Science Advances最新文献

Fibroblasts are dynamic structural cells that direct both beneficial tissue repair and pathological organ fibrosis through interactions with tissue-resident type 2 lymphocytes (T2Ls) and type 3/17 lymphocytes (T3Ls). The cytokines interleukin-13 (IL-13) and IL-17A, produced by T2Ls and T3Ls, respectively, are linked to both tissue inflammation and fibrosis, but how their spatial positioning influences beneficial or pathological organ remodeling remains unclear. Using mouse models of liver injury and fibrosis, three-dimensional microscopy, and spatial transcriptomics, we found an accumulation of periportal and fibrotic tract T2Ls, predominantly group 2 innate lymphoid cells (ILC2s), positioned near T3Ls and niche adventitial fibroblasts and adjacent to discrete profibrotic myofibroblasts. Unexpectedly, T2L ablation worsened both carbon tetrachloride- and bile duct ligation-induced liver fibrosis, accompanied by increased IL-17A⁺ T3Ls, predominantly γδ T cells. In contrast, concurrent T2L and T3L ablation reduced liver fibrosis. Our work suggests a spatially associated cross-talk between liver lymphocytes and fibroblast niches that tunes liver repair but can go awry in pathological liver fibrosis.

Although energy density and cycling stability remain central to lithium metal battery (LMB) research, particularly in solid-state systems, two critical yet underappreciated challenges are wide-temperature operability and recyclability. These key parameters are fundamentally governed by electrolyte design. Here, we introduce a persistent-range hydrogen-bonded (PHB) gel polymer electrolyte (GPE) for LMBs. Constructed via continuous hydrogen-bonding interactions between perfluorinated branches and ─NH─ groups on fluorinated polyurethane backbones, this dynamic network architecture synergizes seemingly incompatible properties: chemically cross-linked-level mechanical robustness and chemical stability, alongside physically cross-linked-level dynamicity and ionic conductivity (8.6 mS cm^-1 in regular carbonate electrolytes). The resulting PHB-GPE endows Li-metal pouch cells with stable cycling across a -60° to 100°C temperature range. Moreover, PHB-GPE exhibits recyclability potential, enabling the reuse of the Li salt and polymer at the end of battery life. These findings provide transformative insights into designing multifunctional GPE structures for next-generation LMBs, addressing both performance and sustainability imperatives.

Selective separation of like-charged ions is a central challenge in applications such as critical mineral recovery. Electrochemical membrane-based separations offer promising pathways to address this need, but a limited fundamental understanding of ion transport in charged polymer membranes hampers the development of highly selective materials. This study elucidates the role of specific ion effects (SIEs) in ion transport through charged polymer membranes by integrating experimental measurements of ion mobility and in situ ion/ion and ion/water interactions in model charged polymer membranes with results from molecular dynamics simulations on analogous systems. We demonstrate that solvent-mediated ion interactions drive pronounced SIEs within the studied membranes, with the ion softness, i.e., the malleability of ion hydration shells, from hard/soft acid/base (HSAB) theory emerging as a key predictor of transport properties. HSAB theory also explains the observed mechanism of solvent-mediated ion interactions. Our findings offer a mechanistic framework for designing membranes with tailored ion selectivity, potentially enabling efficient separations of chemically similar ions.

Commonly expressed at developmental transitions, microRNAs operate as fine-tuners of gene expression to facilitate cell fate acquisition and lineage segregation. Nevertheless, how they might regulate the earliest developmental transitions in early mammalian embryogenesis remains obscure. Here, in a strictly in vivo approach based on genetically engineered mouse models and single-cell RNA sequencing, we identify microRNA-203 (miR-203) as a critical regulator of timely progression in preimplantation mouse embryos. Genetically engineered mouse models including a generated embryonic reporter (early embryo reporter) transgenic mouse carrying murine endogenous retrovirus-L (MERVL)-Tomato and SRY-box 2 (Sox2)-green fluorescent protein transgenes show that loss of miR-203 slows down early preimplantation development leading to the accumulation of embryos with high expression of totipotency-associated markers, including MERVL endogenous retroviral elements. A combination of single-cell transcriptional studies and epigenetic analyses identified histone acetylases including the central coactivator and histone acetyltransferase EP300 as critical miR-203 targets in the control of cell specification in early embryos. These data suggest that miR-203 carves the epigenetic rewiring required for early developmental transitions, allowing a timely and correctly paced development, at least partially by fine-tuning EP300 levels.

Bats serve as critical reservoirs of zoonotic pathogens but also play essential ecological roles. To mitigate spillover risks without harming bat populations, we developed a multiroute vaccination strategy using recombinant vesicular stomatitis virus (rVSV)-based vaccines. Vaccine-carrying mosquitoes delivered rVSV-based rabies and Nipah vaccines, conferring protection in rodent and bat models. Under simulated natural conditions, cohabitation with vaccine-carrying mosquitoes elicited strong immune responses in bats, supporting feasibility beyond laboratory settings. As a complementary approach, saline traps exploiting bats' mineral-seeking behavior achieved comparable immune protection through oral vaccination. Together, these results demonstrate a flexible, ecology-informed vaccination platform for immunizing wild bats, offering a scalable strategy to reduce zoonotic spillover risk while supporting bat conservation.

Heterogeneity in cancer gene expression is typically linked to genetic and epigenetic alterations, yet the extent of contribution from posttranscriptional regulation remains unclear. Here, we systematically measured messenger RNA (mRNA) dynamics across diverse breast cancer models, revealing that mRNA stability substantially shapes gene expression variability. To decipher these dynamics, we developed GreyHound, an interpretable multimodal deep-learning framework integrating RNA sequence features and RNA binding protein (RBP) expression. GreyHound identified an extensive network of RBPs and their regulons underlying variations in mRNA stability, including a regulatory axis centered on RBP RBMS3 and redox regulator TXNIP. RBMS3 depletion resulted in targeted transcript destabilization-associated with poor clinical outcomes and enhanced metastatic potential in xenograft models. In vivo epistasis studies confirmed that RBMS3-mediated regulation of TXNIP mRNA stability drives this metastasis-suppressive program. These findings identify a key posttranscriptional mechanism in breast cancer and illustrate how interpretable models of RNA dynamics can uncover regulatory programs in disease.

Mid-Paleozoic oceanic anoxic events (OAEs) have long posed an enigma, with their drivers and dynamics being markedly distinct from the hyperthermal-related events of later eras. Here, we investigate a prominent mid-Silurian OAE, which was associated with the Ireviken Extinction Event and coincided with a cooling climate. We apply Fe speciation, redox-sensitive trace metals, and elemental weathering proxies, alongside sedimentological records and coupled uranium-molybdenum isotope analyses, to deep shelf and basinal sections from the UK. These data demonstrate a gradual spread of anoxia from basinal to shelfal settings, which we postulate was driven by an enhanced nutrient supply delivered via cooling-induced upwelling. Isotope mass balance modeling supports a major increase in the extent of deeper water ferruginous conditions at this time, while euxinia developed on the continental shelf, stressing the shallower water biota. A subsequent transition to ferruginous anoxia occurred on the shelf during the later stages of the event, as climatic conditions recovered and terrestrial chemical weathering rates increased. These changes, occurring when the ocean was poised at a lower redox state under the prevailing, low atmospheric oxygen levels of the mid-Paleozoic, led to OAE dynamics that were markedly different to those of the Mesozoic.

Functional persistence of chimeric antigen receptor T cells (CAR T cells) is limited by conventional CAR T cell manufacturing using anti-CD3/CD28 (αCD3/28) stimulation, which generates terminally differentiated and shorter-lived CAR T cells. We demonstrated that HCW9206, a unique protein scaffold linking interleukin-7 (IL-7), an IL-15/IL-15 receptor α (IL-15Rα) complex, and IL-21, generates CAR T cells without requiring αCD3/28 activation, which are highly enriched in long-lived T memory stem cells (T_SCM cells) (>50%) and display potent activity across distinct disease models, HIV-1 or B cell leukemia. In a humanized mouse HIV infection model, HCW9206-generated anti-HIV duoCAR T cells suppressed viremia more effectively than αCD3/28-generated anti-HIV duoCAR T cells. In a xenograft leukemia mouse model, a recall proliferative response and complete clearance of leukemia rechallenge were displayed by HCW9206-generated but not by αCD3/28-generated anti-CD19 CAR T cells. HCW9206, a first-in-class cytokine scaffold-based platform, enables production of more potent CAR T cell-based immunotherapies by generating a CAR T cell population, which is highly functional and also markedly enriched for long-lived T_SCM cells. This strategy is broadly applicable to increase persistence and functionality of CAR T cells, enhancing their efficacy for treating infectious disease and cancer.

Ultrahigh magnetic fields enable substantial advancements across a wide range of scientific disciplines. Traditionally, steady fields above 40 tesla have been achievable only with large resistive magnets that consume megawatts of power. Here, we demonstrate peak fields of 38 and 42 tesla using two compact all-HTS magnets, composed of two and four pancake coils, respectively. These magnets achieve current densities of up to 2257 amps per square millimeter and feature an exceptionally small bore diameter of 3.1 millimeters. Furthermore, the magnet coils are small enough to fit in the palm of a hand and consume less than 1 watt of power. Such compact magnets are realized through specialized winding methods that enable seamless winding over the small diameter while preserving the current-carrying capacity of the HTS tape. Nuclear magnetic resonance (NMR) experiments were performed inside the 3-millimeter magnet bore to provide calibration points for Hall sensors. These results show the potential of compact all-HTS magnets to enable widely accessible high-field NMR and other applications.