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An ambipolar ferromagnet with both electron- and hole-doped ferromagnetism in a single material would facilitate understanding of ferromagnetic semiconductors for spintronic applications. Here the authors demonstrate ambipolar ferromagnetism in LaMnO3, using ionic liquid gating enabled electrostatic doping to produce electron–hole asymmetry.

Forests are invaluable natural resources that provide essential services to humanity. However, the effects of global warming on forest carbon and nitrogen cycling remain uncertain. Here we project a decrease in total nitrogen input and accumulation by 7 ± 2 and 28 ± 9 million tonnes (Tg), respectively, and an increase in reactive nitrogen losses to the environment by 9 ± 3 Tg for 2100 due to warming in a fossil-fueled society. This would compromise the global carbon sink capacity by 0.45 ± 0.14 billion tonnes annually. Furthermore, warming-induced inequality in forest carbon and nitrogen cycles could widen the economic gap between the Global South and Global North. High-income countries are estimated to gain US$179 billion in benefits from forest assets under warming, while other regions could face net damages of US$31 billion. Implementing climate-smart forest management, such as comprehensive restoration and optimizing tree species composition, is imperative in the face of future climate change., (© 2024. The Author(s).)

The low cultivability of environmental bacteria has been widely acknowledged, but most previous estimates focused on the proportion of cultivable cells rather than cultivable taxa. Here, we estimate the proportions of cultivable cells and cultivable taxa for two sample types (soil and activated sludge) using cell counting, 16S rRNA gene amplicon sequencing, metagenomics, and cultivation on agar plates under various conditions. We find that the proportion of cultivable taxa exceeds that of cultivable cells at the sample level. A large proportion of cultivable taxa are taxonomically novel but tend to be present at very low abundance on agar plates, forming microcolonies, and some of them cease to grow during subculture. Compared with uncultivable taxa (under the conditions used in our study), cultivatable taxa tend to display higher metabolic activity as inferred by measuring rRNA copies per cell. Finally, we use the generated taxonomic and genomic information as a guide to isolate a strain representing a yet-uncultured class within the Bacteroidota and to enhance the cultivable diversity of Burkholderiales from activated sludge., (© 2024. The Author(s).)

Rechargeable batteries with high durability over wide temperature is needed in aerospace and submarine fields. Unfortunately, Current battery technologies suffer from limited operating temperatures due to the rapid performance decay at extreme temperatures. A major challenge for wide-temperature electrolyte design lies in restricting the parasitic reactions at elevated temperatures while improving the reaction kinetics at low temperatures. Here, we demonstrate a temperature-adaptive electrolyte design by regulating the dipole-dipole interactions at various temperatures to simultaneously address the issues at both elevated and subzero temperatures. This approach prevents electrolyte degradation while endowing it with the ability to undergo adaptive changes as temperature varies. Such electrolyte favors to form solvation structure with high thermal stability with rising temperatures and transits to one that prevents salt precipitation at lower temperatures. This ensures stably within a wide temperature range of ‒60 -55 °C. This temperature-adaptive electrolyte opens an avenue for wide-temperature electrolyte design, highlighting the significance of dipole-dipole interactions in regulating solvation structures., (© 2024. The Author(s).)

Listeria monocytogenes (LM) possesses the ability to breach multiple barriers and elicit intricate immune responses. However, there remains a lack of explicit understanding regarding how LM evades innate immune surveillance within the body. Here, we utilized liver intravital imaging to elucidate the dynamic process of LM during infection in the liver. We discovered that LM can rapidly escape from Kupffer cells (KCs) through listeriolysin O (LLO) and proliferate within hepatocytes. Upon LM exposure to the hepatic sinusoids, neutrophils rapidly aggregate at the site of infection. Subsequently, LM can induce type I interferon (IFN-I) production primarily in the spleen, which acts systemically on neutrophils to hamper their swarming by deactivating the ERK pathway, thus evading neutrophil-mediated eradication. Furthermore, our findings suggest that virus-induced IFN-I suppresses neutrophil swarming, and COVID-19 patients exhibit impaired neutrophil aggregation function. In conclusion, our findings provide compelling evidence demonstrating that intracellular bacteria represented by LM can hijack host defense mechanisms against viral infections to evade immune surveillance. Additionally, impaired neutrophil swarming caused by IFN-I is one of the significant factors contributing to the increased susceptibility to bacterial infections following viral infections., (© 2024. The Author(s).)

Developing highly active and durable air cathode catalysts is crucial yet challenging for rechargeable zinc-air batteries. Herein, a size-adjustable, flexible, and self-standing carbon membrane catalyst encapsulating adjacent Cu/Na dual-atom sites is prepared using a solution blow spinning technique combined with a pyrolysis strategy. The intrinsic activity of the Cu-N 4 site is boosted by the neighboring Na-containing functional group, which enhances O 2 adsorption and optimizes the rate-determining step of O 2 activation (*O 2  → *OOH) during the oxygen reduction reaction process. Meanwhile, the Cu-N 4 sites are encapsulated within carbon nanofibers and anchored by the carbon matrix to form a C 2 -Cu-N 4 configuration, thereby reinforcing the stability of the Cu centers. Moreover, the introduction of Na-containing functional groups on the carbon atoms significantly reduces the positive charge on their outer shell C atoms, rendering the carbon skeletons less susceptible to corrosion by oxygen species and further preventing the dissolution of Cu centers. Under these multi-type regulations, the zinc-air battery with Cu/Na-carbon membrane catalyst as the air cathode demonstrates long-term discharge/charge cycle stability of over 5000 h. This considerable stability improvement represents a critical step towards developing Cu-N 4 active sites modified with the neighboring main-group metal-containing functional groups to overcome the durability barriers of zinc-air batteries for future practical applications., (© 2024. The Author(s).)

The lower respiratory tract (LRT) microbiome impacts human health, especially among critically ill patients. However, comprehensive characterizations of the LRT microbiome remain challenging due to low microbial mass and host contamination. We develop a chelex100-based low-biomass microbial-enrichment method (CMEM) that enables deep metagenomic profiling of LRT samples to recover near-complete microbial genomes. We apply the method to 453 longitudinal LRT samples from 157 intensive care unit (ICU) patients in three geographically distant hospitals. We recover 120 high-quality metagenome-assembled genomes (MAGs) and associated plasmids without culturing. We detect divergent longitudinal microbiome dynamics and hospital-specific dominant opportunistic pathogens and resistomes in pneumonia patients. Diagnosed pneumonia and the ICU stay duration were associated with the abundance of specific antibiotic-resistance genes (ARGs). Moreover, CMEM can serve as a robust tool for genome-resolved analyses. MAG-based analyses reveal strain-specific resistome and virulome among opportunistic pathogen strains. Evolutionary analyses discover increased mobilome in prevailing opportunistic pathogens, highly conserved plasmids, and new recombination hotspots associated with conjugative elements and prophages. Integrative analysis with epidemiological data reveals frequent putative inter-patient strain transmissions in ICUs. In summary, we present a genome-resolved functional, transmission, and evolutionary landscape of the LRT microbiota in critically ill patients., (© 2024. The Author(s).)

CRISPR/Cas-based transcriptional activators can be enhanced by intrinsically disordered regions (IDRs). However, the underlying mechanisms are still debatable. Here, we examine 12 well-known IDRs by fusing them to the dCas9-VP64 activator, of which only seven can augment activation, albeit independently of their phase separation capabilities. Moreover, modular domains (MDs), another class of multivalent molecules, though ineffective in enhancing dCas9-VP64 activity on their own, show substantial enhancement in transcriptional activation when combined with dCas9-VP64-IDR. By varying the number of gRNA binding sites and fusing dCas9-VP64 with different IDRs/MDs, we uncover that optimal, rather than maximal, cis-trans cooperativity enables the most robust activation. Finally, targeting promoter-enhancer pairs yields synergistic effects, which can be further amplified via enhancing chromatin interactions. Overall, our study develops a versatile platform for efficient gene activation and sheds important insights into CRIPSR-based transcriptional activators enhanced with multivalent molecules., (© 2024. The Author(s).)

Constructing powerful anode/cathode interphases by modulate ion solvation structure is the principle of electrolyte design. However, the methodological and theoretical design principles of electrolyte/solvation structure and their effect on electrochemical performance are still vague. Here, we propose a cationic weakly coordinating-intervention strategy for modulating the Na + solvation sheathes and constructing robust anode/cathode interphases in sodium-metal batteries. Unlike the local highly concentrated electrolytes, 1,2-difluorobenzene can weakly coordinate with Na + thus transforming the solvation structure into Na + -anion-incorporated structures and strengthening anode/cathode interphases formation by combining with salt decomposition. Furthermore, the correlations between the electrode interface properties and solvation structure are revealed, which can be tuned by the weakly coordination. Ultimately, the modulated electrolyte achieves 97.5% Coulombic efficiency for 600 cycles in Na‖Cu cells at 1 mA cm -2 and a beneficial lifetime (2500 h) in Na‖Na cells. Meanwhile, Na‖PB cells have achieved long-term operation at 4.8 V, along with operation at wide temperatures., (© 2024. The Author(s).)

Eunicellane diterpenoids, containing a typical 6,10-bicycle, are bioactive compounds widely present in marine corals, but rarely found in bacteria and plants. The intrinsic macrocycle exhibits innate structural flexibility resulting in dynamic conformational changes. However, the mechanisms controlling flexibility remain unknown. The discovery of a terpene synthase, MicA, that is responsible for the biosynthesis of a nearly non-flexible eunicellane skeleton, enable us to propose a feasible theory about the flexibility in eunicellane structures. Parallel studies of all eunicellane synthases in nature discovered to date, including 2Z-geranylgeranyl diphosphate incubations and density functional theory-based Boltzmann population computations, reveale that a trans-fused bicycle with a 2Z-configuration alkene restricts conformational flexibility resulting in a nearly non-flexible eunicellane skeleton. The catalytic route and the enzymatic mechanism of MicA are also elucidated by labeling experiments, density functional theory calculations, structural analysis of the artificial intelligence-based MicA model, and mutational studies., (© 2024. The Author(s).)

Carbon chain elongation (CCE) is normally carried out using either chemical catalysts or bioenzymes. Herein we demonstrate a catalyst-free approach to promote demethylation C-C coupling reactions for advanced CCE constructed with functional groups under ambient conditions. Accelerated by the electric field, two organic cations containing a methyl group (e.g., ketones, acids, and aldehydes) approach each other with such proximity that the energy of the repulsive Coulomb interaction between these two cations exceeds the bond energy of the methyl group. This results in the elimination of a methyl cation and the coupling of the residual carbonyl carbon groups. As confirmed by high-resolution mass spectrometry and isotope-labeling experiments, the C-C coupling reactions (yields up to 76.5%) were commonly observed in the gas phase or liquid phase, for which the mechanism was further studied using molecular dynamics simulations and stationary-point calculations, revealing deep insights and perspectives of chemistry., (© 2024. The Author(s).)

Diatoms often outnumber other eukaryotic algae in the oceans, especially in coastal environments characterized by frequent fluctuations in light intensity. The identities and operational mechanisms of regulatory factors governing diatom acclimation to high light stress remain largely elusive. Here, we identified the AUREO1c protein from the coastal diatom Phaeodactylum tricornutum as a crucial regulator of non-photochemical quenching (NPQ), a photoprotective mechanism that dissipates excess energy as heat. AUREO1c detects light stress using a light-oxygen-voltage (LOV) domain and directly activates the expression of target genes, including LI818 genes that encode NPQ effector proteins, via its bZIP DNA-binding domain. In comparison to a kinase-mediated pathway reported in the freshwater green alga Chlamydomonas reinhardtii, the AUREO1c pathway exhibits a faster response and enables accumulation of LI818 transcript and protein levels to comparable degrees between continuous high-light and fluctuating-light treatments. We propose that the AUREO1c-LI818 pathway contributes to the resilience of diatoms under dynamic light conditions., (© 2024. The Author(s).)

Artificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations like lack of well-defined targets. While chemical-induced transcriptional profiles offer a comprehensive view of drug mechanisms, inherent noise often obscures the true signal, hindering their potential for meaningful insights. Here, we highlight the development of TranSiGen, a deep generative model employing self-supervised representation learning. TranSiGen analyzes basal cell gene expression and molecular structures to reconstruct chemical-induced transcriptional profiles with high accuracy. By capturing both cellular and compound information, TranSiGen-derived representations demonstrate efficacy in diverse downstream tasks like ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. Notably, in vitro validation of TranSiGen's application in pancreatic cancer drug discovery highlights its potential for identifying effective compounds. We envisage that integrating TranSiGen into the drug discovery and mechanism research holds significant promise for advancing biomedicine., (© 2024. The Author(s).)

As the most abundant organic substances in nature, carbohydrates are essential for life. Understanding how carbohydrates regulate proteins in the physiological and pathological processes presents opportunities to address crucial biological problems and develop new therapeutics. However, the diversity and complexity of carbohydrates pose a challenge in experimentally identifying the sites where carbohydrates bind to and act on proteins. Here, we introduce a deep learning model, DeepGlycanSite, capable of accurately predicting carbohydrate-binding sites on a given protein structure. Incorporating geometric and evolutionary features of proteins into a deep equivariant graph neural network with the transformer architecture, DeepGlycanSite remarkably outperforms previous state-of-the-art methods and effectively predicts binding sites for diverse carbohydrates. Integrating with a mutagenesis study, DeepGlycanSite reveals the guanosine-5'-diphosphate-sugar-recognition site of an important G-protein coupled receptor. These findings demonstrate DeepGlycanSite is invaluable for carbohydrate-binding site prediction and could provide insights into molecular mechanisms underlying carbohydrate-regulation of therapeutically important proteins., (© 2024. The Author(s).)

Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression., (© 2024. The Author(s).)

Hexachlorobutadiene (HCBD) is a concerning chemical that is included in the United States Toxic Substances Control Act, and the Stockholm Convention. Knowledge of the sources of HCBD is insufficient and is pivotal for accurate inventory and implementing global action. In this study, unintentional HCBD release and source emission factors of 121 full-scale industrial plants from 12 industries are investigated. Secondary copper smelting, electric arc furnace steelmaking, and hazardous waste incineration show potential for large emission reductions, which are found of high HCBD emission concentrations of > 20 ng/g in fine particulate matter in this study. The highest HCBD emission concentration is observed for the secondary copper smelting industry (average: 1380 ng/g). Source emission factors of HCBD for the 12 industries range from 0.008 kg/t for coal fire power plants to 0.680 kg/t for secondary lead smelting, from which an estimation of approximately 8452.8 g HCBD emissions annually worldwide achieved. The carcinogenic risks caused by HCBD emissions from countries and regions with intensive 12 industrial sources are 1.0-80 times higher than that without these industries. These results will be useful for formulating effective strategies of HCBD control., (© 2024. The Author(s).)

Photosynthetic organisms have evolved an essential energy-dependent quenching (qE) mechanism to avoid any lethal damages caused by high light. While the triggering mechanism of qE has been well addressed, candidates for quenchers are often debated. This lack of understanding is because of the tremendous difficulty in measuring intact cells using transient absorption techniques. Here, we have conducted femtosecond pump-probe measurements to characterize this photophysical reaction using micro-sized cell fractions of the green alga Chlamydomonas reinhardtii that retain physiological qE function. Combined with kinetic modeling, we have demonstrated the presence of an ultrafast excitation energy transfer (EET) pathway from Chlorophyll a (Chl a) Q y to a carotenoid (car) S 1 state, therefore proposing that this carotenoid, likely lutein1, is the quencher. This work has provided an easy-to-prepare qE active thylakoid membrane system for advanced spectroscopic studies and demonstrated that the energy dissipation pathway of qE is evolutionarily conserved from green algae to land plants., (© 2024. The Author(s).)

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction., (© 2024. The Author(s).)

Transcortical vessels (TCVs) provide effective communication between bone marrow vascular system and external circulation. Although osteocytes are in close contact with them, it is not clear whether osteocytes regulate the homeostasis of TCVs. Here, we show that osteocytes maintain the normal network of TCVs by transferring mitochondria to the endothelial cells of TCV. Partial ablation of osteocytes causes TCV regression. Inhibition of mitochondrial transfer by conditional knockout of Rhot1 in osteocytes also leads to regression of the TCV network. By contrast, acquisition of osteocyte mitochondria by endothelial cells efficiently restores endothelial dysfunction. Administration of osteocyte mitochondria resultes in acceleration of the angiogenesis and healing of the cortical bone defect. Our results provide new insights into osteocyte-TCV interactions and inspire the potential application of mitochondrial therapy for bone-related diseases., (© 2024. The Author(s).)

Reducing the silver film to 10 nm theoretically allows higher transparency but in practice leads to degraded transparency and electrical conductivity because the ultrathin film tends to be discontinuous. Herein, we developed a thinning-back process to address this dilemma, in which silver film is first deposited to a larger thickness with high continuity and then thinned back to a reduced thickness with an ultrasmooth surface, both implemented by a flood ion beam. Contributed by the shallow implantation of silver atoms into the substrate during deposition, the thinness of silver films down to 4.5 nm can be obtained, thinner than ever before. The atomic-level surface smooth permits excellent visible transparency, electrical conductivity, and the lowest haze among all existing transparent conductors. Moreover, the ultrathin silver film exhibits the unique robustness of mechanical flexibility. Therefore, the ion-beam thinning-back process presents a promising solution towards the excellent transparent conductor for flexible optoelectronic devices., (© 2024. The Author(s).)

Rechargeable lithium batteries using 5 V positive electrode materials can deliver considerably higher energy density as compared to state-of-the-art lithium-ion batteries. However, their development remains plagued by the lack of electrolytes with concurrent anodic stability and Li metal compatibility. Here we report a new electrolyte based on dimethyl 2,5-dioxahexanedioate solvent for 5 V-class batteries. Benefiting from the particular chemical structure, weak interaction with lithium cation and resultant peculiar solvation structure, the resulting electrolyte not only enables stable, dendrite-free lithium plating-stripping, but also displays anodic stability up to 5.2 V (vs. Li/Li + ), in additive or co-solvent-free formulation, and at low salt concentration of 1 M. Consequently, the Li | |LiNi 0.5 Mn 1.5 O 4 cells using the 1 M LiPF 6 in 2,5-dioxahexanedioate based electrolyte retain >97% of the initial capacity after 250 cycles, outperforming the conventional carbonate-based electrolyte formulations, making this, and potentially other dicarbonate solvents promising for future Lithium-based battery practical explorations., (© 2024. The Author(s).)

Integrated urban water management is a well-accepted concept for managing urban water. It requires efficient and integrated technological solutions that enable system-wide gains via a whole-of-system approach. Here, we create a solid link between the manufacturing of an iron salt, its application in an urban water system, and high-quality bioenergy recovery from wastewater. An iron-oxidising electrochemical cell is used to remove CO 2 (also H 2 S and NH 3 ) from biogas, thus achieving biogas upgrading, and simultaneously producing FeCO 3 . The subsequent dose of the electrochemically produced FeCO 3 to wastewater and sludge removes sulfide and phosphate, and enhances sludge settleability and dewaterability, with comparable or superior performance compared to the imported and hazardous iron salts it substitutes (FeCl 2 , and FeCl 3 ). The process enables water utilities to establish a self-reliant and more secure supply chain to meet its demand for iron salts, at lower economic and environmental costs, and simultaneously achieve recovery of high-quality bioenergy., (© 2023. Springer Nature Limited.)

Nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind transcribed or damaged chromatin. By combining genome-wide approaches with live imaging of model loci, we uncover a correlation between NPC association and the accumulation of R-loops, which are genotoxic structures formed through hybridization of nascent RNAs with their DNA templates. Manipulating hybrid formation demonstrates that R-loop accumulation per se, rather than transcription or R-loop-dependent damages, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves their recognition by the ssDNA-binding protein RPA, and SUMO-dependent interactions with NPC-associated factors. Preventing R-loop-dependent relocation leads to lethality in hybrid-accumulating conditions, while NPC tethering of a model hybrid-prone locus attenuates R-loop-dependent genetic instability. Remarkably, this relocation pathway involves molecular factors similar to those required for the association of stalled replication forks with NPCs, supporting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses., (© 2023. Springer Nature Limited.)

The interactions between charges and excitons involve complex many-body interactions at high densities. The exciton-polaron model has been adopted to understand the Fermi sea screening of charged excitons in monolayer transition metal dichalcogenides. The results provide good agreement with absorption measurements, which are dominated by dilute bright exciton responses. Here we investigate the Fermi sea dressing of spin-forbidden dark excitons in monolayer WSe 2 . With a Zeeman field, the valley-polarized dark excitons show distinct p-doping dependence in photoluminescence when the carriers reach a critical density. This density can be interpreted as the onset of strongly modified Fermi sea interactions and shifts with increasing exciton density. Through valley-selective excitation and dynamics measurements, we also infer an intervalley coupling between the dark trions and exciton-polarons mediated by the many-body interactions. Our results reveal the evolution of Fermi sea screening with increasing exciton density and the impacts of polaron-polaron interactions, which lay the foundation for understanding electronic correlations and many-body interactions in 2D systems., (© 2023. Springer Nature Limited.)

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease., (© 2023. Springer Nature Limited.)

Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting the activity of F 0 F 1 ATPase complex V. However, its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue/cell uptake, leading to insufficient Gboxin accumulation at GBM sites, which limits its further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) by coating cancer cell-mitochondria hybrid membrane (HM) on the surface of Gboxin-loaded nanoparticles. An additional design element uses a reactive oxygen species responsive polymer to facilitate at-site Gboxin release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. The results suggest that HM-NPs@G achieve improved blood circulation (4.90 h versus 0.47 h of free Gboxin) and tumour accumulation (7.73% ID/g versus 1.06% ID/g shown by free Gboxin). Effective tumour inhibition in orthotopic U87MG GBM and patient derived X01 GBM stem cell xenografts in female mice with extended survival time and negligible side effects are also noted. We believe that the biomimetic Gboxin nanomedicine represents a promising treatment for brain tumours with clinical potential., (© 2023. The Author(s).)

Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning. We validate this concept in three stages. First, we design TransformerCPI2.0 as a core tool for the concept, which demonstrates generalization ability across proteins and compounds. Second, we interpret the binding knowledge that TransformerCPI2.0 learned. Finally, we use TransformerCPI2.0 to discover new hits for challenging drug targets, and identify new target for an existing drug based on an inverse application of the concept. Overall, this proof-of-concept study shows that the sequence-to-drug concept adds a perspective on drug design. It can serve as an alternative method to SBDD, particularly for proteins that do not yet have high-quality 3D structures available., (© 2023. The Author(s).)

While photosynthesis transforms sunlight energy into sugar, aerobic and anaerobic respiration (fermentation) catabolizes sugars to fuel cellular activities. These processes take place within one cell across several compartments, however it remains largely unexplored how they interact with one another. Here we report that the weak acids produced during fermentation down-regulate both photosynthesis and aerobic respiration. This effect is mechanistically explained with an "ion trapping" model, in which the lipid bilayer selectively traps protons that effectively acidify subcellular compartments with smaller buffer capacities - such as the thylakoid lumen. Physiologically, we propose that under certain conditions, e.g., dim light at dawn, tuning down the photosynthetic light reaction could mitigate the pressure on its electron transport chains, while suppression of respiration could accelerate the net oxygen evolution, thus speeding up the recovery from hypoxia. Since we show that this effect is conserved across photosynthetic phyla, these results indicate that fermentation metabolites exert widespread feedback control over photosynthesis and aerobic respiration. This likely allows algae to better cope with changing environmental conditions., (© 2023. The Author(s).)

Polyhalogenated carbazoles (PHCZs) are emerging global pollutants found in environmental matrices, e.g., 3000 tonnes of PHCZs have been detected in the sediments of the Great Lakes. Recognition of PHCZ emissions from ongoing industrial activities worldwide is still lacking. Here, we identify and quantify PHCZ emissions from 13 large-scale industries, 12 of which previously have no data. Congener profiles of PHCZs from investigated industrial sources are clarified, which enables apportioning of PHCZ sources. Annual PHCZ emissions from major industries are estimated on the basis of derived emission factors and then mapped globally. Coke production is a prime PHCZ emitter of 9229 g/yr, followed by iron ore sintering with a PHCZ emission of 3237 g/yr. China, Australia, Japan, India, USA, and Russia are found to be significant emitters through these industrial activities. PHCZ pollution is potentially a global human health and environmental issue., (© 2023. The Author(s).)

Electrochemical conversion of nitrate to ammonia offers an efficient approach to reducing nitrate pollutants and a potential technology for low-temperature and low-pressure ammonia synthesis. However, the process is limited by multiple competing reactions and NO 3 - adsorption on cathode surfaces. Here, we report a Fe/Cu diatomic catalyst on holey nitrogen-doped graphene which exhibits high catalytic activities and selectivity for ammonia production. The catalyst enables a maximum ammonia Faradaic efficiency of 92.51% (-0.3 V(RHE)) and a high NH 3 yield rate of 1.08 mmol h -1 mg -1 (at - 0.5 V(RHE)). Computational and theoretical analysis reveals that a relatively strong interaction between NO 3 - and Fe/Cu promotes the adsorption and discharge of NO 3 - anions. Nitrogen-oxygen bonds are also shown to be weakened due to the existence of hetero-atomic dual sites which lowers the overall reaction barriers. The dual-site and hetero-atom strategy in this work provides a flexible design for further catalyst development and expands the electrocatalytic techniques for nitrate reduction and ammonia synthesis., (© 2023. The Author(s).)

How climate change in the middle to late Holocene has influenced the early human migrations in Central Asian Steppe remains poorly understood. To address this issue, we reconstructed a multiproxy-based Holocene climate history from the sediments of Kanas Lake and neighboring Tiewaike Lake in the southern Altai Mountains. The results show an exceptionally warm climate during ~6.5-3.6 kyr is indicated by the silicon isotope composition of diatom silica (δ 30 Si diatom ) and the biogenic silica (BSi) content. During 4.7-4.3 kyr, a peak in δ 30 Si diatom reflects enhanced lake thermal stratification and periodic nutrient limitation as indicated by concomitant decreasing BSi content. Our geochemical results indicate a significantly warm and wet climate in the Altai Mountain region during 6.5-3.6 kyr, corresponding to the Altai Holocene Climatic Optimum (AHCO), which is critical for promoting prehistoric human population expansion and intensified cultural exchanges across the Central Asian steppe during the Bronze Age., (© 2023. The Author(s).)

Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target., (© 2023. The Author(s).)

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2 + ACE2 + small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2 + ACE2 + cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27 + memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2 + ACE2 + small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2 + ACE2 + cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC., (© 2023. The Author(s).)

Discoid lupus erythematosus (DLE) and systemic lupus erythematosus (SLE) are both types of lupus, yet the characteristics, and differences between them are not fully understood. Here we show single-cell RNA sequencing data of cutaneous lesions from DLE and SLE patients and skin tissues from healthy controls (HCs). We find significantly higher proportions of T cells, B cells and NK cells in DLE than in SLE. Expanded CCL20 + keratinocyte, CXCL1 + fibroblast, ISG hi CD4/CD8 T cell, ISG hi plasma cell, pDC, and NK subclusters are identified in DLE and SLE compared to HC. In addition, we observe higher cell communication scores between cell types such as fibroblasts and macrophage/dendritic cells in cutaneous lesions of DLE and SLE compared to HC. In summary, we clarify the heterogeneous characteristics in cutaneous lesions between DLE and SLE, and discover some specific cell subtypes and ligand-receptor pairs that indicate possible therapeutic targets of lupus erythematosus., (© 2022. The Author(s).)

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival., (© 2022. The Author(s).)

The dynamics of epidemic spreading is often reduced to the single control parameter R 0 (reproduction-rate), whose value, above or below unity, determines the state of the contagion. If, however, the pathogen evolves as it spreads, R 0 may change over time, potentially leading to a mutation-driven spread, in which an initially sub-pandemic pathogen undergoes a breakthrough mutation. To predict the boundaries of this pandemic phase, we introduce here a modeling framework to couple the inter-host network spreading patterns with the intra-host evolutionary dynamics. We find that even in the extreme case when these two process are driven by mutually independent selection forces, mutations can still fundamentally alter the pandemic phase-diagram. The pandemic transitions, we show, are now shaped, not just by R 0 , but also by the balance between the epidemic and the evolutionary timescales. If mutations are too slow, the pathogen prevalence decays prior to the appearance of a critical mutation. On the other hand, if mutations are too rapid, the pathogen evolution becomes volatile and, once again, it fails to spread. Between these two extremes, however, we identify a broad range of conditions in which an initially sub-pandemic pathogen can breakthrough to gain widespread prevalence., (© 2022. The Author(s).)

Incorporating fluorescent quantum defects in the sidewalls of semiconducting single-wall carbon nanotubes (SWCNTs) through chemical reaction is an emerging route to predictably modify nanotube electronic structures and develop advanced photonic functionality. Applications such as room-temperature single-photon emission and high-contrast bio-imaging have been advanced through aryl-functionalized SWCNTs, in which the binding configurations of the aryl group define the energies of the emitting states. However, the chemistry of binding with atomic precision at the single-bond level and tunable control over the binding configurations are yet to be achieved. Here, we explore recently reported photosynthetic protocol and find that it can control chemical binding configurations of quantum defects, which are often referred to as organic color centers, through the spin multiplicity of photoexcited intermediates. Specifically, photoexcited aromatics react with SWCNT sidewalls to undergo a singlet-state pathway in the presence of dissolved oxygen, leading to ortho binding configurations of the aryl group on the nanotube. In contrast, the oxygen-free photoreaction activates previously inaccessible para configurations through a triplet-state mechanism. These experimental results are corroborated by first principles simulations. Such spin-selective photochemistry diversifies SWCNT emission tunability by controlling the morphology of the emitting sites., (© 2022. The Author(s).)

Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-β type II receptor (TβRII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-β signaling in recipient cells. Up-take of extracellular vesicle-TβRII (EV-TβRII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TβRII delivered as cargo to CD8 + T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8 + T cell exhaustion, resulting in failure of immunotherapy. The levels of TβRII + circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors., (© 2022. The Author(s).)

PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy., (© 2022. The Author(s).)

Organic heterostructure nanowires, such as multiblock, core/shell, branch-like and related compounds, have attracted chemists' extensive attention because of their novel physicochemical properties. However, owing to the difficulty in solving the lattice mismatch of distinct molecules, the construction of organic heterostructures at large scale remains challenging, which restricts its wide use in future applications. In this work, we define a concept of lattice-mismatch-free for hierarchical self-assembly of organic semiconductor molecules, allowing for the large-scale synthesis of organic heterostructure nanowires composed of the organic alloys and cocrystals. Thus, various types of organic triblock nanowires are prepared in large scale, and the length ratio of different segments of the triblock nanowires can be precisely regulated by changing the stoichiometric ratio of different components. These results pave the way towards fine synthesis of heterostructures in a large scale and facilitate their applications in organic optoelectronics at micro/nanoscale., (© 2022. The Author(s).)

Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (P trend ranging from 2.79 × 10 -7 to 4.79 × 10 -44 ). By incorporating the PRS into EBV-serology-based NPC screening, the test's positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening., (© 2022. The Author(s).)

Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N 6 -methyladenosine (m 6 A) methylation) is unclear. Here we report decreased expression of the m 6 A "writer" METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m 6 A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m 6 A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells., (© 2021. The Author(s).)

Room temperature phosphorescence materials have inspired extensive attention owing to their great potential in optical applications. However, it is hard to achieve a room temperature phosphorescence material with simultaneous long lifetime and high phosphorescence quantum efficiency. Herein, multi-confined carbon dots were designed and fabricated, enabling room temperature phosphorescence material with simultaneous ultralong lifetime, high phosphorescence quantum efficiency, and excellent stability. The multi-confinement by a highly rigid network, stable covalent bonding, and 3D spatial restriction efficiently rigidified the triplet excited states of carbon dots from non-radiative deactivation. The as-designed multi-confined carbon dots exhibit ultralong lifetime of 5.72 s, phosphorescence quantum efficiency of 26.36%, and exceptional stability against strong oxidants, acids and bases, as well as polar solvents. This work provides design principles and a universal strategy to construct metal-free room temperature phosphorescence materials with ultralong lifetime, high phosphorescence quantum efficiency, and high stability for promising applications, especially under harsh conditions.

Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.

Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4 + T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.

Signal transduction systems enable organisms to monitor their external environments and accordingly adjust the cellular processes. In mast cells, the second messenger Ap 4 A binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. How the HINT1 protein recognizes and is regulated by Ap 4 A remain unclear. Here, using eight crystal structures, biochemical experiments, negative stain electron microscopy, and cellular experiments, we report that Ap 4 A specifically polymerizes HINT1 in solution and in activated rat basophilic leukemia cells. The polymerization interface overlaps with the area on HINT1 for MITF interaction, suggesting a possible competitive mechanism to release MITF for transcriptional activation. The mechanism depends precisely on the length of the phosphodiester linkage of Ap 4 A. These results highlight a direct polymerization signaling mechanism by the second messenger.