recognition to pH regulation. This mechanism is consistent with an evolutionary link to proton-coupled prokaryotic homologues. Overall, our findings provide a structural and functional basis for pH-gated leucine transport by the human SLC7A4 transporter and provides a framework for understanding amino acid selectivity within the wider SLC7 family.
IL-22 induces Paneth cell metaplasia in the colonic epithelium of ulcerative colitis, promoting wound healing via REG3A
Role of the primate ventral striatum as a neural hub bridging option valuation and action selection
Abstract Making appropriate decisions relies on the brain’s capacity to evaluate the expected outcomes of available options and select the most rewarding action. The ventral striatum and midbrain dopamine neurons have been implicated in the option valuation process, consistent with the brain’s reinforcement learning theory in which these brain structures encode and update value representations of expected outcomes. Extending beyond this framework, we found that the dopamine–ventral striatum system plays a more proactive role in action selection. We recorded single-unit activity from ventral striatum neurons in macaque monkeys as they sequentially evaluated an option, decided whether to perform an action to choose it, and expressed that motor action. The activity of these neurons initially reflected the value of the option but gradually shifted to reflect monkey’s action selection, as if the ventral striatum translates the value information into the action. Moreover, optogenetic facilitation of dopamine input to the ventral striatum as well as electrical stimulation of this region altered monkey’s action selection. Our findings reveal a previously unappreciated function of the ventral striatum as a neural hub that bridges option valuation and action selection, and demonstrate the contribution of dopamine in the process leading to action selection within this region.
Ultrasmall oral Saccharibacteria modulate gingival immunoactivation through type IV pili and TLR2-dependent endocytosis
A bridge-like lipid transfer protein is critical for generation of invasive stages in malaria parasites
Abstract Malaria blood stages build and maintain an intricate system of membranes during their cycle of rapid growth and schizogony (daughter-cell formation), requiring precise mechanisms of lipid synthesis and trafficking. Lipid transfer proteins (LTPs) at ER membrane contact sites (MCSs) have emerged as key for lipid distribution processes but remain largely unexplored in protozoans. Here we use the ER adapter VAP to identify essential mechanisms of lipid transfer at ER-MCSs in P. falciparum . One PfVAP-interacting LTP is the bridge-like PfVPS13L1, which allows bulk flow of lipids between two apposed membranes. PfVPS13L1 bridges the ER with the nascent inner membrane complex (IMC), a de novo-generated organelle required for schizogony. Its loss-of-function reduces IMC growth and leads to smaller anucleated progeny, impairing schizogony. Our data supports a model in which VPS13L1 is critical for the formation of apicomplexan invasive stages by mediating bulk transfer of lipids from the ER to the growing IMC.
Hydrogen transfer-triggered C(sp3)−C(sp3) cleavage of 1,3-diols for mono-N-methylation of primary amines
CBP phosphorylation maintains intestinal homeostasis by supporting the stem cell niche through versican
Abstract CREB-binding protein (CBP) is a transcriptional coactivator, and we reported its phosphorylation regulates cell fate. Impaired CBP phosphorylation alters its binding preference for p53 in CBP AA mice, leading to distal colonic abnormalities. These changes are accompanied by reduced expression of versican, an extracellular matrix component that supports the intestinal stem cell niche, leading to impaired intestinal epithelial cell (IEC) proliferation and organoid formation. Deleting p53 in the IECs of CBP AA mice ( CBP AA p53 ΔIEC ) restores versican expression and reverses the colonic phenotype. Versican replenishment and phosphomimetic CBP mutants rescue versican expression and IEC stemness in CBP AA organoids. Importantly, colonic tissues from ulcerative colitis patients exhibit impaired CBP phosphorylation, increased CBP–p53 binding, decreased versican expression and IEC proliferation, highlighting the clinical relevance of this phenomenon. In this work, we demonstrate CBP phosphorylation safeguards intestinal homeostasis by maintaining the stem cell niche through versican, highlighting versican as a potential therapeutic target for inflammatory bowel disease.
Photo-electrochemical reduction of PFAS in complex water matrices
Two-dimensional crystals catalyse hydrogen into protons
The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment
Emerging energy signals advance early warnings of extreme precipitation
Asymmetric hydrophilicity-driven fast water diffusion enabling heterogeneous hygroscopic gels toward high-yield atmospheric water harvest
Unlocking the reactivity of difluoroketene and its synthetic applications
Underestimated barrier effects of ocean fronts shape global fishery distribution
Abstract Marine ecosystems exhibit high spatiotemporal heterogeneity, making it crucial to understand the mechanisms sustaining biological hotspots. Ocean fronts shape local biogeochemical processes and have long been recognized as biological hotspots aggregating organisms from phytoplankton to top predators and attracting fisheries (hotspot effects). However, fronts also exhibit pronounced environmental differences between their two sides (barrier effects), and how species and fishery distributions respond to these effects remains poorly understood. By integrating satellite-based front detection with commercial catch records, fishery-independent surveys, and global fishing datasets, we show that fishery distributions across diverse regions and major commercial stocks worldwide respond strongly to barrier effects, exhibiting 15–70% differences in distribution between the frontal warm and cold zones, driven by species-specific local thermal preferences. In contrast, responses to hotspot effects are generally sporadic with only 5–20% differences between frontal and non-frontal zones, and they emerge only when aggregations on one side of fronts offset avoidance on the other. This offset has led earlier studies to conservatively underestimate front-induced fishery variations by 55–75%. Our findings complement the traditional front-induced hotspot paradigm by clarifying the importance of barrier effects and underscore the need to reassess the role of ocean fronts in marine ecosystems.
Iminium-linked hyperporphyrin covalent organic framework mediates type I photodynamic therapy via a photoredox process
Abstract Most photosensitizers (PSs) mediate type II photodynamic therapy (PDT) via energy transfer to produce singlet oxygen. However, this mechanism is oxygen-dependent and less effective in hypoxic tumors. Type I PDT, which generates radical reactive oxygen species such as superoxide through electron transfer, is more hypoxia-tolerant, yet molecular design strategies remain limited. Herein, we report an iminium-linked hyperporphyrin covalent organic framework (IH-COF) that facilitates efficient type I PDT via a photoredox process. In a one-pot synthesis, trimethyloxonium tetrafluoroborate simultaneously quaternizes imine bonds to introduce electron acceptors and protonates porphyrins, red-shifting the Q-band to 725 nm via the hyperporphyrin effect. Mechanistic studies reveal that photoinduced electron transfer from hyperporphyrin units to iminium ions generates α-amino radicals, which reduce oxygen to superoxide while regenerating iminium ions. The oxidized hyperporphyrins are then reduced by biomolecules such as 1,4-dihydronicotinamide adenine dinucleotide, sustaining the photocatalytic cycle. Consequently, IH-COF exhibits excellent PDT performance under both normoxic and hypoxic conditions and elicits potent antitumor efficacy in colorectal and triple-negative breast cancer models in female mice. This study highlights the potential of COFs as versatile and biocompatible platforms for synergistic photomedicine applications.