Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion.

DNA-induced liquid-liquid phase separation of cyclic GMP-AMP synthase (cGAS) triggers a potent response to detect pathogen infection and promote innate immune signaling. Whether and how pathogens manipulate cGAS-DNA condensation to mediate immune evasion is unknown. We report the identification of a structurally related viral tegument protein family, represented by ORF52 and VP22 from gamma- and alpha-herpesvirinae, respectively, that employs a conserved mechanism to restrict cGAS-DNA phase separation. ORF52/VP22 proteins accumulate into, and effectively disrupt, the pre-formed cGAS-DNA condensation both in vitro and in cells. The inhibition process is dependent on DNA-induced liquid-liquid phase separation of the viral protein rather than a direct interaction with cGAS. Moreover, highly abundant ORF52 proteins carried within viral particles are able to target cGAS-DNA phase separation in early infection stage. Our results define ORF52/VP22-type tegument proteins as a family of inhibitors targeting cGAS-DNA phase separation and demonstrate a mechanism for how viruses overcome innate immunity.

Recognition of cyclic dinucleotides and folates by human SLC19A1.

Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A122,23. Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.

Designing 3d Transition Metal Cation-Doped MRuOx As Durable Acidic Oxygen Evolution Electrocatalysts for PEM Water Electrolyzers.

The continuous dissolution and oxidation of active sites in Ru-based electrocatalysts have greatly hindered their practical application in proton exchange membrane water electrolyzers (PEMWE). In this work, we first used density functional theory (DFT) to calculate the dissolution energy of Ru in the 3d transition metal-doped MRuOx (M = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) to evaluate their stability for acidic oxygen evolution reaction (OER) and screen out ZnRuOx as the best candidate. To confirm the theoretical predictions, we experimentally synthesized these MRuOx materials and found that ZnRuOx indeed displays robust acidic OER stability with a negligible decay of η10 after 15 000 CV cycles. Of importance, using ZnRuOx as the anode, the PEMWE can run stably for 120 h at 200 mA cm-2. We also further uncover the stability mechanism of ZnRuOx, i.e., Zn atoms doped in the outside of ZnRuOx nanocrystal would form a "Zn-rich" shell, which effectively shortened average Ru-O bond lengths in ZnRuOx to strengthen the Ru-O interaction and therefore boosted intrinsic stability of ZnRuOx in acidic OER. In short, this work not only provides a new study paradigm of using DFT calculations to guide the experimental synthesis but also offers a proof-of-concept with 3d metal dopants as RuO2 stabilizer as a universal principle to develop high-durability Ru-based catalysts for PEMWE.

Kinetically Controlled Structural Modulation of the Self-Assembled Silver Nanoclusters.

Metal nanoclusters (NCs) with atomic precision are growing into a fascinating class of building blocks for supramolecular chemistry. What makes it more interesting is the enhanced optical properties of the ordered structures, including aggregation-induced emission (AIE). However, algorithm dictating the self-assembly of metal NCs in multicomponent environment remains largely unknown, and effective means to manipulate the self-assembly is still lacking, especially under kinetic control. Herein, nanofibers which contain sub-1 nm nanowires and exhibit circularly polarized phosphorescence (CPP) are obtained from crystallization-induced self-assembly (CISA) of water-soluble, negatively charged silver NCs (Ag9 -NCs) in the presence of glutamic acid (Glu). By the introduction of a positively-charged additive (choline chloride, CC), the structure of the nanowires is modulated and the lateral interaction between adjacent nanofibers is adjusted, leading to simultaneous improvement of the phosphorescence and chirality which finally enhances CPP. Importantly, changing the time at which CC is introduced altered the kinetic pathway of the CISA, which enables to effectively manipulate both the final structures of the self-assembled Ag9 -NCs and the output of the optical signals.

Baicalin ameliorates the gut barrier function and intestinal microbiota of broiler chickens.

The deoxynivalenol (DON)-contaminated feeds can impair chicken gut barrier function, disturb the balance of the intestinal microbiota, decrease chicken growth performance and cause major economic loss. With the aim of investigating the ameliorating effects of baicalin on broiler intestinal barrier damage and gut microbiota dysbiosis induced by DON, a total of 150 Arbor Acres broilers are used in the present study. The morphological damage to the duodenum, jejunum, and ileum caused by DON is reversed by treatment with different doses of baicalin, and the expression of tight junction proteins (ZO-1, claudin-1, and occludin) is also significantly increased in the baicalin-treated groups. Moreover, the disturbance of the intestinal microbiota caused by DON-contaminated feed is altered by baicalin treatment. In particular, compared with those in the DON group, the relative abundances of Lactobacillus, Lachnoclostridium, Ruminiclostridium and other beneficial microbes in the baicalin-treated groups are significantly greater. However, the percentage of unclassified_f__Lachnospiraceae in the baicalin-treated groups is significantly decreased in the DON group. Overall, the current results demonstrate that different doses of baicalin can improve broiler intestinal barrier function and the ameliorating effects on broiler intestinal barrier damage may be related to modulations of the intestinal microbiota.

Direct Measurement of Dissolved Gas Using a Tapered Single-Mode Silica Fiber.

Dissolved gases in the aquatic environment are critical to understanding the population of aquatic organisms and the ocean. Currently, laser absorption techniques based on membrane separation technology have made great strides in dissolved gas detection. However, the prolonged water-gas separation time of permeable membranes remains a key obstacle to the efficiency of dissolved gas analysis. To mitigate these limitations, we demonstrated direct measurement of dissolved gas using the evanescent-wave absorption spectroscopy of a tapered silica micro-fiber. It enhanced the analysis efficiency of dissolved gases without water-gas separation or sample preparation. The feasibility of this sensor for direct measurement of dissolved gases was verified by taking the detection of dissolved ammonia as an example. With a sensing length of 5 mm and a consumption of ~50 µL, this sensor achieves a system response time of ~11 min and a minimum detection limit (MDL) of 0.015%. Possible strategies are discussed for further performance improvement in in-situ applications requiring fast and highly sensitive dissolved gas sensing.

Co-Assembled Supramolecular Organohydrogels of Amphiphilic Zwitterion and Polyoxometalate with Controlled Microstructures.

The organization of modifiable and functional building components into various superstructures is of great interest due to their broad applications. Supramolecular self-assembly, based on rationally designed building blocks and appropriately utilized driving forces, is a promising and widely used strategy for constructing superstructures with well-defined nanostructures and diverse morphologies across multiple length scales. In this study, two homogeneous organohydrogels with distinct appearances were constructed by simply mixing polyoxometalate (phosphomolybdic acid, HPMo) and a double-tailed zwitterionic quaternary ammonium amphiphile in a binary solvent of water and dimethyl sulfoxide (DMSO). The delicate balance between electrostatic attraction and repulsion of anionic HPMo clusters and zwitterionic structures drove them to co-assemble into homogeneous organohydrogels with diverse microstructures. Notably, the morphologies of the organohydrogels, including unilamellar vesicles, onion-like vesicles, and spherical aggregates, can be controlled by adjusting the ionic interactions between the zwitterionic amphiphiles and phosphomolybdic acid clusters. Furthermore, we observed an organohydrogel fabricated with densely stacked onion-like structures (multilamellar vesicles) consisting of more than a dozen layers at certain proportions. Additionally, the relationships between the self-assembled architectures and the intermolecular interactions among the polyoxometalate, zwitterionic amphiphile, and solvent molecules were elucidated. This study offers valuable insights into the mechanisms of polyoxometalate-zwitterionic amphiphile co-assembly, which are essential for the development of materials with specific structures and emerging functionalities.

Developing Superior Hydrophobic 3D Hierarchical Electrocatalysts Embedding Abundant Catalytic Species for High Power Density Zn-Air Battery.

It is essential but still challenging to design and construct inexpensive, highly active bifunctional oxygen electrocatalysts for the development of high power density zinc-air batteries (ZABs). Herein, a CoFe-S@3D-S-NCNT electrocatalyst with a 3D hierarchical structure of carbon nanotubes growing on leaf-like carbon microplates is designed and prepared through chemical vapour deposition pyrolysis of CoFe-MOF and subsequent hydrothermal sulfurization. Its 3D hierarchical structure shows excellent hydrophobicity, which facilitates the diffusion of oxygen and thus accelerates the oxygen reduction reaction (ORR) kinetic process. Alloying and sulfurization strategies obviously enrich the catalytic species in the catalyst, including cobalt or cobalt ferroalloy sulfides, their heterojunction, core-shell structure, and S, N-doped carbon, which simultaneously improve the ORR/OER catalytic activity with a small potential gap (ΔE = 0.71 V). Benefiting from these characteristics, the corresponding liquid ZABs show high peak power density (223 mW cm-2 ), superior specific capacity (815 mA h gZn -1 ), and excellent stability at 5 mA cm-2 for ≈900 h. The quasi-solid-state ZABs also exhibit a very high peak power density of 490 mW cm-2 and an excellent voltage round-trip efficiency of more than 64%. This work highlights that simultaneous composition optimization and microstructure design of catalysts can effectively improve the performance of ZABs.

Pan-cancer analyses reveal regulation and clinical outcome association of the shelterin complex in cancer.

Shelterin, a protective complex at telomeres, plays essential roles in cancer. In addition to maintain telomere integrity, shelterin functions in various survival pathways. However, the detailed mechanisms of shelterin regulation in cancer remain elusive. Here, we perform a comprehensive analysis of shelterin in 9125 tumor samples across 33 cancer types using multi-omic data from The Cancer Genome Atlas, and validate some findings in Chinese Glioma Genome Atlas and cancer cell lines from Cancer Cell Line Encyclopedia. In the genomic landscape, we identify the amplification of TRF1 and POT1, co-amplification/deletion of TRF2-RAP1-TPP1 as the dominant alteration events. Clustering analysis based on shelterin expression reveals three cancer clusters with different degree of genome instability. To measure overall shelterin activity in cancer, we derive a shelterin score based on shelterin expression. Pathway analysis shows shelterin is positively correlated with E2F targets, while is negatively correlated with p53 pathway. Importantly, shelterin links to tumor immunity and predicts response to PD-1 blockade immune therapy. In-depth miRNA analysis reveals a miRNA-shelterin interaction network, with p53 regulated miRNAs targeting multiple shelterin components. We also identify a significant amount of lncRNAs regulating shelterin expression. In addition, we find shelterin expression could be used to predict patient survival in 24 cancer types. Finally, by mining the connective map database, we discover a number of potential drugs that might target shelterin. In summary, this study provides broad molecular signatures for further functional and therapeutic studies of shelterin, and also represents a systemic approach to characterize key protein complex in cancer.

Predictive model containing gene signature and shear wave elastography to predict patient outcomes after Kasai surgery in biliary atresia.

AIMS: Infants with biliary atresia (BA) are treated with Kasai portoenterostomy (KPE) surgery, but many BA patients need subsequent salvage liver transplants. The aim of this study is to develop a comprehensive gene-clinical model based on two-dimensional shear wave elastography (2DSWE), liver gene expression, and other clinical parameters to predict response to KPE for BA patients. METHODS: Differentially expressed gene patterns between liver samples of BA (n = 102) and non-BA control (n = 14) were identified using RNA sequencing analysis. Biliary atresia patients were then randomly assigned to training and validation cohorts. Gene classifier based on the differentially expressed genes was built in the training cohort. Nomogram models with and without gene classifier were further constructed and validated for predicting native liver survival of BA patients. The utility of the nomograms was compared by C-index. RESULTS: Using the least absolute shrinkage and selection operator model, we generated a nine-gene prognostic classifier. The nomogram based on the nine-gene classifier, age, preoperative 2DSWE, and albumin had the better C-index compared to gene classifier alone in the training cohort (0.83 [0.76-0.90] vs. 0.69 [0.61-0.77], p = 0.003) and the validation cohort (0.74 [0.67-0.82] vs. 0.62 [0.55-0.70], p = 0.001). Using risk scores developed from the nomogram, the 12-month survival rates of BA patients with native liver were 35.7% (95% confidence interval [CI], 22.7-56.3) in the high-risk group and 80.8% (95% CI, 63.4-100.0) in the low-risk group in the validation cohort. CONCLUSIONS: The comprehensive genetic-clinical nomogram based on preoperative 2DSWE, liver gene expression, and other clinical parameters can accurately predict response to KPE.

Matrine combined with Osthole inhibited the PERK apoptosis of splenic lymphocytes in PCV2-infected mice model.

BACKGROUND: Porcine circovirus type 2 (PCV2) is one of the major pathogens commonly found in pigs, which causes immunosuppression and apoptosis. Vaccination and a single drug cannot totally prevent and treat PCV2 infection. Our previous in vitro study reported that the synergistic anti-PCV2 effect of Matrine and Osthole was better than that of Matrine or Osthole alone, This study was aimed to evaluate the synergistic anti-PCV2 effect as well as the underline molecular mechanism of Matrine and Osthole in Kunming (KM) mice model infected with PCV2. KM mice were randomly divided into 8 groups namely control group, PCV2 infected, Matrine combined with Osthole high dose treatment (40 mg/kg + 12 mg/kg), medium dose treatment (20 mg/kg + 6 mg/kg), low dose treatment (10 mg/kg + 3 mg/kg), Matrine treatment (40 mg/kg), Osthole treatment (12 mg/kg) and Ribavirin positive control (40 mg/kg) groups. PCV2 was intraperitoneally (i.p.) injected in all mice except the control group. 5 days of post-infection (dpi), mice in different treatment groups were injected i.p. with various doses of Matrine, Osthole and Ribavirin once daily for the next 5 consecutive days. RESULTS: The synergistic inhibitory effect of Matrine and Osthole on PCV2 replication in mouse liver was significantly heigher than that of Matrine and Osthole alone. The expression of GRP78, p-PERK, p-eIF2α, ATF4, CHOP, cleaved caspase-3 and Bax proteins were significantly reduced, while that of Bcl-2 was significantly increased in Matrine combined with Osthole groups, which alleviated the pathological changes caused by PCV2, such as interstitial pneumonia, loss of spleen lymphocytes, infiltration of macrophages and eosinophils. CONCLUSIONS: The synergistic anti-apoptotic effect of Matrine and Osthole was better than their alone effect, Both Matrine and Osthole had directly inhibited the expression of PCV2 Cap and the apoptosis of spleen cells induced by PCV2 Cap through the PERK pathway activated by endoplasmic reticulum (ER) GRP78. These results provided a new insight to control PCV2 infection and provide good component prescription candidate for the development of novel anti-PCV2 drugs.

Baicalin ameliorates high fat diet-induced nonalcoholic fatty liver disease in mice via adenosine monophosphate-activated protein kinase-mediated regulation of SREBP1/Nrf2/NF-κB signaling pathways.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease around the world, imposing severe threats on human health. Unfortunately, no clinically approved drugs are available for use as yet. Baicalin (BA) is reported to have hepatoprotective effects, and it is not clear whether BA can treat NAFLD and how. Here, a high-fat diet (HFD)-induced NAFLD mouse model was established to explore the protective roles and mechanisms of BA against HFD-induced NAFLD. Physiochemical results showed that BA exhibited significantly protective effects against HFD-induced NAFLD in mice. Liver transcriptomic analysis revealed that BA attenuated HFD-induced NAFLD via activating AMPK pathway, which was confirmed by the AMPK inhibitor Compound C. Additionally, the expression changes of AMPK downstream genes demonstrated that BA exerted ameliorative effects against NAFLD through AMPK-mediated inhibition of SREBP1 and NF-κB pathways, and activation of Nrf2 pathway. Taken together, our study reveals the protective roles of BA against HFD-caused NAFLD through AMPK-mediated modulation of SREBP1/Nrf2/NF-κB pathways, suggesting that BA has potential drug development implications. Most importantly, our study creates a paradigm through the combination of molecular biology and bioinformatics for further studies of action mechanisms of biomolecules combating diseases.

Matrine Targets Intestinal Lactobacillus acidophilus to Inhibit Porcine Circovirus Type 2 Infection in Mice.

Porcine circovirus type 2 (PCV2) has caused huge economic losses to the pig industry across the world. Matrine is a natural compound that has been shown to regulate intestinal flora and has anti-PCV2 activity in mouse models. PCV2 infection can lead to changes in intestinal flora. The intestinal flora has proved to be one of the important pharmacological targets of the active components of Traditional Chinese Medicine. This study aimed to determine whether matrine exerts anti-PCV2 effects by regulating intestinal flora. In this study, fecal microbiota transplantation (FMT) was used to evaluate the effect of matrine on the intestinal flora of PCV2-infected Kunming (KM) mice. The expression of the Cap gene in the liver and the ileum, the relative expression of IL-1ß mRNA, and the Lactobacillus acidophilus (L. acidophilus) gene in the ileum of mice were determined by real-time quantitative polymerase chain reaction (qPCR). ELISA was used to analyze the content of secretory immunoglobulin A (SIgA) in small intestinal fluid. L. acidophilus was isolated and identified from the feces of KM mice in order to study its anti-PCV2 effect in vivo. The expression of the Cap gene in the liver and the ileum and the relative expression of L. acidophilus and IL-1ß mRNA in the ileum were determined by qPCR. The results showed that matrine could reduce the relative expression of IL-1ß mRNA by regulating intestinal flora, and that its pharmacological anti-PCV2 and effect may be related to L. acidophilus. L. acidophilus was successfully isolated and identified from the feces of KM mice. The in vivo experiment revealed that administration of L. acidophilus also reduced the relative expression of IL-1ß mRNA, and that it had anti-PCV2 effects in PCV2-infected mice. It was found that matrine could regulate the abundance of L. acidophilus in the gut of mice to exert an anti-PCV2 effect and inhibit PCV2-induced inflammatory response.

Target Discovery of Matrine against PRRSV in Marc-145 Cells via Activity-Based Protein Profiling.

Porcine reproductive and respiratory syndrome (PRRS) seriously endangers the sustainable development of the pig industry. Our previous studies have shown that matrine can resist porcine reproductive and respiratory syndrome virus (PRRSV) infection. This study aimed to explore the anti-PRRSV targets of matrine in Marc-145 cells. Biotin-labeled matrine 1 and 2 were used as probes. MTT assay was used to determine the maximum non-cytotoxic concentration (MNTC) of each probe in Marc-145 cells. The anti-PRRSV activity of each probe was evaluated via MTT, qPCR and Western blot, and its anti-inflammatory activity was evaluated via qPCR and Western blot. The targets of matrine in Marc-145 cells were searched using activity-based protein profiling (ABPP), and compared with the targets predicted via network pharmacology for screening the potential targets of matrine against PRRSV. The protein-protein interaction networks (PPI) of potential targets were constructed using a network database and GO/KEGG enrichment analysis was performed. ACAT1, ALB, HMOX1, HSPA8, HSP90AB1, PARP1 and STAT1 were identified as potential targets of matrine, and their functions were related to antiviral capacity and immunity. Matrine may play an anti-PRRSV role by directly acting on ACAT1, ALB, HMOX1, HSPA8, HSP90AB1, PARP1 and STAT1.

Matrine Targets BTF3 to Inhibit the Growth of Canine Mammary Tumor Cells.

The canine mammary tumor model is more suitable for studying human breast cancer, and the safety concentrations of matrine and the biotin-labeled matrine probe were determined in canine primary mammary epithelial cells, and then selected canine mammary tumor cell lines CHMm and CHMp were incubated with matrine, and cell viability was detected by CCK-8. The biotin-labeled matrine probe was used to pull-down the targets of matrine in canine mammary tumor cells, and the targets were screened in combination with activity-based protein profiling (ABPP) and Genecards database, and verified by qPCR and western blot. The results showed that the maximum non-cytotoxic concentrations of matrine and biotin-labeled matrine probe in canine primary mammary epithelial cells were 250 µg/mL and 500 µg/mL, respectively. Matrine and biotin-labeled matrine probe had a proliferation inhibitory effect time-dependently on CHMm and CHMp cells within a safe concentration range, and induced autophagy in cells. Then BTF3 targets were obtained by applying ABPP and Genecards screening. Cellular thermal shift assay (CETSA) findings indicated that matrine could increase the heat stability of BTF3 protein. Pull-down employing biotin-labeled matrine probe with CHMm and CHMp cell lysates revealed that BTF3 protein was detected in the biotin-labeled matrine probe group and that BTF3 protein was significantly decreased by the addition of matrine. The qPCR and western blot findings of CHMm and CHMp cells treated with matrine revealed that matrine decreased the expression of the BTF3 gene and protein with the extension of the action time, and the impact was more substantial at the protein level, respectively.

Molecular Simulation Study on the Interaction between Porcine CR1-like and C3b.

The molecular basis of porcine red blood cell immune adhesion function stems from the complement receptor type 1-like (CR1-like) on its cell membrane. The ligand for CR1-like is C3b, which is produced by the cleavage of complement C3; however, the molecular mechanism of the immune adhesion of porcine erythrocytes is still unclear. Here, homology modeling was used to construct three-dimensional models of C3b and two fragments of CR1-like. An interaction model of C3b-CR1-like was constructed by molecular docking, and molecular structure optimization was achieved using molecular dynamics simulation. A simulated alanine mutation scan revealed that the amino acids Tyr761, Arg763, Phe765, Thr789, and Val873 of CR1-like SCR 12-14 and the amino acid residues Tyr1210, Asn1244, Val1249, Thr1253, Tyr1267, Val1322, and Val1339 of CR1-like SCR 19-21 are key residues involved in the interaction of porcine C3b with CR1-like. This study investigated the interaction between porcine CR1-like and C3b using molecular simulation to clarify the molecular mechanism of the immune adhesion of porcine erythrocytes.

Atomically Dispersed Zn-Pyrrolic-N4 Cathode Catalysts for Hydrogen Fuel Cells.

To achieve practical application of fuel cell, it is vital to develop highly efficient and durable Pt-free catalysts. Herein, we prepare atomically dispersed ZnNC catalysts with Zn-Pyrrolic-N4 moieties and abundant mesoporous structure. The ZnNC-based anion-exchange membrane fuel cell (AEMFC) presents an ultrahigh peak power density of 1.63 and 0.83 W cm-2 in H2 -O2 and H2 -air (CO2 -free), and also exhibits long-term stability with more than 120 and 100 h for H2 -air (CO2 -free) and H2 -O2 , respectively. Density functional calculations further unveil that the Zn-Pyrrolic-N4 structure is the origin of high activity of as-synthesized ZnNC catalyst, while the Zn-Pyridinic-N4 moiety is inactive for oxygen reduction reaction (ORR), which successfully explain the puzzle why most Zn-metal-organic framework -derived ZnNC catalysts in previous reports did not present good ORR activity because of their Zn-Pyridinic-N4 moieties. This work offers a new route for speeding up development of AEMFCs.

Multi-layer 3D Chirality and Double-Helical Assembly in a Copper Nanocluster with a Triple-Helical Cu15 Core.

Conceptually mimicking biomolecules' ability to construct multiple-helical aggregates with emergent properties and functions remains a long-standing challenge. Here we report an atom-precise 18-copper nanocluster (NC), Cu18 H(PET)14 (TPP)6 (NCS)3 (Cu18 H) which contains a pseudo D3 -symmetrical triple-helical Cu15 core. Structurally, Cu18 H may be also viewed as sandwich type of sulfur-bridged chiral copper cluster units [Cu6 -Cu6 -Cu6 ], endowing three-layered 3D chirality. More importantly, the chiral NCs are aggregated into an infinite double-stranded helix supported by intra-strand homonuclear C-H⋅⋅⋅H-C dihydrogen contacts and inter-strand C-H/π and C-H/S interactions. The unique multi-layered 3D chirality and the double-helical assembly of Cu18 H are evocative of DNA. Moreover, the collective behaviours of the aggregated NCs not only exhibit crystallization-induced emission enhancement (CIEE) and aggregation-induced emission enhancement (AIEE) effects in the deep-red region, but also efficiently catalyze electron transfer (ET) reaction. This study thus presents that hierarchical assemblies of atomically defined copper NCs could be intricate as observed for important biomolecules like DNA with emergent properties arising from aggregated behaviours.

Atomically Precise Copper Nanoclusters for Highly Efficient Electroreduction of CO2 towards Hydrocarbons via Breaking the Coordination Symmetry of Cu Site.

We propose an effective highest occupied d-orbital modulation strategy engendered by breaking the coordination symmetry of sites in the atomically precise Cu nanocluster (NC) to switch the product of CO2 electroreduction from HCOOH/CO to higher-valued hydrocarbons. An atomically well-defined Cu6 NC with symmetry-broken Cu-S2 N1 active sites (named Cu6 (MBD)6 , MBD=2-mercaptobenzimidazole) was designed and synthesized by a judicious choice of ligand containing both S and N coordination atoms. Different from the previously reported high HCOOH selectivity of Cu NCs with Cu-S3 sites, the Cu6 (MBD)6 with Cu-S2 N1 coordination structure shows a high Faradaic efficiency toward hydrocarbons of 65.5 % at -1.4 V versus the reversible hydrogen electrode (including 42.5 % CH4 and 23 % C2 H4 ), with the hydrocarbons partial current density of -183.4 mA cm-2 . Theoretical calculations reveal that the symmetry-broken Cu-S2 N1 sites can rearrange the Cu 3d orbitals with d x 2 - y 2 ${d_{x^2 - y^2 } }$ as the highest occupied d-orbital, thus favoring the generation of key intermediate *COOH instead of *OCHO to favor *CO formation, followed by hydrogenation and/or C-C coupling to produce hydrocarbons. This is the first attempt to regulate the coordination mode of Cu atom in Cu NCs for hydrocarbons generation, and provides new inspiration for designing atomically precise NCs for efficient CO2 RR towards highly-valued products.

Simultaneous Sensing of H2S and ATP with a Two-Photon Fluorescent Probe in Alzheimer's Disease: toward Understanding Why H2S Regulates Glutamate-Induced ATP Dysregulation.

Energy deprivation and reduced levels of hydrogen sulfide (H2S) in the brain is closely associated with Alzheimer's disease (AD). However, there is currently no fluorescent probe for precise exploration of both H2S and adenosine triphosphate (ATP) to directly demonstrate their relationship and their dynamic pattern changes. Herein, we developed a two-photon fluorescent probe, named AD-3, to simultaneously image endogenous H2S and ATP from two emission channels of fluorescent signals in live rat brains with AD. The probe achieved excellent selectivity and good detection linearity for H2S in the 0-100 µM concentration range and ATP in the 2-5 mM concentration range, respectively, with a detection limit of 0.19 µM for H2S and 0.01 mM for ATP. Fluorescence imaging in live cells reveals that such probe could successfully apply for simultaneous imaging and accurate quantification of H2S and ATP in neuronal cells. Further using real-time quantitative polymerase chain reaction and Western blots, we confirmed that H2S regulates ATP synthesis by acting on cytochrome C, cytochrome oxidase subunit 3 of complex IV, and protein 6 of complex I in the mitochondrial respiratory chain. Subsequently, we constructed a high-throughput screening platform based on AD-3 probe to rapidly screen the potential anti-AD drugs to control glutamate-stimulated oxidative stress associated with abnormal H2S and ATP levels. Significantly, AD-3 probe was found capable of imaging of H2S and ATP in APP/PS1 mice, and the concentration of H2S and ATP in the AD mouse brain was found to be lower than that in wild-type mice.