Search

Abstract Protoberberine alkaloids and benzophenanthridine alkaloids (BZDAs) are subgroups of benzylisoquinoline alkaloids (BIAs), which represent a diverse class of plant-specialized natural metabolites with many pharmacological properties. Microbial biosynthesis has been allowed for accessibility and scalable production of high-value BIAs. Here, we engineer Saccharomyces cerevisiae to de novo produce a series of protoberberines and BZDAs, including palmatine, berberine, chelerythrine, sanguinarine and chelirubine. An ER compartmentalization strategy is developed to improve vacuole protein berberine bridge enzyme (BBE) activity, resulting in >200% increase on the production of the key intermediate (S)-scoulerine. Another promiscuous vacuole protein dihydrobenzophenanthridine oxidase (DBOX) has been identified to catalyze two-electron oxidation on various tetrahydroprotoberberines at N7-C8 position and dihydrobenzophenanthridine alkaloids. Furthermore, cytosolically expressed DBOX can alleviate the limitation on BBE. This study highlights the potential of microbial cell factories for the biosynthesis of a diverse group of BIAs through engineering of heterologous plant enzymes.

Abstract Using a transfer printing technique, we imprint a layer of a designated near-infrared fluorescent dye BTP-eC9 onto a thin layer of Pt(II) complex, both of which are capable of self-assembly. Before integration, the Pt(II) complex layer gives intense deep-red phosphorescence maximized at ~740 nm, while the BTP-eC9 layer shows fluorescence at > 900 nm. Organic light emitting diodes fabricated under the imprinted bilayer architecture harvest most of Pt(II) complex phosphorescence, which undergoes triplet-to-singlet energy transfer to the BTP-eC9 dye, resulting in high-intensity hyperfluorescence at > 900 nm. As a result, devices achieve 925 nm emission with external quantum efficiencies of 2.24% (1.94 ± 0.18%) and maximum radiance of 39.97 W sr−1 m−2. Comprehensive morphology, spectroscopy and device analyses support the mechanism of interfacial energy transfer, which also is proved successful for BTPV-eC9 dye (1022 nm), making bright and far-reaching the prospective of hyperfluorescent OLEDs in the near-infrared region.

Abstract In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.

Abstract Millirobots must have low cost, efficient locomotion, and the ability to track target trajectories precisely if they are to be widely deployed. With current materials and fabrication methods, achieving all of these features in one millirobot remains difficult. We develop a series of graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced polymer-to-graphene conversion process; this distortion resulted in the spontaneous twisting and peeling off of graphene sheets from the polymer substrate. The lightweight nature of graphene in combine with the laser-induced porous microstructure provides a millirobot scaffold with a low density and high surface hydrophobicity. Magnetically driven nickel-coated graphene-based helical millirobots with rapid locomotion, excellent trajectory tracking, and precise drug delivery ability were fabricated from the scaffold. Importantly, such high-performance millirobots are fabricated at a speed of 77 scaffolds per second, demonstrating their potential in high-throughput and large-scale production. By using drug delivery for gastric cancer treatment as an example, we demonstrate the advantages of the graphene-based helical millirobots in terms of their long-distance locomotion and drug transport in a physiological environment. This study demonstrates the potential of the graphene-based helical millirobots to meet performance, versatility, scalability, and cost-effectiveness requirements simultaneously.

Abstract Although the motor cortex has been found to be modulated by sensory or cognitive sequences, the linkage between multiple movement elements and sequence-related responses is not yet understood. Here, we recorded neuronal activity from the motor cortex with implanted micro-electrode arrays and single electrodes while monkeys performed a double-reach task that was instructed by simultaneously presented memorized cues. We found that there existed a substantial multiplicative component jointly tuned to impending and subsequent reaches during preparation, then the coding mechanism transferred to an additive manner during execution. This multiplicative joint coding, which also spontaneously emerged in recurrent neural networks trained for double reach, enriches neural patterns for sequential movement, and might explain the linear readout of elemental movements.

Abstract CO2 fixation plays a key role to make biobased production cost competitive. Here, we use 3-hydroxypropionic acid (3-HP) to showcase how CO2 fixation enables approaching theoretical-yield production. Using genome-scale metabolic models to calculate the production envelope, we demonstrate that the provision of bicarbonate, formed from CO2, restricts previous attempts for high yield production of 3-HP. We thus develop multiple strategies for bicarbonate uptake, including the identification of Sul1 as a potential bicarbonate transporter, domain swapping of malonyl-CoA reductase, identification of Esbp6 as a potential 3-HP exporter, and deletion of Uga1 to prevent 3-HP degradation. The combined rational engineering increases 3-HP production from 0.14 g/L to 11.25 g/L in shake flask using 20 g/L glucose, approaching the maximum theoretical yield with concurrent biomass formation. The engineered yeast forms the basis for commercialization of bio-acrylic acid, while our CO2 fixation strategies pave the way for CO2 being used as the sole carbon source.

Abstract Efficient Förster energy transfer from a phosphorescent sensitizer to a thermally activated delayed fluorescent terminal emitter constitutes a potential solution for achieving superb blue emissive organic light-emitting diodes, which are urgently needed for high-performance displays. Herein, we report the design of four Ir(III) metal complexes, f-ct1a ‒ d, that exhibit efficient true-blue emissions and fast radiative decay lifetimes. More importantly, they also undergo facile isomerization in the presence of catalysts (sodium acetate and p-toluenesulfonic acid) at elevated temperature and, hence, allow for the mass production of either emitter without decomposition. In this work, the resulting hyper-OLED exhibits a true-blue color (Commission Internationale de I’Eclairage coordinate CIEy = 0.11), a full width at half maximum of 18 nm, a maximum external quantum efficiency of 35.5% and a high external quantum efficiency 20.3% at 5000 cd m‒2, paving the way for innovative blue OLED technology.

Abstract Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p‑aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.

Abstract Organic small-molecule contrast agents have attracted considerable attention in the field of multispectral optoacoustic imaging, but their weak optoacoustic performance resulted from relatively low extinction coefficient and poor water solubility restrains their widespread applications. Herein, we address these limitations by constructing supramolecular assemblies based on cucurbit[8]uril (CB[8]). Two dixanthene-based chromophores (DXP and DXBTZ) are synthesized as the model guest compounds, and then included in CB[8] to prepare host-guest complexes. The obtained DXP-CB[8] and DXBTZ-CB[8] display red-shifted and increased absorption as well as decreased fluorescence, thereby leading to a substantial enhancement in optoacoustic performance. Biological application potential of DXBTZ-CB[8] is investigated after co-assembly with chondroitin sulfate A (CSA). Benefiting from the excellent optoacoustic property of DXBTZ-CB[8] and the CD44-targeting feature of CSA, the formulated DXBTZ-CB[8]/CSA can effectively detect and diagnose subcutaneous tumors, orthotopic bladder tumors, lymphatic metastasis of tumors and ischemia/reperfusion-induced acute kidney injury in mouse models with multispectral optoacoustic imaging.

Abstract Cancer immunotherapy is revolutionizing oncology. The marriage of nanotechnology and immunotherapy offers a great opportunity to amplify antitumor immune response in a safe and effective manner. Here, electrochemically active Shewanella oneidensis MR-1 can be applied to produce FDA-approved Prussian blue nanoparticles on a large-scale. We present a mitochondria-targeting nanoplatform, MiBaMc, which consists of Prussian blue decorated bacteria membrane fragments having further modifications with chlorin e6 and triphenylphosphine. We find that MiBaMc specifically targets mitochondria and induces amplified photo-damages and immunogenic cell death of tumor cells under light irradiation. The released tumor antigens subsequently promote the maturation of dendritic cells in tumor-draining lymph nodes, eliciting T cell-mediated immune response. In two tumor-bearing mouse models using female mice, MiBaMc triggered phototherapy synergizes with anti-PDL1 blocking antibody for enhanced tumor inhibition. Collectively, the present study demonstrates biological precipitation synthetic strategy of targeted nanoparticles holds great potential for the preparation of microbial membrane-based nanoplatforms to boost antitumor immunity.

Abstract Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Within the highly proliferative neighborhood, we find that TREM2+ skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. SCAMs represent a unique tumor-specific TREM2+ population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies.

Abstract Circulating tumor cells (CTCs) are recognized as direct seeds of metastasis. However, CTC count may not be the “best” indicator of metastatic risk because their heterogeneity is generally neglected. In this study, we develop a molecular typing system to predict colorectal cancer metastasis potential based on the metabolic fingerprints of single CTCs. After identification of the metabolites potentially related to metastasis using mass spectrometry-based untargeted metabolomics, setup of a home-built single-cell quantitative mass spectrometric platform for target metabolite analysis in individual CTCs and use of a machine learning method composed of non-negative matrix factorization and logistic regression, CTCs are divided into two subgroups, C1 and C2, based on a 4-metabolite fingerprint. Both in vitro and in vivo experiments demonstrate that CTC count in C2 subgroup is closely associated with metastasis incidence. This is an interesting report on the presence of a specific population of CTCs with distinct metastatic potential at the single-cell metabolite level.

Abstract Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases.

The atomic pathway in the photoinduced ultrafast structural phase transition of VO2 has been a controversial problem for a long time. Here the authors, using MeV ultrafast electron diffraction, show that the melting of V-V dimers and the transformation of crystal symmetry are two processes with different timescales.

In this work, authors demonstrate reversible vertical alignment of Ti3C2Tx MXene sheets induced by an applied in-plane electric field. Further modulation of the field can achieve programmed patterns onto various electrode substrates.

Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins’ activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage.

This study presents seismic images across the central Tianshan. The results show that Tianshan’s crust was extensively deformed according to its inherited properties, but was limitedly underthrusted by surrounding blocks

The relationship between the charge density wave and excitonic correlations in a layered compound 1T-TiSe2 has remained controversial. Here, the authors observe a photo-induced dimensional crossover of the charge density wave and conclude that excitonic correlations are responsible for its out-of-plane phase coherence.

Isoflavonoids are a class of industrially important plant natural products, but their low abundance and structural complexity limits their availability. Here, the authors engineer Saccharomyces cerevisiae metabolism to become a platform for efficient production of daidzein which is core chemical scaffold for isoflavonoid biosynthesis, and show its application for production of bioactive glucosides from glucose.

Human RBM42 associates with the spliceosome complex. Here the authors show that the fungus counterpart of RBM42, FgRbp1 regulates splicing by interacting with FgU2AF23.

Plant and animal tissues produce nitric oxide and reactive nitrogen species that induce nitrosative stress in pathogens. Here, Jian et al. identify two transcriptional regulators in the phytopathogen Fusarium graminearum that control the nitrosative stress response by modulating the recruitment of a chromatin-remodelling complex at the promoters of the response genes.

Topological phononic (TP) materials are attracting wide attentions and it is more difficult to seek TP materials compared to electronic materials. Here, the authors present a high-throughput screening and data-driven approach to discover 5014 TP materials and further clarify the mechanism for the occurrence of various TPs.

Green synthesis of graphite is a great challenge in the absence of the graphitization of amorphous carbon at high temperatures. Here, the authors report a green approach of synthesizing graphite from carbon dioxide at low temperature in seconds timescale.

It has been reported that several phytohormones are involved in the regulation of grain weight, but the role of jasmonic acids (JA) remains elusive. Here, via bulked segregant analysis (BSA)-based cloning, the authors show keto-acyl thiolase 2B involved in β-oxidation during JA synthesis is a positive regulator of wheat grain weight.

Regeneration of corneal stroma has been a challenge due to its sophisticated structure and the easy transformation of the keratocyte. Here, the authors use a hydrogel reinforced with orthogonally aligned fibres and serum free medium to maintain keratocyte phenotype for the in vivo stromal regeneration.

Adsorption of molecules at surfaces is at the basis of many processes in chemistry. Here the authors propose an approach to determine the adsorption energies of different chemical species on a variety of solid surfaces based on fundamental and accessible properties of adsorbate and surface atoms.

Microbial production of aromatic amino acid (AAA)-derived chemicals remains an outstanding metabolic engineering challenge. Here, the authors engineer baker’s yeast for high levels p-coumaric acid production by rewiring the central carbon metabolism and channeling more flux to the AAA biosynthetic pathway.

The fungus Fusarium graminearum is a pathogen of cereal crops. Here, Liu et al. identify a transcription factor that regulates sterol biosynthesis and virulence in this organism.

Reducing aerobic ethanol production, a phenomenon referred to as the Crabtree effect, may open up new perspectives for using yeast as a cell factory. Here, the authors turn the Crabtree-positive yeast into Crabtree negative by combined engineering of cytosolic acetyl-CoA metabolism and mutating the RNA polymerase II mediator complex.

The molecular mechanisms behind the interactions between bacteria and fungi are largely unclear. Here, Chen et al. show that a compound secreted by bacteria from the wheat head microbiome inhibits growth and virulence of a plant pathogenic fungus by manipulating fungal histone modification.

The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.

Many SNPs associated with inflammatory bowel disease are located in non-coding genomic regions. Here, the authors perform CAGE-sequencing on descending colon biopsies of Crohn’s disease and ulcerative colitis patients to map transcription start sites and enhancer activity for analysis of regulatory regions.

Intrinsic limitations of nanoporous graphene limit its applications in water treatment. Here the authors produce post-treatment-free, low-cost graphene-based membranes from renewable biomass and demonstrate their high water permeance and antifouling properties using real seawater.

Esophageal squamous cell carcinoma (ESCC) exhibits differences in incidence and survival patterns among races. Here, analysis of Chinese and TCGA ESCC patients reveals that Asian patients exhibit higher TP53, EP300 and NFE2L2 mutational frequencies, and mutated CSMD3 associates with better prognosis.

mTORC1 is a critical kinase that regulates cell growth and proliferation. Here the authors show that glutamine metabolism is sufficient to restore mTORC1 activity during prolonged amino acid starvation in an autophagy-dependent manner.

The role of long noncoding RNAs in regulating T-cell differentiation within the tumour microenvironment is unclear. Here the authors identify a lncRNA that, through direct interactions with EGFR, promotes T-regulatory cell differentiation within the microenvironment of hepatocellular carcinoma, thus promoting tumour growth via immune suppression.

p53 is an oncosuppressor regulating several genes at the transcriptional level. Here, the authors identify a negative feedback loop between PHLDB3 and p53; PHLDB3 is a transcriptional target of p53 which facilitates MDM2-mediated p53 ubiquitination and degradation, impacting on tumorigenesis.

Parity-time phase transition and exceptional points contribute to the design of many components, but are hard to access due to the dispersive nature of the required materials. Here, the authors introduce a method to systematically control acoustic parity-time phase transition through an active element.

Chitin is one of the most abundant natural biopolymers and serves as a critical structural component of extracellular matrices, including fungal cell walls and insect exoskeletons. As a linear polymer of β-(1,4)-linked N-acetylglucosamine, chitin is synthesized by chitin synthases, which are recognized as targets for antifungal and anti-insect drugs. In this study, we determine seven different cryo-electron microscopy structures of a Saccharomyces cerevisiae chitin synthase in the absence and presence of glycosyl donor, acceptor, product, or peptidyl nucleoside inhibitors. Combined with functional analyses, these structures show how the donor and acceptor substrates bind in the active site, how substrate hydrolysis drives self-priming, how a chitin-conducting transmembrane channel opens, and how peptidyl nucleoside inhibitors inhibit chitin synthase. Our work provides a structural basis for understanding the function and inhibition of chitin synthase., (© 2023. Springer Nature Limited.)

The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8 + T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5 lo Ly6C - , CD5 hi Ly6C - , and CD5 hi Ly6C + cells. CD5 hi Ly6C + cells differ from CD5 lo Ly6C - and CD5 hi Ly6C - cells in terms of gene expression profiles and functional properties. Moreover, CD5 hi Ly6C + cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5 hi Ly6C + cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8 + T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8 + T cells by co-opting tonic type I interferon signaling., (© 2021. The Author(s).)

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8 + T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8 + T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8 + T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.