Nature最新文献

Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and have critical roles in virtually every eukaryotic cellular process¹. IDRs exist in a broad ensemble of structurally distinct conformations. This structural plasticity facilitates diverse molecular recognition and function^2-4. Here we combine advances in physics-based force fields with the power of multi-modal generative deep learning to develop STARLING, a framework for rapid generation of accurate IDR ensembles and ensemble-aware representations from sequence. STARLING supports environmental conditioning across ionic strengths and demonstrates proof of concept for the interpolative ability of generative models beyond their training domain. Moreover, we enable ensemble refinement under experimental constraints using a Bayesian maximum-entropy reweighting scheme. Beyond ensemble characterization, STARLING sequence representations can be used in multiple ways. We showcase two examples: first, STARLING lets us perform ensemble-based search for 'biophysical look-alikes'. Second, we demonstrate how these latent representations can be used to accelerate ensemble-first sequence design from weeks or hours per candidate to seconds, enabling library-scale designs. Together, STARLING dramatically lowers the barrier to the computational interrogation of IDR function through the lens of emergent biophysical properties, complementing bioinformatic protein sequence analysis. We evaluate the accuracy of STARLING against extant experimental data and offer a series of vignettes illustrating how STARLING can enable rapid hypothesis generation for IDR function and aid the interpretation of experimental data.

Colloidal perovskite nanocrystal (PeNC) has long been synthesized using the hot-injection method and room-temperature ligand-assisted reprecipitation as the prominent techniques^1,2. However, both methods have challenges for industrial-scale production^3-5: the hot-injection method requires high temperatures, an inert gas environment and rapid cooling, which raise safety concerns, whereas ligand-assisted reprecipitation can exhibit limited productivity on scale-up. Here we present a cold-injection method based on pseudo-emulsion, enabling scalable synthesis of PeNCs with near-unity photoluminescence quantum yield (PLQY, ~100%) and enhanced stability by injecting precursor solution below 4 °C. In the cold-injection method, PeNCs grow through the assembly of fully coordinated plumbates out of the pseudo-emulsion with the assistance of a demulsifier. We discovered that slow assembly of polybromide plumbates, assisted by cold temperature, is essential for defect suppression, resulting in reproducible, stable and pure-green-emitting PeNCs with near-unity PLQY. Furthermore, this method enables efficient large-scale production, achieving 20-l-scale synthesis with remarkable batch weight while maintaining near-unity PLQY. Our findings represent a substantial advancement in synthesis of high-quality PeNCs, offering potential for broad applications in display and lighting industries.

Triple-negative breast cancer (TNBC) is frequently associated with metastatic relapse, even at an early stage¹. Here we assessed an individualized neoantigen mRNA vaccine in 14 patients with TNBC following surgery and after neoadjuvant or adjuvant therapy. In peripheral blood of nearly all patients, high-magnitude, vaccine-induced, mostly de novo T cell responses to multiple neoantigens were detected that remained functional for several years. Characterization of individual patients revealed that a large proportion of these T cells developed into two subsets: a late-differentiated phenotype with markers indicative of 'ready-to-act' cytotoxic effector T cells, and T cells with a stem cell-like memory phenotype. Eleven patients remained relapse-free for up to six years post-vaccination. Recurrence occurred in three patients: the individual with the weakest vaccine-induced T cell response relapsed, but achieved complete remission on subsequent anti-PD-1 therapy; another patient had a tumour with low major histocompatibility complex (MHC) class I expression with MHC class I-deficient cells growing out under vaccination; and the third patient was BRCA-positive and had a recurrence from a genetically distinct primary tumour. These findings demonstrate the feasibility of individualized RNA vaccines in TNBC, document persistence of vaccine-induced, functional neoantigen-specific T cells and provide insights into possible immune escape mechanisms that will guide future approaches.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy¹. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth^2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

Telecommunication systems are evolving towards ultrawide bandwidth and low latency, supporting wired and wireless links and their non-blocking interconnection¹. However, a long-standing bandwidth mismatch between fibre communication and its wireless counterpart arises from fundamental disparities in signal architectures and hardware constraints^2,3, which prevent high-speed and compatible transmission across the two domains. This challenge further complicates unified system design and hinders the realization of high-throughput-density, congestion-free fibre-wireless links under wideband-access scenarios⁴. Here we present an ultra-wideband (UWB) integrated photonics scheme that facilitates fibre-wireless communication over a shared-bandwidth infrastructure. Built on electro-optic (EO) and optic-electro (OE) conversions featuring 3-dB operational bandwidths exceeding 250 GHz and cross-architecture adaptability, our system demonstrates unprecedented data transmission capabilities in both wired and wireless links. Using the same set of devices and powered by the proposed complex bidirectional gated recurrent unit (complex-biGRU) algorithm, ultrahigh single-lane data rates of 512 Gbps for short-reach fibre and, for the first time to the authors' knowledge, 400-Gbps high-speed wireless transmission have been achieved. Furthermore, high-density access is enabled by an all-optically assisted ultra-broadband wireless scheme. Real-time multichannel 8K video transmission is successfully demonstrated across 86 channels, seamlessly using a spectral range from 138 to 223 GHz. These findings in unified telecommunication development show the potential for the development of high-speed, densified and low-latency communication networks.