Cas12n nucleases, early evolutionary intermediates of type V CRISPR, comprise a distinct family of miniature genome editors.

Type V CRISPR-associated systems (Cas)12 family nucleases are considered to have evolved from transposon-associated TnpB, and several of these nucleases have been engineered as versatile genome editors. Despite the conserved RNA-guided DNA-cleaving functionality, these Cas12 nucleases differ markedly from the currently identified ancestor TnpB in aspects such as guide RNA origination, effector complex composition, and protospacer adjacent motif (PAM) specificity, suggesting the presence of earlier evolutionary intermediates that could be mined to develop advanced genome manipulation biotechnologies. Using evolutionary and biochemical analyses, we identify that the miniature type V-U4 nuclease (referred to as Cas12n, 400-700 amino acids) is likely the earliest evolutionary intermediate between TnpB and large type V CRISPR systems. We demonstrate that with the exception of CRISPR array emergence, CRISPR-Cas12n shares several similar characteristics with TnpB-ωRNA, including a miniature and likely monomeric nuclease for DNA targeting, origination of guide RNA from nuclease coding sequence, and generation of a small sticky end following DNA cleavage. Cas12n nucleases recognize a unique 5'-AAN PAM sequence, of which the A nucleotide at the -2 position is also required for TnpB. Moreover, we demonstrate the robust genome-editing capacity of Cas12n in bacteria and engineer a highly efficient CRISPR-Cas12n (termed Cas12Pro) with up to 80% indel efficiency in human cells. The engineered Cas12Pro enables base editing in human cells. Our results further expand the understanding regarding type V CRISPR evolutionary mechanisms and enrich the miniature CRISPR toolbox for therapeutic applications.

Selective lignin arylation for biomass fractionation and benign bisphenols.

Lignocellulose is mainly composed of hydrophobic lignin and hydrophilic polysaccharide polymers, contributing to an indispensable carbon resource for green biorefineries1,2. When chemically treated, lignin is compromised owing to detrimental intra- and intermolecular crosslinking that hampers downstream process3,4. The current valorization paradigms aim to avoid the formation of new C-C bonds, referred to as condensation, by blocking or stabilizing the vulnerable moieties of lignin5-7. Although there have been efforts to enhance biomass utilization through the incorporation of phenolic additives8,9, exploiting lignin's proclivity towards condensation remains unproven for valorizing both lignin and carbohydrates to high-value products. Here we leverage the proclivity by directing the C-C bond formation in a catalytic arylation pathway using lignin-derived phenols with high nucleophilicity. The selectively condensed lignin, isolated in near-quantitative yields while preserving its prominent cleavable ß-ether units, can be unlocked in a tandem catalytic process involving aryl migration and transfer hydrogenation. Lignin in wood is thereby converted to benign bisphenols (34-48 wt%) that represent performance-advantaged replacements for their fossil-based counterparts. Delignified pulp from cellulose and xylose from xylan are co-produced for textile fibres and renewable chemicals. This condensation-driven strategy represents a key advancement complementary to other promising monophenol-oriented approaches targeting valuable platform chemicals and materials, thereby contributing to holistic biomass valorization.

Ultrafiltration separation of Am(VI)-polyoxometalate from lanthanides.

Partitioning of americium from lanthanides (Ln) present in used nuclear fuel plays a key role in the sustainable development of nuclear energy1-3. This task is extremely challenging because thermodynamically stable Am(III) and Ln(III) ions have nearly identical ionic radii and coordination chemistry. Oxidization of Am(III) to Am(VI) produces AmO22+ ions distinct with Ln(III) ions, which has the potential to facilitate separations in principle. However, the rapid reduction of Am(VI) back to Am(III) by radiolysis products and organic reagents required for the traditional separation protocols including solvent and solid extractions hampers practical redox-based separations. Herein, we report a nanoscale polyoxometalate (POM) cluster with a vacancy site compatible with the selective coordination of hexavalent actinides (238U, 237Np, 242Pu and 243Am) over trivalent lanthanides in nitric acid media. To our knowledge, this cluster is the most stable Am(VI) species in aqueous media observed so far. Ultrafiltration-based separation of nanoscale Am(VI)-POM clusters from hydrated lanthanide ions by commercially available, fine-pored membranes enables the development of a once-through americium/lanthanide separation strategy that is highly efficient and rapid, does not involve any organic components and requires minimal energy input.

Variation in WIDTH OF LEAF AND GRAIN contributes to grain and leaf size by controlling LARGE2 stability in rice.

Grain and flag leaf size are two important agronomic traits that influence grain yield in rice (Oryza sativa). Many quantitative trait loci (QTLs) and genes that regulate these traits individually have been identified, however, few QTLs and genes that simultaneously control these two traits have been identified. In this study, we conducted a genome-wide association analysis in rice and detected a major locus, WIDTH OF LEAF AND GRAIN (WLG), that was associated with both grain and flag leaf width. WLG encodes a RING-domain E3 ubiquitin ligase. WLGhap.B, which possesses five single nucleotide polymophysim (SNP) variations compared to WLGhap.A, encodes a protein with enhanced ubiquitination activity that confers increased rice leaf width and grain size, whereas mutation of WLG leads to narrower leaves and smaller grains. Both WLGhap.A and WLGhap.B interact with LARGE2, a HETC-type E3 ligase, however, WLGhap.B exhibits stronger interaction with LARGE2, thus higher ubiquitination activity toward LARGE2 compared with WLGhap.A. Lysine1021 is crucial for the ubiquitination of LARGE2 by WLG. Loss-of-function of LARGE2 in wlg-1 phenocopies large2-c in grain and leaf width, suggesting that WLG acts upstream of LARGE2. These findings reveal the genetic and molecular mechanism by which the WLG-LARGE2 module mediates grain and leaf size in rice and suggest the potential of WLGhap.B in improving rice yield.

Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1.

Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation, but its functional significance in cells has been difficult to discern. Previous enzymatic studies revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine-specific demethylase 1 (LSD1). In the present study, we engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation. K562 cells with the Y391K LSD1 CRISPR knockin show decreased expression of a set of genes associated with cellular adhesion and myeloid leukocyte activation. Chromatin profiling revealed that the cis-regulatory regions of these silenced genes display a higher level of H3 Lys14 acetylation, and edited K562 cells show diminished H3 mono-methyl Lys4 near these silenced genes, consistent with a role for enhanced LSD1 demethylase activity. These findings illuminate the functional consequences of disconnecting histone modification crosstalk for a key epigenetic enzyme.

A KDPG sensor RccR governs Pseudomonas aeruginosa carbon metabolism and aminoglycoside antibiotic tolerance.

Pseudomonas aeruginosa harbors sophisticated transcription factor (TF) networks to coordinately regulate cellular metabolic states for rapidly adapting to changing environments. The extraordinary capacity in fine-tuning the metabolic states enables its success in tolerance to antibiotics and evading host immune defenses. However, the linkage among transcriptional regulation, metabolic states and antibiotic tolerance in P. aeruginosa remains largely unclear. By screening the P. aeruginosa TF mutant library constructed by CRISPR/Cas12k-guided transposase, we identify that rccR (PA5438) is a major genetic determinant in aminoglycoside antibiotic tolerance, the deletion of which substantially enhances bacterial tolerance. We further reveal the inhibitory roles of RccR in pyruvate metabolism (aceE/F) and glyoxylate shunt pathway (aceA and glcB), and overexpression of aceA or glcB enhances bacterial tolerance. Moreover, we identify that 2-keto-3-deoxy-6-phosphogluconate (KDPG) is a signal molecule that directly binds to RccR. Structural analysis of the RccR/KDPG complex reveals the detailed interactions. Substitution of the key residue R152, K270 or R277 with alanine abolishes KDPG sensing by RccR and impairs bacterial growth with glycerol or glucose as the sole carbon source. Collectively, our study unveils the connection between aminoglycoside antibiotic tolerance and RccR-mediated central carbon metabolism regulation in P. aeruginosa, and elucidates the KDPG-sensing mechanism by RccR.

Multifaceted regulation of sirtuin 2 (Sirt2) deacetylase activity.

Sirtuin 2 (Sirt2) is a member of the sirtuin family of NAD-dependent lysine deacylases and plays important roles in regulation of the cell cycle and gene expression. As a nucleocytoplasmic deacetylase, Sirt2 has been shown to target both histone and nonhistone acetylated protein substrates. The central catalytic domain of Sirt2 is flanked by flexible N and C termini, which vary in length and composition with alternative splicing. These termini are further subject to posttranslational modifications including phosphorylation. Here, we investigate the function of the N and C termini on deacetylation of nuclear substrates by Sirt2. Remarkably, we find that the C terminus autoinhibits deacetylation, while the N terminus enhances deacetylation of proteins and peptides, but not nucleosomes-a chromatin model substrate. Using protein semisynthesis, we characterize the effect of cell cycle-linked N-terminal phosphorylation at two major phosphorylation sites (Ser23/Ser25) and find that these further enhance protein/peptide deacetylation, with no effect on nucleosome deacetylation. Additionally, we find that VRK1, an established binding partner of both Sirt2 and nucleosomes, can stimulate deacetylation of nucleosomes by Sirt2, likely through an electrostatic mechanism. Taken together, these findings reveal multiple mechanisms regulating the activity of Sirt2, which allow for a broad range of activities across its multiple biological roles.

Modified bone marrow mesenchymal stem cells derived exosomes loaded with MiRNA ameliorates non-small cell lung cancer.

The study aimed to reveal the function of LXY30 peptide-modified bone marrow mesenchymal stem cell-derived exosomes (LXY30-Exos) in NSCLC. LXY30 peptide is a peptide ligand targeting α3ß1 integrin, and LXY30 specifically binds to Exos derived from different cells. We use transmission electron microscopy to identify LXY30-Exos and tracking analysis for particles, and the LXY30-Exos internalized by NSCLC cells in vitro and targeted NSCLC tumours in vivo were verified by multiple molecular technologies. The functions of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 were assessed using cell proliferation, migration and cell apoptosis assays. Meanwhile, the safety of the above engineered Exos was evaluated in vivo. After LXY30-Exos were isolated and identified, LXY30-Exos were confirmed to be internalized by NSCLC cells in vitro and specifically targeted NSCLC tumours in vivo. Functionally, LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 weakened the proliferation, migration and cell cycle of NSCLC cells induced cellular apoptosis in vitro and restrained the tumour progression in vivo. Meanwhile, the safety of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 was confirmed in vivo. Overall, miR-30c, miR-181b and miR-613 encapsulated in LXY30 peptide-modified BMSC-Exos relieved NSCLC.

Integrated analysis of bulk and single-cell RNA-seq data reveals cell differentiation-related subtypes and a scoring system in bladder cancer.

Bladder cancer (BLCA) exhibits notable molecular heterogeneity, influencing diverse clinical outcomes. However, the molecular subtypes associated with cell differentiation-related genes (CDR) and their prognostic implications remain unexplored. Analysing two GEO single-cell datasets, we identified genes linked to cell differentiation. Utilizing these genes, we explored distinct molecular subtypes. WGCNA analysis further identified CDR-associated genes, and the CDR score system, constructed using Lasso and Cox regression, was developed. Clinical prognosis and variations in immune-related factors among patient groups were assessed. Core genes were selected and confirmed through in vitro experiments. Two BLCA subtypes related to cell differentiation were identified: Subtype B demonstrated a favourable prognosis, while Subtype A exhibited significant immune cell infiltration. The CDR score system of nine genes revealed a positive correlation between higher scores and a poorer prognosis. The comprehensive analysis uncovered a positive association between CDR genes and M2 macrophages and unresponsiveness to immune therapy. Functional experiments validated that ANXA5 downregulation influences tumour cell migration without affecting proliferation. Our study reveals distinct cell differentiation-related molecular subtypes and introduces the CDR scoring system in BLCA. ANXA5 emerges as a potential therapeutic target, offering promising avenues for personalized treatment strategies.

Observation of Chiral Channels in Helical Covalent Organic Frameworks.

Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67.

BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.

Panoramic transcriptome analysis and functional screening of long noncoding RNAs in mouse spermatogenesis.

Long noncoding RNAs (lncRNAs) have emerged as diverse functional regulators involved in mammalian development; however, large-scale functional investigation of lncRNAs in mammalian spermatogenesis in vivo is lacking. Here, we delineated the global lncRNA expression landscape in mouse spermatogenesis and identified 968 germ cell signature lncRNAs. By combining bioinformatics and functional screening, we identified three functional lncRNAs (Gm4665, 1700027A15Rik, and 1700052I22Rik) that directly influence spermatogenesis in vivo. Knocking down Gm4665 hampered the development of round spermatids into elongating spermatids and disrupted key spermatogenic gene expression. Mechanistically, lncRNA Gm4665 localized in the nucleus of round spermatids and occupied the genomic regulatory region of important spermatogenic genes including Ip6k1 and Akap3 These findings provide a valuable resource and framework for future functional analysis of lncRNAs in spermatogenesis and their potential roles in other biological processes.

Tailoring the Li+ Intercalation Energy of Carbon Nanocage Anodes Via Atomic Al-Doping for High-Performance Lithium-Ion Batteries.

Graphitic carbon materials are widely used in lithium-ion batteries (LIBs) due to their stability and high conductivity. However, graphite anodes have low specific capacity and degrade over time, limiting their application. To meet advanced energy storage needs, high-performance graphitic carbon materials are required. Enhancing the electrochemical performance of carbon materials can be achieved through boron and nitrogen doping and incorporating 3D structures such as carbon nanocages (CNCs). In this study, aluminum (Al) is introduced into CNC lattices via chemical vapor deposition (CVD). The hollow structure of CNCs enables fast electrolyte penetration. Density functional theory (DFT) calculations show that Al doping lowers the intercalation energy of Li+. The Al-boron (B)-nitrogen (N-doped CNC (AlBN-CNC) anode demonstrates an ultrahigh rate capacity (≈300 mAh g-1 at 10 A g-1) and a prolonged fast-charging lifespan (862.82 mAh g-1 at 5 A g-1 after 1000 cycles), surpassing the N-doped or BN-doped CNCs. Al doping improves charging kinetics and structural stability. Surprisingly, AlBN-CNCs exhibit increased capacity upon cycling due to enlarged graphitic interlayer spacing. Characterization of graphitic nanostructures confirms that Al doping effectively tailors and enhances their electrochemical properties, providing a new strategy for high-capacity, fast-charging graphitic carbon anode materials for next-generation LIBs.

Role of miRNAs in glucose metabolism of mouse cumulus cells†.

It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment. Summary sentence:  We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.

Identification of vancomycin exposure target in neonates: how much is enough?

OBJECTIVES: Vancomycin is commonly used in neonates with the same pharmacokinetics/pharmacodynamics (PK/PD) target as adults. However, no evidence supports this practice, and the association between trough concentrations and treatment outcomes has been widely questioned. This study aimed to identify the optimal PK/PD predictor and assess the correlation between AUC/MIC, trough concentration and the vancomycin efficacy in neonates. METHODS: This study retrospectively collected neonates who used vancomycin and constructed a population pharmacokinetic (PPK) model to estimate the AUC. Logistic analyses were used to identify the variables related to efficacy. Classification and regression tree analysis was used to explore thresholds. The correlation between trough concentration and AUC/MIC on the first day was analysed using a linear regression model. RESULTS: PPK modelling involved 131 neonates. Postmenstrual age and current weight were included in the covariate analysis. Forty-eight patients were included in the efficacy analysis, 13 of whom were infected with MRSA. The best-performance PK/PD target for efficacy was AUC0-24  h/MIC ≥ 331. The trough concentration was correlated with AUC0-24  h/MIC (r2 = 0.32), but individual differences existed. AUC0-24  h/MIC ranged up to 2.5-fold for a given trough concentration. CONCLUSIONS: AUC0-24  h/MIC ≥ 331 was the optimal target of vancomycin efficacy in neonates. The trough concentration was not a reliable predictor of efficacy and AUC0-24  h/MIC. AUC-guided dosage adjustments are more valuable in clinical applications.

Glycosylation mode of phloretin affects the morphology and stress resistance of apple plant.

Phloretin has different glycosylation modes in plants. Phlorizin (phloretin 2'-O-glucoside) is one of the glycosylation products of phloretin, and accumulates abundantly in apple plants. However, it is still unclear whether phlorizin is more beneficial for apple plants compared with other glycosylation products of phloretin. We created transgenic apple plants with different glycosylation modes of phloretin. In transgenic plants, the accumulation of phlorizin was partly replaced by that of trilobatin (phloretin 4'-O-glucoside) or phloretin 3',5'-di-C-glycoside. Compared with wild type, transgenic plants with less phlorizin showed dwarf phenotype, larger stomatal size, higher stomatal density and less tolerance to drought stress. Transcriptome and phytohormones assay indicate that phlorizin might regulate stomatal development and behaviour via controlling auxin and abscisic acid signalling pathways as well as carbonic anhydrase expressions. Transgenic apple plants with less phlorizin also showed less resistance to spider mites. Apple plants may hydrolyse phlorizin to produce phloretin, but cannot hydrolyse trilobatin or phloretin 3',5'-di-C-glycoside. Compared with its glycosylation products, phloretin is more toxic to spider mites. These results suggest that the glycosylation of phloretin to produce phlorizin is the optimal glycosylation mode in apple plants, and plays an important role in apple resistance to stresses.

Bottom-Up Construction of Ni(II)-Incorporated Covalent Organic Framework for Metallaphotoredox Catalysis.

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts.

Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.

Hydrolysis-Induced Cu2O Networks and the Triggered Peroxidase-Mimic Activity by Cr6+ under Neutral Conditions.

The current small-scale synthesis and relatively large size of Cu2O have limited its practical applications. Herein, we developed a hydrolysis strategy to prepare phase-pure Cu2O networks composed of small granules (ca. 25 nm) on a gram scale. The preparation involves in situ hydrolyzing the Hx[CuxCl2x] complexes prereduced in N,N'-dimethylformamide (DMF). The DMF-soluble Hx[CuxCl2x] complexes are critical for the homogeneous nucleation of CuCl seeds and subsequent hydrolysis, allowing for separate control over the nucleation and growth stages to regulate the formation of Cu2O networks. The novel Cu2O networks possess numerous exposed active sites and hierarchical porosities, conferring high catalytic activity and fast mass transfer capability. The inherent peroxidase-mimic activity of Cu2O is severely inhibited under neutral conditions but can be triggered by Cr6+, enabling the colorimetric assay of Cr6+ with the assistance of the oxidation-induced color change of 3,3',5,5'-tetramethylbenzidine. Through density functional theory calculation, we confirmed that the attachment of Cr6+ on the Cu2O surface reduced the dissociation energy of H2O2, enhancing the enzyme-mimic activity. The colorimetric detection method demonstrated a sensitive and specific assay capability for Cr6+ (LOD = 0.095 µM). Our work offers a straightforward protocol for novel design of metal or metal-based nanomaterials for nanozymes or other applications.