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Abstract Vigilance refers to being alertly watchful or paying sustained attention to avoid potential threats. Animals in vigilance states reduce locomotion and have an enhanced sensitivity to aversive stimuli so as to react quickly to dangers. Here we report that an unconventional 5-HT driven mechanism operating at neural circuit level which shapes the internal state underlying vigilance behavior in zebrafish and male mice. The neural signature of internal vigilance state was characterized by persistent low-frequency high-amplitude neuronal synchrony in zebrafish dorsal pallium and mice prefrontal cortex. The neuronal synchronization underlying vigilance was dependent on intense release of 5-HT induced by persistent activation of either DRN 5-HT neuron or local 5-HT axon terminals in related brain regions via activation of 5-HTR7. Thus, we identify a mechanism of vigilance behavior across species that illustrates the interplay between neuromodulators and neural circuits necessary to shape behavior states.

The mechanisms involved in regeneration of the spinal cord after injury are unclear. Here, the authors show that a subpopulation of intraspinal serotonergic neurons localized at the injury site stimulates axonal regrowth of interneurons via 5-HT1B receptor, resulting in recovery of function following SCI in zebrafish.

Abstract Single-atom catalysts (SACs) have attracted interest in photodynamic therapy (PDT), while they are normally limited by the side effects on normal tissues and the interference from the Tumor Microenvironment (TME). Here we show a TME-activated in situ synthesis of SACs for efficient tumor-specific water-based PDT. Upon reduction by upregulated GSH in TME, C3N4-Mn SACs are obtained in TME with Mn atomically coordinated into the cavity of C3N4 nanosheets. This in situ synthesis overcomes toxicity from random distribution and catalyst release in healthy tissues. Based on the Ligand-to-Metal charge transfer (LMCT) process, C3N4-Mn SACs exhibit enhanced absorption in the red-light region. Thereby, a water-splitting process is induced by C3N4-Mn SACs under 660 nm irradiation, which initiates the O2-independent generation of highly toxic hydroxyl radical (·OH) for cancer-specific PDT. Subsequently, the ·OH-initiated lipid peroxidation process is demonstrated to devote effective cancer cell death. The in situ synthesized SACs facilitate the precise cancer-specific conversion of inert H2O to reactive ·OH, which facilitates efficient cancer therapy in female mice. This strategy achieves efficient and precise cancer therapy, not only avoiding the side effects on normal tissues but also overcoming tumor hypoxia.

Abstract Proteins containing a ubiquitin regulatory X (UBX) domain are cofactors of Cell Division Cycle 48 (CDC48) and function in protein quality control. However, whether and how UBX-containing proteins participate in host–microbe interactions remain unclear. Here we show that MoNLE1, an effector from the fungal pathogen Magnaporthe oryzae, is a core virulence factor that suppresses rice immunity by specifically interfering with OsPUX8B.2. The UBX domain of OsPUX8B.2 is required for its binding to OsATG8 and OsCDC48-6 and controls its 26 S proteasome–dependent stability. OsPUX8B.2 and OsCDC48-6 positively regulate plant immunity against blast fungus, while the high-temperature tolerance heat-shock protein OsBHT, a putative cytoplasmic substrate of OsPUX8B.2–OsCDC48-6, negatively regulates defense against blast infection. MoNLE1 promotes the nuclear migration and degradation of OsPUX8B.2 and disturbs its association with OsBHT. Given the high conservation of MoNLE1 among fungal isolates, plants with broad and durable blast resistance might be generated by engineering intracellular proteins resistant to MoNLE1.

Micro- and nanostructures found in nature can be adopted to new uses and materials in engineered composites. Here authors demonstrate large enhancements in toughness and electrical conductivity in a ceramic upon addition of graphene at low (1 volume %) levels.

Thermal conductivity and electrical resistivity at ultralow temperatures and high magnetic fields are studied in the topological compensated semimetals TaAs 2 , NbAs 2 , and NdSb. A striking phenomenon is observed where the thermal conductivity shows a T 4 scaling at very low temperatures, while the resistivity shows a T-independent residual term. This indicates a strong violation of the Wiedemann-Franz (WF) law, since the field dependence of κ shows that the low-temperature thermal conductivity is dominated by electronic transport. The obtained Lorenz ratio is hundreds of times lower than Sommerfeld's value even when approaching the zero-temperature limit. The strong downward deviation of the WF law at very low temperatures point to a non-Fermi liquid state in these materials. In addition, the giant thermal quantum oscillations accompanied by antiphase characteristics have been observed. Our findings not only point to a possible non-Fermi liquid ground state of these topological compensated semimetals, but also reveal an unusual T 4 temperature dependence for the electronic thermal conductivity., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Unsymmetric disulfides are prevalent in natural products and are essential in medicinal chemistry and materials science, but their robust synthesis poses significant challenges. In this paper, we report an expeditous transition-metal-free methodology for synthesizing unsymmetric disulfides through the addition of perthiyl radicals to alkenes. This study marks the use of generating perthiyl radicals by reacting SO 2 with unactivated alkyl (pseudo)halides (Cl/Br/I/OTs). Various primary, secondary and tertiary alkyl (pseudo)halides substituted with different functional groups successfully function as suitable reactants. The formation of perthiyl radicals and their involvement in the reaction process are verified through mechanistic studies and DFT calculations. Overall, this method leverages readily available alkyl electrophiles and alkenes alongside SO 2 in a single reaction setup to efficiently form both carbon-sulfur and sulfur-sulfur bonds simultaneously., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Extending ferroelectric materials to two-dimensional limit provides versatile applications for the development of next-generation nonvolatile devices. Conventional ferroelectricity requires materials consisting of at least two constituent elements associated with polar crystalline structures. Monolayer graphene as an elementary two-dimensional material unlikely exhibits ferroelectric order due to its highly centrosymmetric hexagonal lattices. Here, we report the observations of electronic ferroelectricity in monolayer graphene by introducing asymmetric moiré superlattice at the graphene/h-BN interface, in which the electric polarization stems from electron-hole dipoles. The polarization switching is probed through the measurements of itinerant Hall carrier density up to room temperature, manifesting as standard polarization-electric field hysteresis loops. We find ferroelectricity in graphene moiré systems exhibits generally similar characteristics in monolayer, bilayer, and trilayer graphene, which indicates layer polarization is not essential to observe the ferroelectricity. Furthermore, we demonstrate the applications of this ferroelectric moiré structures in multi-state nonvolatile data storage with high retention and the emulation of versatile synaptic behaviors. Our work not only provides insights into the fundamental understanding of ferroelectricity, but also demonstrates the potential of graphene for high-speed and multi-state nonvolatile memory applications., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Recent advances have uncovered an exotic sliding ferroelectric mechanism, which endows to design atomically thin ferroelectrics from non-ferroelectric parent monolayers. Although notable progress has been witnessed in understanding the fundamental properties, functional devices based on sliding ferroelectrics remain elusive. Here, we demonstrate the rewritable, non-volatile memories at room-temperature with a two-dimensional (2D) sliding ferroelectric semiconductor of rhombohedral-stacked bilayer MoS 2 . The 2D sliding ferroelectric memories (SFeMs) show superior performances with a large memory window of >8 V, a high conductance ratio of above 10 6 , a long retention time of >10 years, and a programming endurance greater than 10 4 cycles. Remarkably, flexible SFeMs are achieved with state-of-the-art performances competitive to their rigid counterparts and maintain their performances post bending over 10 3 cycles. Furthermore, synapse-specific Hebbian forms of plasticity and image recognition with a high accuracy of 97.81% are demonstrated based on flexible SFeMs., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The proximity ligation-based Hi-C and derivative methods are the mainstream tools to study genome-wide chromatin interactions. These methods often fragment the genome using enzymes functionally irrelevant to the interactions per se, restraining the efficiency in identifying structural features and the underlying regulatory elements. Here we present Footprint-C, which yields high-resolution chromatin contact maps built upon intact and genuine footprints protected by transcription factor (TF) binding. When analyzed at one-dimensional level, the billions of chromatin contacts from Footprint-C enable genome-wide analysis at single footprint resolution, and reveal preferential modes of local TF co-occupancy. At pairwise contact level, Footprint-C exhibits higher efficiency in identifying chromatin structural features when compared with other Hi-C methods, segregates chromatin interactions emanating from adjacent TF footprints, and uncovers multiway interactions involving different TFs. Altogether, Footprint-C results suggest that rich regulatory modes of TF may underlie both local residence and distal chromatin interactions, in terms of TF identity, valency, and conformational configuration., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The anthroponotic Cryptosporidium hominis differs from the zoonotic C. parvum in its lack of infectivity to animals, but several divergent subtypes have recently been found in nonhuman primates and equines. Here, we sequence 17 animal C. hominis isolates and generate a new IbA12G3 genome at the chromosome level. Comparative analysis with 222 human isolates shows significant genetic divergence of the animal isolates, with genetic recombination among them. They have additional subtelomeric insulinase and MEDLE genes. In interferon-γ knockout mice, three monkey isolates show differences in infectivity and induce higher and longer oocyst shedding than a reference C. parvum isolate. Deletion of the MEDLE genes significantly reduces the growth and pathogenicity of a virulent strain in mice. Co-infection of two fluorescence-tagged C. hominis subtypes produces bicolored oocysts, supporting the conclusion that mixed subtype infections can lead to genetic recombination. These data provide insight into potential determinants of host infectivity in Cryptosporidium, and a convenient animal model for biological studies of C. hominis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Two-dimensional (2D) semiconductors, combining remarkable electrical properties and mechanical flexibility, offer fascinating opportunities for flexible integrated circuits (ICs). Despite notable progress, so far the showcased 2D flexible ICs have been constrained to basic logic gates and ring oscillators with a maximum integration scale of a few thin film transistors (TFTs), creating a significant disparity in terms of circuit scale and functionality. Here, we demonstrate medium-scale flexible ICs integrating both combinational and sequential elements based on 2D molybdenum disulfide (MoS 2 ). By co-optimization of the fabrication processes, flexible MoS 2 TFTs with high device yield and homogeneity are implemented, as well as flexible NMOS inverters with robust rail-to-rail operation. Further, typical IC modules, such as NAND, XOR, half-adder and latch, are created on flexible substrates. Finally, a medium-scale flexible clock division module consisting of 112 MoS 2 TFTs is demonstrated based on an edge-triggered Flip-Flop circuit. Our work scales up 2D flexible ICs to medium-scale, showing promising developments for various applications, including internet of everything, health monitoring and implantable electronics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The recent worldwide outbreaks of mpox prioritize the development of a safe and effective mRNA vaccine. The contemporary mpox virus (MPXV) exhibits changing virological and epidemiological features, notably affecting populations already vulnerable to human immunodeficiency virus (HIV). Herein, we profile the immunogenicity of AR-MPXV5, a penta-component mRNA vaccine targeting five specific proteins (M1R, E8L, A29L, A35R, and B6R) from the representative contemporary MPXV clade II strain, in both naive and simian immunodeficiency virus (SIV)-infected nonhuman primates. Immunization with two doses of AR-MPXV5 to cynomolgus macaques effectively elicits antibody responses and cellular responses. Importantly, based on the challenge model with a contemporary MPXV clade II strain, AR-MPXV5 demonstrates effective efficacy in preventing skin lesions, eliminating viremia and reducing viral loads in multiple tissues after challenge in naive male animals. More importantly, AR-MPXV5 is well-tolerated in stable chronic SIV-infected rhesus monkeys, while eliciting comparable MPXV-specific humoral and cellular responses in both naive and SIV-infected monkeys. Together, these results support further clinical development of the AR-MPXV5 vaccine., Competing Interests: Competing interests: C.F.Q., Q.Y., R.R.Z., and Z.J.W. have filed a patent related to the vaccine reported in the study. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Noncollinear dipole textures greatly extend the scientific merits and application perspective of ferroic materials. In fact, noncollinear spin textures have been well recognized as one of the core issues of condensed matter, e.g. cycloidal/conical magnets with multiferroicity and magnetic skyrmions with topological properties. However, the counterparts in electrical polarized materials are less studied and thus urgently needed, since electric dipoles are usually aligned collinearly in most ferroelectrics/antiferroelectrics. Molecular crystals with electric dipoles provide a rich ore to explore the noncollinear polarity. Here we report an organic salt (H 2 Dabco)BrClO 4 (H 2 Dabco = N,N'-1,4-diazabicyclo[2.2.2]octonium) that shows a transition between the ferroelectric and antiferroelectric phases. Based on experimental characterizations and ab initio calculations, it is found that its electric dipoles present nontrivial noncollinear textures with 60 o -twisting angle between the neighbors. Then the ferroelectric-antiferroelectric transition can be understood as the coding of twisting angle sequence. Our study reveals the unique science of noncollinear electric polarity., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Ni-rich layered oxides (LiNi x Co y Mn 1-x-y O 2 , x > 0.8, NCM) are technologically important cathode (i.e., positive electrode) materials for next-generation high-energy batteries. However, they face challenges in cycle stability and durability due to internal strain accumulation and particle fracture as the batteries cycle. Here we report a simple molten-salt-assisted synthesis route to introduce gradiently distributed pores into the polycrystalline NCM secondary particles. The gradient porous strategy creates void spaces to buffer the anisotropic volume change of the primary particles, effectively mitigating the intergranular fracture and limiting the impedance growth. It not only increases the maximum accessible capacity of the NCM cathodes but also greatly enhances their cycle stability in practical pouch-type batteries and all-solid-state-batteries. It further enables a high nickel, low cobalt cathode (LiNi 0.96 Co 0.02 Mn 0.02 O 2 ) with a combination of high specific energy (941.2 Wh kg -1 based on cathode weight at 0.1 C and 25 °C, 1 C = 245 mA g -1 ) and high stability during cycling (80.5% capacity retention after 800 cycles at 1 C relative to that of the first cycle) and high-temperature storage (reversible capacity retention >95.5% after 42-day storage at 60 °C at the fully charged state) in pouch cells., Competing Interests: Competing interests: The authors declare no competing interest., (© 2024. The Author(s).)

Coronavirus Disease 2019 (COVID-19) emerged in December 2019, prompting the implementation of a "zero-COVID" policy in Mainland China. The easing of this policy in December 2022 led to a surge in COVID cases, which was believed to significantly increase antibiotic usage, potentially due to antibiotic misuse or increased coinfections. Our study aimed to compare antibiotic consumption and patterns before and after this policy adjustment. We utilised wastewater-based epidemiology (WBE) to analyse antibiotic levels in samples collected from five wastewater treatment plants in Eastern China during January and February of 2021 and 2023. 27 antibiotics were quantified using ultra-high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-MS/MS) and analysed via WBE, with the resulting estimates compared with catchment-specific prescription data. 23 antibiotics were detected in wastewater samples, with a substantial increase in usage in 2023 (ranging from 531% to 3734%), consistent with prescription data. Here, we show a significant rise in antibiotic consumption during the COVID-19 surge and this underscores the need for further investigation into the impacts of inappropriate antibiotic use in China., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Somatic variations can give rise to bud sports with advantageous traits, serving as the foundation for bud sport breeding in perennial plants. Here, we report a fully phased genome assembly of 'Fuji' apple, enabling comprehensive identification of somatic variants across 74 clonally propagated 'Fuji' varieties. Phylogenetic analysis indicates that spur-type and early-maturation traits in 'Fuji' sport varieties arise from multiple independent events. Several putative functional somatic variants have been identified, including a spur-type-specific deletion in the promoter of the TCP transcription factor gene MdTCP11. DNA methylation level of the deletion-associated miniature inverted-repeat transposable element is lower in spur-type varieties compared to standard-type varieties, while the expression of MdTCP11 is significantly higher. Overexpression of MdTCP11 in apple decreases plant height, highlighting its important role in the development of spur-type apple varieties. This study sheds light on the cloning history of 'Fuji' and provides valuable resources for apple breeding., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Little is known about the long-term effectiveness of risk-based treat-to-target cholesterol-lowering interventions on cardiovascular risk. Here, we show the emulated effectiveness of guideline-recommended low-density and non-high-density lipoprotein cholesterol-lowering interventions using the absolute risk reduction (ARR) and the restricted mean event-free time-based number needed to treat (NNT). With 5,375 participants, the 29-year risks for cardiovascular disease (CVD), all-cause mortality, and atherosclerotic CVD were 18.6%, 25.6%, and 17.7%, respectively. Long-term treat-to-target interventions showed significant reductions in CVD (ARR -2.3%, 95%CI -3.4% to -0.8%; NNT 115), all-cause mortality (-3.0%, -4.3% to -1.8%; 95), and atherosclerotic CVD (-2.6%, -3.5% to -1.2%; 104). Such effects appear more pronounced in women, smokers, and those with body mass index < 24 kg/m² or higher adherence rates., Competing Interests: Competing interests The Authors declare no competing interests., (© 2024. The Author(s).)

Diverse post-translational modifications have been shown to play important roles in regulating protein function in eukaryotes. By contrast, the roles of post-translational modifications in bacteria are not so well understood, particularly as they relate to pathogenesis. Here, we demonstrate post-translational protein modification by covalent addition of lactate to lysine residues (lactylation) in the human pathogen Staphylococcus aureus. Lactylation is dependent on lactate concentration and specifically affects alpha-toxin, in which a single lactylated lysine is required for full activity and virulence in infection models. Given that lactate levels typically increase during infection, our results suggest that the pathogen can use protein lactylation as a mechanism to increase toxin-mediated virulence during infection., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Ruthenium (Ru) is widely recognized as a low-cost alternative to iridium as anode electrocatalyst in proton-exchange membrane water electrolyzers (PEMWE). However, the reported Ru-based catalysts usually only operate within tens of hours in PEMWE because of their intrinsically high reactivity of lattice oxygen that leads to irrepressible Ru leaching and structural collapse. Herein, we report a design concept by employing large-sized and acid-resistant lattice lead (Pb) as a second element to induce a pinning effect for effectively narrowing the moving channels of oxygen atoms, thereby lowering the reactivity of lattice oxygen in Ru oxides. The Pb-RuO 2 catalyst presents a low overpotential of 188 ± 2 mV at 10 mA cm -2 and can sustain for over 1100 h in an acid medium with a negligible degradation rate of 19 μV h -1 . Particularly, the Pb-RuO 2 -based PEMWE can operate for more than 250 h at 500 mA cm -2 with a low degradation rate of only 17 μV h -1 . Experimental and theoretical calculation results reveal that Ru-O covalency is reduced due to the unique 6s-2p-4d orbital hybridization, which increases the loss energy of lattice oxygen and suppresses the over-oxidation of Ru for improved long-term stability in PEMWE., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Asparagales, the largest monocot order, is renowned for its ecological, economic, and medicinal significance. Here, we leverage transcriptome data from 455 Asparagales species to explore the phylogeny of Asparagales. Moreover, we investigate the evolutionary patterns of the genes involved in allium flavor formation. We not only establish a robust bifurcating phylogeny of Asparagales but also explore their reticulate relationships. Notably, we find that eight genes involved in the biosynthesis of allium flavor compounds underwent expansion in Allium species. Furthermore, we observe Allium-specific mutations in one amino acid within alliinase and three within lachrymatory factor synthase. Overall, our findings highlight the role of gene expansion, increased expression, and amino acid mutations in driving the evolution of Allium-specific compounds. These insights not only deepen our understanding of the phylogeny of Asparagales but also illuminate the genetic mechanisms underpinning specialized compounds., (© 2024. The Author(s).)

Ceria (CeO 2 ) is a widely used oxide catalyst, yet the nature of its active sites remains elusive. This study combines model and powder catalyst studies to elucidate the structure-activity relationships in ceria-catalyzed CO activation and hydrogenation. Well-defined ceria clusters are synthesized on planar CeO 2 (111) and exhibit dynamic and tunable ranges of Ce coordination numbers, which enhance their interaction with CO. Reduced ceria clusters (e.g., Ce 3 O 3 ) bind CO strongly and facilitate its dissociation, while near-stoichiometric clusters (e.g., Ce 3 O 7 ) adsorb CO weakly and promote oxidation via carbonate formation. Unlike planar ceria surfaces, supported ceria clusters exhibit dynamic properties and enhanced catalytic activity, that mimic those of powder ceria catalysts. Insight from model studies provide a method to quantify active sites on powder ceria and guide further optimization of ceria catalysts for syngas conversion. This work marks a leap toward model-guided catalyst design and highlights the importance of site-specific catalysis., (© 2024. The Author(s).)

TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet's disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD., (© 2024. The Author(s).)

During non-rapid eye movement (NREM) sleep, neural ensembles in the entorhinal-hippocampal circuit responsible for encoding recent memories undergo reactivation to facilitate the process of memory consolidation. This reactivation is widely acknowledged as pivotal for the formation of stable memory and its impairment is closely associated with memory dysfunction. To date, the neural mechanisms driving the reactivation of neural ensembles during NREM sleep remain poorly understood. Here, we show that the neural ensembles in the medial entorhinal cortex (MEC) that encode spatial experiences exhibit reactivation during NREM sleep. Notably, this reactivation consistently coincides with isolated theta waves. In addition, we found that the nucleus reuniens (RE) in the midline thalamus exhibits typical theta waves during NREM sleep, which are highly synchronized with those occurring in the MEC in male mice. Closed-loop optogenetic inhibition of the RE-MEC pathway specifically suppressed these isolated theta waves, resulting in impaired reactivation and compromised memory consolidation following a spatial memory task in male mice. The findings suggest that theta waves originating from the ventral midline thalamus play a role in initiating memory reactivation and consolidation during sleep., (© 2024. The Author(s).)

Near-neutral HCO 3 - aqueous solution plays an essential role in respiratory, mineralization and catalysis, yet the interconversion between hydrated CO 2 , HCO 3 - and CO 3 2- and the associated proton transfer under such proton-deficient conditions remain uncovered. Here we reveal that cation enables HCO 3 - to self-dissociate into OH - and CO 2 through a pH-independent process, where CO 2 hydration and subsequent proton transfer in acid-base reactions lead to the overall exchange of oxygen isotopes between HCO 3 - and H 2 O tracked by oxygen isotope-labeled Raman spectroscopy. Isolating HCO 3 - from cations with crown ether impedes HCO 3 - dissociation and the following reactions. Further molecular dynamics simulations demonstrate that the interplay between HCO 3 - and hydrated cations drives HCO 3 - dissociation. This study suggests a natural proton channel upon coupling HCO 3 - with cations., (© 2024. The Author(s).)

The stacking order and twist angle provide abundant opportunities for engineering band structures of two-dimensional materials, including the formation of moiré bands, flat bands, and topologically nontrivial bands. The inversion symmetry breaking in rhombohedral-stacked transitional metal dichalcogenides endows them with an interfacial ferroelectricity associated with an out-of-plane electric polarization. By utilizing twist angle as a knob to construct rhombohedral-stacked transitional metal dichalcogenides, antiferroelectric domain networks with alternating out-of-plane polarization can be generated. Here, we demonstrate that such spatially periodic ferroelectric polarizations in parallel-stacked twisted WSe 2 can imprint their moiré potential onto a remote bilayer graphene. This remote moiré potential gives rise to pronounced satellite resistance peaks besides the charge-neutrality point in graphene, which are tunable by the twist angle of WSe 2 . Our observations of ferroelectric hysteresis at finite displacement fields suggest the moiré is delivered by a long-range electrostatic potential. The constructed superlattices by moiré ferroelectricity represent a highly flexible approach, as they involve the separation of the moiré construction layer from the electronic transport layer. This remote moiré is identified as a weak potential and can coexist with conventional moiré. Our results offer a comprehensive strategy for engineering band structures and properties of two-dimensional materials by utilizing moiré ferroelectricity., (© 2024. The Author(s).)

Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity., (© 2024. The Author(s).)

The high non-radiative energy loss is a bottleneck issue that impedes the improvement of organic solar cells. The formation of triplet exciton is thought to be the main source of the large non-radiative energy loss. Decreasing the rate of back charge transfer is considered as an effective approach to alleviate the relaxation of the charge-transfer state and the triplet exciton generation. Herein, we develops an efficient ternary system based on D18:N3-BO:F-BTA3 by regulating the charge-transfer state disorder and the rate of back charge transfer of the blend. With the addition of F-BTA3, a well-defined morphology with a more condensed molecular packing is obtained. Moreover, a reduced charge-transfer state disorder is demonstrated in the ternary blend, which decreases the rate of back charge transfer as well as the triplet exciton formation, and therefore hinders the non-radiative recombination pathways. Consequently, D18:N3-BO:F-BTA3-based device produces a low non-radiative energy loss of 0.183 eV and a record-high efficiency of 20.25%. This work not only points towards the significant role of the charge-transfer state disorder on the suppression of triplet exciton formation and the non-radiative energy loss, but also provides a valuable insight for enhancing the performance of OSCs., (© 2024. The Author(s).)

Despite recent advances, severe acute pancreatitis (SAP) remains a lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer's medication, as being a protective agent in various male mouse SAP models. Microbiome sequencing, along with intestinal microbiota transplantation and mass cytometry technology, unveil that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both peripheral and intestinal immune systems. A metabolomics analysis of cecal contents from GV-971-treated SAP mice further identifies short-chain fatty acids, including propionate and butyrate, as key metabolites in inhibiting macrophage M1 polarization and subsequent lethal inflammation by blocking the MAPK pathway. These findings suggest GV-971 as a promising therapeutic for SAP by targeting the microbiota metabolic immune axis., (© 2024. The Author(s).)

Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment., (© 2024. The Author(s).)

Cancer is a significant cause of death around the world, and for many varieties, treatment is not successful. Therefore, there is a need for the development of innovative, efficacious, and precisely targeted treatments. Here, we develop a series of Au(I) complexes (1-4) through rational manipulation of ligand structures, thereby achieving tumor cell specific targeting and orchestrated tumor eradication via chemo-phototherapy and induced immunogenic cell death. A comprehensive exploration based on in vitro and in vivo female mice experimentation shows that complex 4 exhibits proficiency in specific tumor imaging, endoplasmic reticulum targeting, and has robust therapeutic capabilities. Mechanistic elucidation indicates that the anticancer effect derives from the synergistic actions of thioredoxin reductase inhibition, highly efficient reactive oxygen species production and immunogenic cell death. This work presents a report on a robust Au(I) complex integrating three therapeutic modalities within a singular system. The strategy presented in this work provides a valuable reference for the development of high-performance therapeutic agents., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Virulence factor genes (VFGs) play pivotal roles in bacterial infections and have been identified within the human gut microbiota. However, their involvement in chronic diseases remains poorly understood. Here, we establish an expanded VFG database (VFDB 2.0) consisting of 62,332 nonredundant orthologues and alleles of VFGs using species-specific average nucleotide identity ( https://github.com/Wanting-Dong/MetaVF&#95;toolkit/tree/main/databases ). We further develop the MetaVF toolkit, facilitating the precise identification of pathobiont-carried VFGs at the species level. A thorough characterization of VFGs for 5452 commensal isolates from healthy individuals reveals that only 11 of 301 species harbour these factors. Further analyses of VFGs within the gut microbiomes of nine chronic diseases reveal both common and disease-specific VFG features. Notably, in type 2 diabetes patients, long HiFi sequencing confirms that shared VF features are carried by pathobiont strains of Escherichia coli and Klebsiella pneumoniae. These findings underscore the critical importance of identifying and understanding VFGs in microbiome-associated diseases., (© 2024. The Author(s).)

Deep vein thrombosis (DVT) is a leading cause of morbidity and mortality after trauma. Here, we integrate plasma metabolomics and proteomics to evaluate the metabolic alterations and their function in up to 680 individuals with and without DVT after trauma (pt-DVT). We identify 28 metabolites and 2 clinical parameter clusters associated with pt-DVT. Then, we develop a panel of 9 metabolites (hexadecanedioic acid, pyruvic acid, L-Carnitine, serotonin, PE(P-18:1(11Z)/18:2(9Z,12Z)), 3-Hydroxycapric acid, 5,6-DHET, 3-Methoxybenzenepropanoic acid and pentanenitrile) that can predict pt-DVT with high performance, which can be verified in an independent cohort. Furthermore, the integration analysis of metabolomics and proteomics data indicates that the upregulation of glycolysis/gluconeogenesis-TCA cycle may promote thrombosis by regulating ROS levels in red blood cells, suggesting that interfering with this process might be potential therapeutic strategies for pt-DVT. Together, our study comprehensively delineates the metabolic and hematological dysregulations for pt-DVT, and provides potential biomarkers for early detection., (© 2024. The Author(s).)

Neovaginas are surgically constructed to correct uterovaginal agenesis in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome or as part of gender-affirming surgery for transfeminine individuals. Understanding the assembly of the neovaginal microbiota is crucial for guiding its management. To address this, we conducted a longitudinal study on MRKH patients following laparoscopic peritoneal vaginoplasty. Our findings reveal that the early microbial assemblage exhibited stochastic characteristics, accompanied with a notable bloom of Enterococcus faecalis and genital Mycoplasmas. While both the pre-surgery dimple microbiota and the fecal microbiota constituted the primary species pool, the neovaginal microbiota developed into a microbiota that resembled that of a normal vagina at 6-12 months post-surgery, albeit with a bacterial vaginosis (BV)-like structure. By 2-4 years post-surgery, the neovaginal microbiota had further evolved into a structure closely resembling with the homeostatic pre-surgery dimple microbiota. This concords with the development of the squamous epithelium in the neovagina and highlights the pivotal roles of progressive selective forces imposed by the evolving neovaginal environment and the colonization tropism of vaginal species. Notably, we observed that strains of Lactobacillus crispatus colonizing the neovagina primarily originated from the dimple. Since L. crispatus is generally associated with vaginal health, this finding suggests potential avenues for future research to promote its colonization., (© 2024. The Author(s).)

Cobalt phthalocyanine immobilized on carbon nanotube has demonstrated appreciable selectivity and activity for methanol synthesis in electrocatalytic CO 2 /CO reduction. However, discrepancies in methanol production selectivity and activity between CO 2 and CO reduction have been observed, leading to inconclusive mechanisms for methanol production in this system. Here, we discover that the interaction between cobalt phthalocyanine molecules and defects on carbon nanotube substrate plays a key role in methanol production during CO 2 /CO electroreduction. Through detailed operando X-ray absorption and infrared spectroscopies, we find that upon application of cathodic potential, this interaction induces the transformation of the planar CoN 4 center in cobalt phthalocyanine to an out-of-plane distorted configuration. Consequently, this potential induced structural change promotes the transformation of linearly bonded *CO at the CoN 4 center to bridge *CO, thereby facilitating methanol production. Overall, these comprehensive mechanistic investigations and the outstanding performance (methanol partial current density over 150 mA cm -2 ) provide valuable insights in guiding the activity and selectivity of immobilized cobalt phthalocyanine for methanol production in CO 2 /CO reduction., (© 2024. The Author(s).)

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3 -/- (Shn3 -/- ) mice with augmented osteoblast activity, we show Shn3 -/- mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3 -/- mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome., (© 2024. The Author(s).)

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention., (© 2024. The Author(s).)

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19 +/- HuDEP2 cells and CD34 + cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia., (© 2024. The Author(s).)

Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The development of accelerated corneal crosslinking (A-CXL) protocols to shorten the treatment time has been hampered by the rapid depletion of stromal oxygen when higher UVA intensities are used, resulting in a reduced cross-linking effect. It is therefore imperative to develop better methods to increase the oxygen concentration within the corneal stroma during the A-CXL process. Photocatalytic oxygen-generating nanomaterials are promising candidates to solve the hypoxia problem during A-CXL. Biocompatible graphitic carbon nitride (g-C 3 N 4 ) quantum dots (QDs)-based oxygen self-sufficient platforms including g-C 3 N 4 QDs and riboflavin/g-C 3 N 4 QDs composites (RF@g-C 3 N 4 QDs) have been developed in this study. Both display excellent photocatalytic oxygen generation ability, high reactive oxygen species (ROS) yield, and excellent biosafety. More importantly, the A-CXL effect of the g-C 3 N 4 QDs or RF@g-C 3 N 4 QDs composite on male New Zealand white rabbits is better than that of the riboflavin 5'-phosphate sodium (RF) A-CXL protocol under the same conditions, indicating excellent strengthening of the cornea after A-CXL treatments. These lead us to suggest the potential application of g-C 3 N 4 QDs in A-CXL for corneal ectasias and other corneal diseases., (© 2024. The Author(s).)

Suppressing the kinetically favorable lattice oxygen oxidation mechanism pathway and triggering the adsorbate evolution mechanism pathway at the expense of activity are the state-of-the-art strategies for Ru-based electrocatalysts toward acidic water oxidation. Herein, atomically dispersed Ru species are anchored into an acidic stable vinyl-linked 2D covalent organic framework with unique crossed π-conjugation, termed as COF-205-Ru. The crossed π-conjugated structure of COF-205-Ru not only suppresses the dissolution of Ru through strong Ru-N motifs, but also reduces the oxidation state of Ru by multiple π-conjugations, thereby activating the oxygen coordinated to Ru and stabilizing the oxygen vacancies during oxygen evolution process. Experimental results including X-ray absorption spectroscopy, in situ Raman spectroscopy, in situ powder X-ray diffraction patterns, and theoretical calculations unveil the activated oxygen with elevated energy level of O 2p band, decreased oxygen vacancy formation energy, promoted electrochemical stability, and significantly reduced energy barrier of potential determining step for acidic water oxidation. Consequently, the obtained COF-205-Ru displays a high mass activity with 2659.3 A g -1 , which is 32-fold higher than the commercial RuO 2 , and retains long-term durability of over 280 h. This work provides a strategy to simultaneously promote the stability and activity of Ru-based catalysts for acidic water oxidation., (© 2024. The Author(s).)

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system., (© 2024. The Author(s).)

Stomatal movement is vital for plants to exchange gases and adaption to terrestrial habitats, which is regulated by environmental and phytohormonal signals. Here, we demonstrate that hydrogen peroxide (H 2 O 2 ) is required for light-induced stomatal opening. H 2 O 2 accumulates specifically in guard cells even when plants are under unstressed conditions. Reducing H 2 O 2 content through chemical treatments or genetic manipulations results in impaired stomatal opening in response to light. This phenomenon is observed across different plant species, including lycopodium, fern, and monocotyledonous wheat. Additionally, we show that H 2 O 2 induces the nuclear localization of KIN10 protein, the catalytic subunit of plant energy sensor SnRK1. The nuclear-localized KIN10 interacts with and phosphorylates the bZIP transcription factor bZIP30, leading to the formation of a heterodimer between bZIP30 and BRASSINAZOLE-RESISTANT1 (BZR1), the master regulator of brassinosteroid signaling. This heterodimer complex activates the expression of amylase, which enables guard cell starch degradation and promotes stomatal opening. Overall, these findings suggest that H 2 O 2 plays a critical role in light-induced stomatal opening across different plant species., (© 2024. The Author(s).)