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Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Abstract The diagnosis of inherited retinal degeneration (IRD) is challenging owing to its phenotypic and genotypic complexity. Clinical information is important before a genetic diagnosis is made. Metabolomics studies the entire picture of bioproducts, which are determined using genetic codes and biological reactions. We demonstrated that the common diagnoses of IRD, including retinitis pigmentosa (RP), cone-rod dystrophy (CRD), Stargardt disease (STGD), and Bietti’s crystalline dystrophy (BCD), could be differentiated based on their metabolite heatmaps. Hundreds of metabolites were identified in the volcano plot compared with that of the control group in every IRD except BCD, considered as potential diagnosing markers. The phenotypes of CRD and STGD overlapped but could be differentiated by their metabolomic features with the assistance of a machine learning model with 100% accuracy. Moreover, EYS-, USH2A-associated, and other RP, sharing considerable similar characteristics in clinical findings, could also be diagnosed using the machine learning model with 85.7% accuracy. Further study would be needed to validate the results in an external dataset. By incorporating mass spectrometry and machine learning, a metabolomics-based diagnostic workflow for the clinical and molecular diagnoses of IRD was proposed in our study.

Abstract Cell-free RNAs (cfRNAs) offer an opportunity to detect diseases from a transcriptomic perspective, however, existing techniques have fallen short in generating a comprehensive cell-free transcriptome profile. We develop a sensitive library preparation method that is robust down to 100 µl input plasma to analyze cfRNAs independent of their 5’-end modifications. We show that it outperforms adapter ligation-based method in detecting a greater number of cfRNA species. We perform transcriptome-wide characterizations in 165 lung cancer, 30 breast cancer, 37 colorectal cancer, 55 gastric cancer, 15 liver cancer, and 133 cancer-free participants and demonstrate its ability to identify transcriptomic changes occurring in early-stage tumors. We also leverage machine learning analyses on the differentially expressed cfRNA signatures and reveal their robust performance in cancer detection and classification. Our work sets the stage for in-depth study of the cfRNA repertoire and highlights the value of cfRNAs as cancer biomarkers in clinical applications.

Abstract Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Abstract Inflammasome activity is important for the immune response and is instrumental in numerous clinical conditions. Here we identify a mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that the function of ASC in assembling the inflammasome is controlled by its modification with SUMO (small ubiquitin-like modifier) and identify that the nuclear ZBTB16 (zinc-finger and BTB domain-containing protein 16) promotes this SUMOylation. The physiological significance of this activity is demonstrated through the reduction of acute inflammatory pathogenesis caused by a constitutive hyperactive inflammasome by ablating ZBTB16 in a mouse model of Muckle-Wells syndrome. Together our findings identify an further mechanism by which ZBTB16-dependent control of ASC SUMOylation assembles the inflammasome to promote this pro-inflammatory response.

Abstract Circular RNAs have been extensively studied in eukaryotes, but their presence and/or biological functionality in bacteria are unclear. Here, we show that a regulatory noncoding RNA (DucS) exists in both linear and circular conformation in Bacillus altitudinis. The linear forms promote B. altitudinis tolerance to H2O2 stress, partly through increased translation of a stress-responsive gene, htrA. The 3′ end sequences of the linear forms are crucial for RNA circularization, and formation of circular forms can decrease the levels of the regulatory linear cognates. Bioinformatic analysis of available RNA-seq datasets from 30 bacterial species revealed multiple circular RNA candidates, distinct from DucS, for all the examined species. Experiments testing for the presence of selected circular RNA candidates in four species successfully validated 7 out of 9 candidates from B. altitudinis and 4 out of 5 candidates from Bacillus paralicheniformis; However, none of the candidates tested for Bacillus subtilis and Escherichia coli were detected. Our work identifies a dual-conformation regulatory RNA in B. altitutidinis, and indicates that circular RNAs exist in diverse bacteria. However, circularization of specific RNAs does not seem to be conserved across species, and the circularization mechanisms and biological functionality of the circular forms remain unclear.

Abstract Despite considerable research efforts on photoelectrochemical water splitting over the past decades, practical application faces challenges by the absence of efficient, stable, and scalable photoelectrodes. Herein, we report a metal-halide perovskite-based photoanode for photoelectrochemical water oxidation. With a planar structure using mesoporous carbon as a hole-conducting layer, the precious metal-free FAPbBr3 photovoltaic device achieves 9.2% solar-to-electrical power conversion efficiency and 1.4 V open-circuit voltage. The photovoltaic architecture successfully applies to build a monolithic photoanode with the FAPbBr3 absorber, carbon/graphite conductive protection layers, and NiFe catalyst layers for water oxidation. The photoanode delivers ultralow onset potential below 0 V versus the reversible hydrogen electrode and high applied bias photon-to-current efficiency of 8.5%. Stable operation exceeding 100 h under solar illumination by applying ultraviolet-filter protection. The photothermal investigation verifies the performance boost in perovskite photoanode by photothermal effect. This study is significant in guiding the development of photovoltaic material-based photoelectrodes for solar fuel applications.

Abstract The oxygen evolution reactions in acid play an important role in multiple energy storage devices. The practical promising Ru-Ir based catalysts need both the stable high oxidation state of the Ru centers and the high stability of these Ru species. Here, we report stable and oxidative charged Ru in two-dimensional ruthenium-iridium oxide enhances the activity. The Ru0.5Ir0.5O2 catalyst shows high activity in acid with a low overpotential of 151 mV at 10 mA cm−2, a high turnover frequency of 6.84 s−1 at 1.44 V versus reversible hydrogen electrode and good stability (618.3 h operation). Ru0.5Ir0.5O2 catalysts can form more Ru active sites with high oxidation states at lower applied voltages after Ir incorporation, which is confirmed by the pulse voltage induced current method. Also, The X-ray absorption spectroscopy data shows that the Ru-O-Ir local structure in two-dimensional Ru0.5Ir0.5O2 solid solution improved the stability of these Ru centers.

Abstract Molecular diagnostics for crop diseases can guide the precise application of pesticides, thereby reducing pesticide usage while improving crop yield, but tools are lacking. Here, we report an in-field molecular diagnostic tool that uses a cheap colorimetric paper and a smartphone, allowing multiplexed, low-cost, rapid detection of crop pathogens. Rapid nucleic acid amplification-free detection of pathogenic RNA is achieved by combining toehold-mediated strand displacement with a metal ion-mediated urease catalysis reaction. We demonstrate multiplexed detection of six wheat pathogenic fungi and an early detection of wheat stripe rust. When coupled with a microneedle for rapid nucleic acid extraction and a smartphone app for results analysis, the sample-to-result test can be completed in ~10 min in the field. Importantly, by detecting fungal RNA and mutations, the approach allows to distinguish viable and dead pathogens and to sensitively identify mutation-carrying fungicide-resistant isolates, providing fundamental information for precision crop disease management.

Abstract Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank for clinical history and follow-up data. It is still challenging to achieve single cell/nucleus RNA (sc/snRNA) profile in FFPE tissues. Here, we develop a droplet-based snRNA sequencing technology (snRandom-seq) for FFPE tissues by capturing full-length total RNAs with random primers. snRandom-seq shows a minor doublet rate (0.3%), a much higher RNA coverage, and detects more non-coding RNAs and nascent RNAs, compared with state-of-art high-throughput scRNA-seq technologies. snRandom-seq detects a median of >3000 genes per nucleus and identifies 25 typical cell types. Moreover, we apply snRandom-seq on a clinical FFPE human liver cancer specimen and reveal an interesting subpopulation of nuclei with high proliferative activity. Our method provides a powerful snRNA-seq platform for clinical FFPE specimens and promises enormous applications in biomedical research.

Abstract Transition metal-based homogeneous photocatalysts offer a wealth of opportunities for organic synthesis. The most versatile ruthenium(II) and iridium(III) polypyridyl complexes, however, are among the rarest metal complexes. Moreover, immobilizing these precious catalysts for recycling is challenging as their opacity may obstruct light transmission. Recovery of homogeneous catalysts by conventional polymeric membranes is promising but limited, as the modulation of their pore structure and tolerance of polar organic solvents are challenging. Here, we report the effective recovery of homogeneous photocatalysts using covalent organic framework (COF) membranes. An array of COF membranes with tunable pore sizes and superior organic solvent resistance were prepared. Ruthenium and iridium photoredox catalysts were recycled for 10 cycles in various types of photochemical reactions, constantly achieving high catalytical performance, high recovery rates, and high permeance. We successfully recovered the photocatalysts at gram-scale. Furthermore, we demonstrated a cascade isolation of an iridium photocatalyst and purification of a small organic molecule product with COF membranes possessing different pore sizes. Our results indicate an intriguing potential to shift the paradigm of the pharmaceutical and fine chemical synthesis campaign.

Abstract Metastable noble metal nanocrystals may exhibit distinctive catalytic properties to address the sluggish kinetics of many important processes, including the hydrogen evolution reaction under alkaline conditions for water-electrolysis hydrogen production. However, the exploration of metastable noble metal nanocrystals is still in its infancy and suffers from a lack of sufficient synthesis and electronic engineering strategies to fully stimulate their potential in catalysis. In this paper, we report a synthesis of metastable hexagonal Pt nanostructures by coherent growth on 3d transition metal nanocrystals such as Ni without involving galvanic replacement reaction, which expands the frontier of the phase-replication synthesis. Unlike noble metal substrates, the 3d transition metal substrate owns more crystal phases and lower cost and endows the hexagonal Pt skin with substantial compressive strains and programmable charge density, making the electronic properties particularly preferred for the alkaline hydrogen evolution reaction. The energy barriers are greatly reduced, pushing the activity to 133 mA cmgeo –2 and 17.4 mA μgPt –1 at –70 mV with 1.5 µg of Pt in 1 M KOH. Our strategy paves the way for metastable noble metal catalysts with tailored electronic properties for highly efficient and cost-effective energy conversion.

Rapid and facile detection of specific nucleic acid modifications could have numerous applications. Here the authors present Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) as a generic and accessible approach, and demonstrate proof-of-principle cancer biomarker detection.

Lateral hypothalamus (LH) plays an role in drug addiction. Here, authors present evidence for disinhibited LH glutamatergic neurons by neural circuits from nucleus accumbens to contribute to context-induced expression of morphine withdrawal memory.

How functional connectivity gradients in the cortex arise and vary dynamically is not fully understood. Here the authors show that gradients are determined by structural wiring but may be modulated by arousal levels.

High-order optical nonlinearities are a key tool in photonics and quantum optics, but their use is hindered by materials’ small intrinsic high-order susceptibility. Here, the authors show how to realize high-order nonlinear processes by combining intrinsic low-order ones in a microcavity.

It is of high interest to convert CO2 into valuable ethanol product. Here the authors demonstrate the asymmetric C-C coupling triggered on Ag-modified oxide-derived Cu sites can accelerate and steer the reaction pathway for ethanol production with high faradaic efficiency and current density.

Negative pressure tailors the physical properties of functional oxide materials. Here, the authors demonstrate an emergent multiferroism with magnetodielectric coupling in EuTiO3 created by a negative pressure control of strong spin-phonon coupling.

Detecting nucleic acids often requires choosing between different amplification mechanisms. Here the authors present a generalisable and programmable isothermal methodology, demonstrated in clinical applications, including for multiplexed detection of short miRNAs.

Covalent organic framework-based membranes are highly tunable materials with potential use in a variety of applications. Here the authors report a dual-activation interfacial polymerization strategy to prepare ionic covalent organic framework membranes with high ion exchange capacity.

The applications of polyolefins are limited by the nonpolar nature of the polymer. Here the authors show a method to copolymerize ethylene with the protic vinyl acetic acid via well defined multinuclear nickel catalysts.

Human ribonuclease 1 (hRNase 1) regulates innate immunity, hemostasis and RNA clearance. Here, the authors report an alternative function of hRNase 1 as a secretory ligand of Eph receptor EphA4 to enhance breast cancer stemness and promote breast tumour initiation.

As human skeletal muscle ages, gene expression programs change and reflect damage accumulation and homeostatic resilience mechanisms. Here, the authors present a detailed framework of the global transcriptome that characterizes skeletal muscle during aging in healthy individuals.

Detailed knowledge of COVID-19 epidemiology is needed to inform public health responses. Here, the authors use large-scale contact tracing data to provide empirical estimates of key parameters, and show that susceptibility increases with age but transmissibility does not vary significantly.

High-resolution electron microscopy requires robust and noise-free substrates to support the specimens. Here, the authors present a polymer- and transfer-free direct-etching method for fabrication of graphene grids with ultraclean surfaces and demonstrate cryo-EM at record high resolution.

Proton-coupled electron transfer (PCET) process is very important for water oxidation catalysis. Here, the authors introduced uncoordinated carboxylate in the second-coordination-sphere of Ni-Fe coordination polymer catalyst as an internal base to promote the water oxidation kinetics by such PCET process.

Tetraspanin 8 (TSPAN8) has been implicated in a number of different tumours, but the underlying mechanisms remain unclear. Here, in breast cancer the authors highlight a role for TSPAN8 in promoting tumorigenesis through the activation of Hedgehog signalling.

The fabrication of defect-free covalent organic framework (COF) membranes for the separation of small molecules is challenging. Here, the authors report robust COF membranes with precise molecular sieving through a mixed-dimensional assembly, exhibiting high performance for alcohol dehydration and salt rejection.

The recycling of CO2 into storable chemicals is critical in order to mitigate climate change, although CO2’s inert nature has limited the reduction’s mechanistic considerations. Here, authors pair in-situ spectroscopy with quantum mechanics to elucidate CO2 adsorption on copper and silver surfaces.

Backscattering is one of the major factors that limit the performance of integrated nanophotonics. Here, He et al. realize topologically protected, robust and unidirectional coupling as well as optical transport on a silicon-on-insulator platform by exploiting the valley degree of freedom.

DNA damage induces checkpoints to ensure that damage is not transferred to the next generation, but the molecular pathways responsible for checkpoint recovery are not clear. Here the authors show that the nutrient sensor mTORC1 is a determinant for G2/M checkpoint recovery through regulation of cyclin B1 and PLK1 expression.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22487-4