CD4+ regulatory T cells (Treg cells) are essential for immune tolerance1. Peripherally induced Treg cells (pTreg cells) complement thymic Treg cells by broadening Treg cell reactivity in response to a changing antigenic landscape2. Although both TGFβ and IL-2 synergistically promote functional pTreg cell development in vitro3-6, their combined roles in inducing pTreg cell generation in vivo have not been exploited for tolerizing immunotherapy. Here we designed an IL-2-TGFβ 'surrogate' co-agonist by creating a single-chain fusion protein between IL-2 and a low-affinity TGFβ mimic agonist derived from a helminth parasite7. This IL-2-TGFβ surrogate functions as an AND-gated co-agonist and enabled simultaneous cis-activation of IL-2-STAT5 and TGFβ-SMAD2/3 signalling specifically in T cells that express IL-2 receptors. The IL-2-TGFβ surrogate agonist robustly induced antigen-specific, functional and stable pTreg cells in vivo within peripheral lymphoid organs in mice immunized with ovalbumin (OVA) and myelin oligodendrocyte glycoprotein (MOG)35-55. The induced pTreg cells display an effector-like, actively expanding state with high RORγt expression, enabling efficient migration and suppression of intestinal inflammation. Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, suggesting a strategy for the induction of antigen-specific pTreg cells in vivo to establish immune tolerance in inflammatory, allergic and autoimmune diseases.

Sexual reproduction is ancient and ubiquitous despite its obvious disadvantages1. Theory predicts that the reassortment of alleles that results from sex is necessary for natural selection to act effectively on individual loci; therefore, a purely clonal organism should rapidly accumulate deleterious mutations and go extinct2-4. Nevertheless, many asexual species have existed for longer than theory predicts is possible5-7, such as the Amazon molly (Poecilia formosa), a clonally reproducing fish arising from a single hybridization event more than 100,000 years ago8-10. Here we show that although the Amazon molly has accumulated mutations faster than its sexual progenitor species, this has not led to functional mutational decay, defying theoretical expectations. Instead, gene conversion facilitates both adaptive and purifying selection by generating new clonal lineages in which previous mutations are either reverted or fixed, and by resolving hybrid incompatibilities between the ancestral haplotypes. The transition to clonality altered chromatin structure, but the asexual haplotypes of the Amazon molly nonetheless maintain the divergent mutational landscapes of their progenitor species. Together, these results provide new insights into long-standing questions about the trade-offs involved in asexual reproduction.

Halide perovskite light-emitting diodes promise high-efficiency1-3, low-cost optoelectronics, yet their operational instability remains a critical barrier to practical deployment. Here we develop a multimodal in situ electron microscopy approach that integrates four-dimensional scanning transmission electron microscopy, energy-dispersive X-ray spectroscopy and atomic-resolution imaging to directly visualize structural and chemical evolution in a working halide perovskite light-emitting diode with nanometre precision. Our in situ biasing measurements uncover nanoscale structural and chemical transformations initiated at transport layer interfaces, including the formation of metallic lead and lead-rich secondary phases, as well as strain-driven grain fragmentation. On biasing, we observe the partial transformation of the metallic Al contact to insulating AlCl3. Crucially, whereas the bulk of the perovskite emitter remains relatively intact, our experiment shows that degradation is localized at interfaces. By comparing in situ and ex situ measurements, these results establish a mechanistic link between interfacial strain, ionic transport and electrochemical reactions in working devices, and provide a broadly applicable framework for nanoscale degradation analysis in complex multilayered optoelectronic systems using multimodal in situ biasing microscopy.

Genome-editing technologies that use recombinases to insert kilobase-scale DNA sequences into mammalian genomes canonically require large double-stranded DNA (dsDNA) donors1,2. However, dsDNA molecules evoke problematic and toxic innate immune responses, limiting integration efficiencies and generally constraining applicability to ex vivo or immune-deficient contexts. By harnessing mechanisms of integrative prokaryotic viruses and mobile genetic elements, here we demonstrate that recombinases are compatible with immune evasive circular single-stranded DNA molecules optimally bearing a partial-duplex region that reconstitutes the recombinase recognition sequence. This approach, which we term integration through nucleus-synthesized template addition of large lengths (INSTALL), is compatible with diverse protein and RNA-guided recombinases for high-fidelity kilobase-scale human genome writing. INSTALL minimizes innate immune responses in primary human cells and in mice, improving recombinase-mediated integration efficiencies and supporting systemic in vivo non-viral DNA delivery by substantially increasing tolerability and broadening the dosing range compared with lipid nanoparticle-delivered dsDNA molecules. Together, INSTALL overcomes fundamental challenges for DNA delivery and integration methods by synergizing immune-stealth nucleic acids with recombinases to enable kilobase-scale integration strategies without viral vectors.

Subtle changes in molecular structure can lead to profound changes in molecular function. However, even minor structural refinements can require the complete resynthesis of a target molecule, adding time and cost to molecular design campaigns1. Recently, editing methods have emerged targeting subtle molecular perturbations, including atomic substitution, stereocentre inversion and functional group repositioning2. These precision tools hold the potential to streamline the optimization of molecular function by fine-tuning molecular structure. Here we report an editing method that enables the migration of common alcohol functional groups to proximal sites with predictable stereo- and regiochemical outcomes. The reaction proceeds through a 1,2-acyloxy radical migration step under reversible H atom transfer catalysis conditions promoted by the excited-state decatungstate polyanion. Proximity effects arising from non-covalent interactions between substrate and reagent enable efficient radical formation at polarity-mismatched positions. Application of this tool at a late synthetic stage allows for the precise repositioning of alcohol functional groups, whereas integration with common alcohol group installation methods provides new synthetic strategies to access challenging oxygenation patterns.

Hybrid back-contact (BC) silicon solar cells1-3 combine the strengths of tunnel oxide passivated contact (TOPCon)-derived4-7 n-type contacts, silicon heterojunction (SHJ)-derived8-12 p-type contacts and interdigitated back-contact (IBC)13,14 device structures. Although high performance in the form of 27.8% efficiency has been demonstrated1, the understanding of the fundamental advantages of the hybrid BC architecture over conventional BC cells (for example, eliminating front-surface metallization shading3) remains unexplored. Here we take advantage of the design flexibility of the hybrid BC architecture to use a multifunctional front layer for both light trapping and passivation. Meanwhile, we improved carrier collection and process compatibility of the rear carrier-selective contacts. We also show that the optimal crystalline silicon (c-Si) absorber thickness is increased to 160 μm, leading to a certified efficiency of 27.62% for industrially compatible c-Si solar cells.