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Abstract Continuous directed evolution of base editors (BEs) has been successful in bacteria cells, but not yet in mammalian cells. Here, we report the development of a Continuous Directed Evolution system in Mammalian cells (CDEM). CDEM enables the BE evolution in a full-length manner with Cas9 nickase. We harness CDEM to evolve the deaminases of cytosine base editor BE3 and adenine base editors, ABEmax and ABE8e. The evolved cytidine deaminase variants on BE4 architecture show not only narrowed editing windows, but also higher editing purity and low off-target activity without a trade-off in on-targeting activity. The evolved ABEmax and ABE8e variants exhibit narrowed or shifted editing windows to different extents, and lower off-target effects. The results illustrate that CDEM is a simple but powerful approach to continuously evolve BEs without size restriction in the mammalian environment, which is advantageous over continuous directed evolution system in bacteria cells.

Abstract Investigating proton transport at the interface in an excited state facilitates the mechanistic investigation and utilization of nanomaterials. However, there is a lack of suitable tools for in-situ and interfacial analysis. Here we addresses this gap by in-situ observing the proton transport of graphene quantum dots (GQDs) in an excited state through reduction of magnetic resonance relaxation time. Experimental results, utilizing 0.1 mT ultra-low-field nuclear magnetic resonance relaxometry compatible with a light source, reveal the light-induced proton dissociation and acidity of GQDs’ microenvironment in the excited state (Hammett acidity function: –13.40). Theoretical calculations demonstrate significant acidity enhancement in –OH functionalized GQDs with light induction ( $${{\mathrm{p}}}{K}_{{\text{a}}}^{*}$$ p K a * = –4.62, stronger than that of H2SO4). Simulations highlight the contributions of edge and phenolic –OH groups to proton dissociation. The light-induced superacidic microenvironment of GQDs benefits functionalization and improves the catalytic performances of GQDs. Importantly, this work advances the understanding of interfacial properties of light-induced sp 2–sp 3 carbon nanostructure and provides a valuable tool for exploring catalyst interfaces in photocatalysis.

Abstract The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P

Abstract Phage predation is generally assumed to reduce microbial proliferation while not contributing to the spread of antibiotic resistance. However, this assumption does not consider the effect of phage predation on the spatial organization of different microbial populations. Here, we show that phage predation can increase the spread of plasmid-encoded antibiotic resistance during surface-associated microbial growth by reshaping spatial organization. Using two strains of the bacterium Escherichia coli, we demonstrate that phage predation slows the spatial segregation of the strains during growth. This increases the number of cell-cell contacts and the extent of conjugation-mediated plasmid transfer between them. The underlying mechanism is that phage predation shifts the location of fastest growth from the biomass periphery to the interior where cells are densely packed and aligned closer to parallel with each other. This creates straighter interfaces between the strains that are less likely to merge together during growth, consequently slowing the spatial segregation of the strains and enhancing plasmid transfer between them. Our results have implications for the design and application of phage therapy and reveal a mechanism for how microbial functions that are deleterious to human and environmental health can proliferate in the absence of positive selection.

Abstract The neocortex comprises six cortical layers that play a crucial role in information processing; however, it remains unclear whether laminar processing is consistent across all regions within a single cortex. In this study, we demonstrate diverse laminar response patterns in the primary visual cortex (V1) of three male macaque monkeys when exposed to visual stimuli at different spatial frequencies (SFs). These response patterns can be categorized into two groups. One group exhibit suppressed responses in the output layers for all SFs, while the other type shows amplified responses specifically at high SFs. Further analysis suggests that both magnocellular (M) and parvocellular (P) pathways contribute to the suppressive effect through feedforward mechanisms, whereas amplification is specific to local recurrent mechanisms within the parvocellular pathway. These findings highlight the non-uniform distribution of neural mechanisms involved in laminar processing and emphasize how pathway-specific amplification selectively enhances representations of high-SF information in primate V1.

Abstract Disease modeling with isogenic Induced Pluripotent Stem Cell (iPSC)-differentiated organoids serves as a powerful technique for studying disease mechanisms. Multiplexed coculture is crucial to mitigate batch effects when studying the genetic effects of disease-causing variants in differentiated iPSCs or organoids, and demultiplexing at the single-cell level can be conveniently achieved by assessing natural genetic barcodes. Here, to enable cost-efficient time-series experimental designs via multiplexed bulk and single-cell RNA-seq of hybrids, we introduce a computational method in our Vireo Suite, Vireo-bulk, to effectively deconvolve pooled bulk RNA-seq data by genotype reference, and thereby quantify donor abundance over the course of differentiation and identify differentially expressed genes among donors. Furthermore, with multiplexed scRNA-seq and bulk RNA-seq, we demonstrate the usefulness and necessity of a pooled design to reveal donor iPSC line heterogeneity during macrophage cell differentiation and to model rare WT1 mutation-driven kidney disease with chimeric organoids. Our work provides an experimental and analytic pipeline for dissecting disease mechanisms with chimeric organoids.

Abstract Conventional food production is restricted by energy conversion efficiency of natural photosynthesis and demand for natural resources. Solar-driven artificial food synthesis from CO2 provides an intriguing approach to overcome the limitations of natural photosynthesis while promoting carbon-neutral economy, however, it remains very challenging. Here, we report the design of a hybrid electrocatalytic−biocatalytic flow system, coupling photovoltaics-powered electrocatalysis (CO2 to formate) with five-enzyme cascade platform (formate to sugar) engineered via genetic mutation and bioinformatics, which achieves conversion of CO2 to C6 sugar (L-sorbose) with a solar-to-food energy conversion efficiency of 3.5%, outperforming natural photosynthesis by over three-fold. This flow system can in principle be programmed by coupling with diverse enzymes toward production of multifarious food from CO2. This work opens a promising avenue for artificial food synthesis from CO2 under confined environments.

Abstract The sterile insect technique is based on the overflooding of a target population with released sterile males inducing sterility in the wild female population. It has proven to be effective against several insect pest species of agricultural and veterinary importance and is under development for Aedes mosquitoes. Here, we show that the release of sterile males at high sterile male to wild female ratios may also impact the target female population through mating harassment. Under laboratory conditions, male to female ratios above 50 to 1 reduce the longevity of female Aedes mosquitoes by reducing their feeding success. Under controlled conditions, blood uptake of females from an artificial host or from a mouse and biting rates on humans are also reduced. Finally, in a field trial conducted in a 1.17 ha area in China, the female biting rate is reduced by 80%, concurrent to a reduction of female mosquito density of 40% due to the swarming of males around humans attempting to mate with the female mosquitoes. This suggests that the sterile insect technique does not only suppress mosquito vector populations through the induction of sterility, but may also reduce disease transmission due to increased female mortality and lower host contact.

Abstract Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.

Abstract Practical photodynamic therapy calls for high-performance, less O2-dependent, long-wavelength-light-activated photosensitizers to suit the hypoxic tumor microenvironment. Iridium-based photosensitizers exhibit excellent photocatalytic performance, but the in vivo applications are hindered by conventional O2-dependent Type-II photochemistry and poor absorption. Here we show a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region. Reactive oxygen species generation of metallopolymer Ir-P1, where the iridium atom is covalently coupled to the polymer backbone, is over 80 times higher than that of its mother polymer without iridium under 680 nm irradiation. This strategy also works effectively when the iridium atom is directly included (Ir-P2) in the polymer backbones, exhibiting wide generality. The metallopolymer nanoparticles exhibiting efficient O2 •− generation are conjugated with integrin αvβ3 binding cRGD to achieve targeted photodynamic therapy.

Abstract Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.

Abstract Designing novel catalysts is key to solving many energy and environmental challenges. Despite the promise that data science approaches, including machine learning (ML), can accelerate the development of catalysts, truly novel catalysts have rarely been discovered through ML approaches because of one of its most common limitations and criticisms—the assumed inability to extrapolate and identify extraordinary materials. Herein, we demonstrate an extrapolative ML approach to develop new multi-elemental reverse water-gas shift catalysts. Using 45 catalysts as the initial data points and performing 44 cycles of the closed loop discovery system (ML prediction + experiment), we experimentally tested a total of 300 catalysts and identified more than 100 catalysts with superior activity compared to those of the previously reported high-performance catalysts. The composition of the optimal catalyst discovered was Pt(3)/Rb(1)-Ba(1)-Mo(0.6)-Nb(0.2)/TiO2. Notably, niobium (Nb) was not included in the original dataset, and the catalyst composition identified was not predictable even by human experts.

Abstract Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4lo neutrophils, CXCR4hi neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4hi neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4hi neutrophil development and characterizes the contribution of CXCR4hi neutrophils to vascular remodeling and inflammatory responses in skin.

Abstract Most terrestrial plants establish a symbiosis with arbuscular mycorrhizal fungi (AMF), which provide them with lipids and sugars in exchange for phosphorus and nitrogen. Nutrient exchange must be dynamically controlled to maintain a mutually beneficial relationship between the two symbiotic partners. The WRI5a and its homologues play a conserved role in lipid supply to AMF. Here, we demonstrate that the AP2/ERF transcription factor MtERM1 binds directly to AW-box and AW-box-like cis-elements in the promoters of MtSTR2 and MtSTR, which are required for host lipid efflux and arbuscule development. The EAR domain-containing transcription factor MtERF12 is also directly activated by MtERM1/MtWRI5a to negatively regulate arbuscule development, and the TOPLESS co-repressor is further recruited by MtERF12 through EAR motif to oppose MtERM1/MtWRI5a function, thereby suppressing arbuscule development. We therefore reveal an ERM1/WRI5a–ERF12–TOPLESS negative feedback loop that enables plants to flexibly control nutrient exchange and ensure a mutually beneficial symbiosis.

Abstract To date, most studies on the DNA polymerase, POLD1, have focused on the effect of POLD1 inactivation mutations in tumors. However, the implications of high POLD1 expression in tumorigenesis remains elusive. Here, we determine that POLD1 has a pro-carcinogenic role in bladder cancer (BLCA) and is associated to the malignancy and prognosis of BLCA. Our studies demonstrate that POLD1 promotes the proliferation and metastasis of BLCA via MYC. Mechanistically, POLD1 stabilizes MYC in a manner independent of its’ DNA polymerase activity. Instead, POLD1 attenuates FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we find that POLD1 forms a complex with MYC to promote the transcriptional activity of MYC. In turn, MYC increases expression of POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study identifies POLD1 as a promotor of BCLA via a MYC driven mechanism and suggest its potential as biomarker for BLCA.

Abstract The emergence of ionic-junction devices has attracted growing interests due to the potential of serving as signal transmission and translation media between electronic devices and biological systems using ions. Among them, fiber-shaped iontronics possesses a great advantage in implantable applications owing to the unique one-dimensional geometry. However, fabricating stable ionic-junction on curved surfaces remains a challenge. Here, we developed a polyelectrolyte based ionic-junction fiber via an integrated opposite charge grafting method capable of large-scale continuous fabrication. The ionic-junction fibers can be integrated into functions such as ionic diodes and ionic bipolar junction transistors, where rectification and switching of input signals are implemented. Moreover, synaptic functionality has also been demonstrated by utilizing the fiber memory capacitance. The connection between the ionic-junction fiber and sciatic nerves of the mouse simulating end-to-side anastomosis is further performed to realize effective nerve signal conduction, verifying the capability for next-generation artificial neural pathways in implantable bioelectronics.

Little is known about the role of glycolysis in cellular senescence. Here, authors report that glycolysis-derived serine biosynthesis activates PKM2 to phosphorylate histone H3T11, prevent cell senescence, and promote healthy aging.

Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.

The presence of activating epidermal growth factor receptor (EGFR) mutations in patients with lung cancer correlates to improved response to EGFR-tyrosine kinase inhibitors. Here, the authors present a fluorescence-activated cell sorting assay to identify EGFR mutations with functional activity in patients and demonstrate its utility in predicting response to EGFR-TKI.

Controlling the high-power laser transmittance is built on the diverse manipulation of multiple nonlinear absorption processes in the nonlinear optical materials. Here, the authors demonstrate the crucial role of hot-carrier effect to tune the nonlinear absorption response in quasi-2D perovskite films.

Here the authors report two structures of human PTH1R-Gs complex bound to ligands PTH and ABL, providing insight into the molecular mechanism of ligand duration.

Helium is the second most abundant element in the universe, and at low temperatures it becomes a quantum crystal with exotic physical properties such as second sound, superfluidity, and giant plasticity. Here authors prepare 2D solid helium at room temperature through diamond lattice confinement.

Soft robots are challenging to model and program. Non-specialists face non-negligible obstacles when working with soft robots to perform tasks. Here, the authors propose a method to interactively teach soft robots complex motions through flexible touchless and tactile multimodal sensors.

‘Protein arginine methyltransferase 5 (PRMT5) is known to regulate the expression of genes involved in metastasis. Here, the authors show that PRMT5 methylates Akt and methylation is required for phosphorylation and activation of Akt; ultimately leading to the increase in expression of pro-metastatic transcription factors.

The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.

Though shape-changing devices are promising for future haptic displays, existing designs fail to provide smooth surfaces for the user during tactile exploration. Here, the authors utilize flexible auxetic structures to realize shape displays with smooth surfaces and different Gaussian curvatures.

Catalytic kinetic resolution of amines is a longstanding challenge in chemical synthesis. Here, the authors report on titanium‐catalysed asymmetric oxygenation with hydrogen peroxide for kinetic resolution of secondary amines through oxygenation to produce enantiopure hydroxylamines involving N–O bond formation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to acute kidney injury. The authors describe that SARS-COV-2 can directly infect human kidney, possibly mediating tubular pathogenesis.

Pathogen entry to plant cells can release cell wall components. Here the authors show that two endoglucanases secreted by the rice blast fungus Magnaporthe oryzae, produce specific oligosaccharides from rice cell walls that trigger immunity by promoting dimerization of OsCERK1 and OsCEBiP receptors.

Though two-dimensional (2D) nanocomposite materials have been attractive for flexible electrochromic (EC) devices, achieving both high performance and durability remains a challenge. Here, the authors report high-performance, environmentally stable 2D MXene/transition metal oxide-based EC devices.

Figs and their wasp pollinators are a classic example of coevolution. By assembling and analysing genomes from across the Ficus clade, authors suggest that fig hybridization driven by pollinator host-switching in this obligate pollination system, is more common than previously thought.

The exciton–phonon coupling (EXPC) affects the opto-electronic properties of atomically thin semiconductors. Here, the authors develop two-dimensional micro-spectroscopy to determine the EXPC of monolayer MoSe2.

In metastatic urothelial carcinoma, it has not been established whether circulating tumor DNA (ctDNA) can replace archival primary tissue to assess mutations and biomarkers. Here, the authors show high mutation concordance between ctDNA and tumour tissue, with high consistency in serial samples.

The primary stages of carrier relaxation in atomically thin transition metal dichalcogenides are hardly accessible due to their fast timescales. Here, the authors measure the first stages of carrier–phonon interaction in monolayer WSe2 via a series of periodic maxima in the hot photoluminescence intensity, assigned to phonon cascades.

The power/energy trade-off is a common feature seen in a Ragone plot for an electrochemical storage device. Here the authors approach this issue by showing water-incorporated α-MoO3 anodes with expanded interlayer gaps, which allow for the assembling of dual-ion energy storage devices.

AsCpf1 is an alternative nuclease to Cas9 for CRISPR mediated genome engineering. Here the authors demonstrate functional genomic screens with AsCpf1 that minimize library size with no loss in gene targeting efficiency.

Cross-dehydrogenative coupling (CDC) is a powerful method for C-C bond formation however the enantioselective variant is underdeveloped. Here, the authors show a formal enantioselective CDC method involving unactivated ethers and carboxylic acid derivatives allowing for the rapid preparation of biologically active molecules.

Fabricating lateral graphene p–n junctions with controlled doping levels is instrumental to realize ultrafast and efficient optoelectronic devices. Here, the authors report a seamless graphene based photodetector doped by selective ion implantation and in-situ chemical vapour deposition.

Materials that exhibit synchronous color change and actuation may benefit biomimetic camouflage, but stimuli can be difficult to control. Here the authors report a composite with electricity-driven electrochromic and actuating capabilities for use in a solid-state ionic polymer-metal composite actuator.

ApoE4 is a risk factor for small vessel disease, which can lead to cognitive impairment. Here the authors assess the microvasculature of the corpus callosum using 3-photon microscopy and find that mice expressing the ApoE4 allele are more susceptible than wild-type to white matter injury and cognitive impairment in a model of hypoperfusion-induced hypoxia.

Multi-exciton states may emerge in atomically thin transition metal dichalcogenides as a result of strong many-body interactions. Here, the authors report experimental evidence of four- and five-particle biexciton complexes in monolayer WSe2 and their electrical control.

Intrinsic deformation with fast response in commercially available materials that can safely contact skin continues to be a challenge for artificial actuating materials. Here the authors incorporate nanoscale molecular channels within perfluorosulfonic acid ionomer for self-adaptive and ambient-driven actuation.

Centrosome duplication is synchronized with cell cycle events but how this is regulated at a molecular level is unclear. Here, the authors show that the DNA replication licensing factor Cdc6 restrains centrosome duplication via binding and inhibiting Sas-6, and the inhibition of Cdc6 on Sas-6 is negatively regulated by Plk4 phosphorylation.

MoS2 is a promising two-dimensional candidate for opto-electronic and spintronic applications. Here, the authors report electrical spin injection and detection in a few-layered MoS2 channel, demonstrating that the spin diffusion length is at least 235 nm in MoS2conduction band.

Two-dimensional materials show remarkable lubrication properties, yet chemical modifications may hinder such capabilities. Here, the authors show that when graphene is aligned on a Ge(111) substrate, ultra-low friction can be preserved even after graphene fluorination or oxidation.

The transcription factor Runx2 regulates osteoblast differentiation of mesenchymal stem cells. In this manuscript, the authors, using a specific conditional knock-out mouse model and molecular studies, demonstrate that the mediator subunit MED23 binds to Runx2 and is essential for driving mesenchymal stem cells toward an osteoblast fate.

Electrochemical carbon dioxide/carbon monoxide reduction reaction offers a promising route to synthesize fuels and value-added chemicals, unfortunately their activities and selectivities remain unsatisfactory. Here, we present a general surface molecular tuning strategy by modifying Cu2O with a molecular pyridine-derivative. The surface modified Cu2O nanocubes by 4-mercaptopyridine display a high Faradaic efficiency of greater than 60% in electrochemical carbon monoxide reduction reaction to acetate with a current density as large as 380 mA/cm2 in a liquid electrolyte flow cell. In-situ attenuated total reflectance surface-enhanced infrared absorption spectroscopy reveals stronger *CO signal with bridge configuration and stronger *OCCHO signal over modified Cu2O nanocubes by 4-mercaptopyridine than unmodified Cu2O nanocubes during electrochemical CO reduction. Density function theory calculations disclose that local molecular tuning can effectively regulate the electronic structure of copper catalyst, enhancing *CO and *CHO intermediates adsorption by the stabilization effect through hydrogen bonding, which can greatly promote asymmetric *CO-*CHO coupling in electrochemical carbon monoxide reduction reaction. [ABSTRACT FROM AUTHOR]