Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

Application of Proteomics and Machine Learning Methods to Study the Pathogenesis of Diabetic Nephropathy and Screen Urinary Biomarkers.

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, causing significant health problems. Early diagnosis of the disease is quite inadequate. To screen urine biomarkers of DN and explore its potential mechanism, this study collected urine from 87 patients with type 2 diabetes mellitus (which will be classified into normal albuminuria, microalbuminuria, and macroalbuminuria groups) and 38 healthy subjects. Twelve individuals from each group were then randomly selected as the screening cohort for proteomics analysis and the rest as the validation cohort. The results showed that humoral immune response, complement activation, complement and coagulation cascades, renin-angiotensin system, and cell adhesion molecules were closely related to the progression of DN. Five overlapping proteins (KLK1, CSPG4, PLAU, SERPINA3, and ALB) were identified as potential biomarkers by machine learning methods. Among them, KLK1 and CSPG4 were positively correlated with the urinary albumin to creatinine ratio (UACR), and SERPINA3 was negatively correlated with the UACR, which were validated by enzyme-linked immunosorbent assay (ELISA). This study provides new insights into disease mechanisms and biomarkers for early diagnosis of DN.

Temporally Decoupled Ammonia Splitting by a Zn-NH3 Battery with an Ammonia Oxidation/Hydrogen Evolution Bifunctional Electrocatalyst as a Cathode.

Ammonia splitting to hydrogen is a decisive route for hydrogen economy but is seriously limited by the complex device and low efficiency. Here, we design and propose a new rechargeable Zn-NH3 battery based on temporally decoupled ammonia splitting to achieve efficient NH3-to-H2 conversion. In this system, ammonia is oxidized into nitrogen during cathodic charging (2NH3 + 6OH- → N2 + 6H2O + 6e-) with external electrical energy conversion and storage, while during cathodic discharging, water is reduced to hydrogen (2H2O + 2e- → H2 + 2OH-) with electrical energy generation. In this loop, continuous and efficient H2 production without separation and purification is achieved. With the help of the ammonia oxidation reaction (AOR) and hydrogen evolution reaction (HER) bifunctional catalyst of Mo2C/NiCu@C, a rechargeable Zn-NH3 battery is realized that exhibits a high NH3-to-H2 FE of 91.6% with outstanding durability for 900 cycles (300 h) at 20 mA/cm2, enabling efficient and continuous NH3-to-H2 conversion.

Single-cell and spatially resolved transcriptomics for liver biology.

Single-cell transcriptomics enables the identification of rare cell types and the inference of state transitions, whereas spatially resolved transcriptomics allows the quantification of cells and genes in the context of tissues. The recent progress in these new technologies is improving our understanding of the cell landscape and its roles in diseases. Here, we review key biological insights into liver homeostasis, development, regeneration, chronic liver disease, and cancer obtained from single-cell and spatially resolved transcriptomics. We highlight recent progress in the liver cell atlas that characterizes the comprehensive cellular composition; diversity and function; the spatial architecture such as liver zonation, cell communication, and proximity; the cell identity conversion and cell-specific alterations that are associated with liver pathology; and new therapeutic targets. We further discuss outstanding challenges, advanced experimental technologies, and computational methods that help to address these challenges.

Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.

BACKGROUND AND AIMS: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity. APPROACH AND RESULTS: Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus -mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH. CONCLUSIONS: Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.

Flat-band Friedrich-Wintgen bound states in the continuum based on borophene metamaterials.

Many applications involve the phenomenon of a material absorbing electromagnetic radiation. By exploiting wave interference, the efficiency of absorption can be significantly enhanced. Here, we propose Friedrich-Wintgen bound states in the continuum (F-W BICs) based on borophene metamaterials to realize coherent perfect absorption with a dual-band absorption peak in commercially important communication bands. Metamaterials consist of borophene gratings and a borophene sheet that can simultaneously support a Fabry-Perot plasmon resonance and a guided plasmon mode. The formation and dynamic modulation of the F-W BIC can be achieved by adjusting the width or carrier density of the borophene grating, while the strong coupling leads to the anti-crossover behavior of the absorption spectrum. Due to the weak angular dispersion originating from the intrinsic flat-band characteristic of the deep sub-wavelength periodic structure, the proposed plasmonic system exhibits almost no change in wavelength and absorption at large incident angles (within 70 degrees). In addition, we employ the temporal coupled-mode theory including near- and far-field coupling to obtain strong critical coupling, successfully achieve coherent perfect absorption, and can realize the absorption switch by changing the phase difference between the two coherent beams. Our findings can offer theoretical support for absorber design and all-optical tuning.

Investigating metabolic dysregulation in serum of triple transgenic Alzheimer's disease male mice: implications for pathogenesis and potential biomarkers.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that lacks convenient and accessible peripheral blood diagnostic markers and effective drugs. Metabolic dysfunction is one of AD risk factors, which leaded to alterations of various metabolites in the body. Pathological changes of the brain can be reflected in blood metabolites that are expected to explain the disease mechanisms or be candidate biomarkers. The aim of this study was to investigate the changes of targeted metabolites within peripheral blood of AD mouse model, with the purpose of exploring the disease mechanism and potential biomarkers. Targeted metabolomics was used to quantify 256 metabolites in serum of triple transgenic AD (3 × Tg-AD) male mice. Compared with controls, 49 differential metabolites represented dysregulation in purine, pyrimidine, tryptophan, cysteine and methionine and glycerophospholipid metabolism. Among them, adenosine, serotonin, N-acetyl-5-hydroxytryptamine, and acetylcholine play a key role in regulating neural transmitter network. The alteration of S-adenosine-L-homocysteine, S-adenosine-L-methionine, and trimethylamine-N-oxide in AD mice serum can served as indicator of AD risk. The results revealed the changes of metabolites in serum, suggesting that metabolic dysregulation in periphery in AD mice may be related to the disturbances in neuroinhibition, the serotonergic system, sleep function, the cholinergic system, and the gut microbiota. This study provides novel insights into the dysregulation of several key metabolites and metabolic pathways in AD, presenting potential avenues for future research and the development of peripheral biomarkers.

An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

Photoinduced Decarboxylative Difluoroalkylation and Perfluoroalkylation of α-Fluoroacrylic Acids.

Herein, a novel and practical methodology for the photoinduced decarboxylative difluoroalkylation and perfluoroalkylation of α-fluoroacrylic acids is reported. A wide range of α-fluoroacrylic acids can be used as applicable feedstocks, allowing for rapid access to structurally important difluoroalkylated and polyfluoroalkylated monofluoroalkenes with high Z-stereoselectivity under mild conditions. The protocol demonstrates excellent functional group compatibility and provides a platform for modifying complex biologically active molecules.

Proteomic analysis of the effects of Dictyophora polysaccharide on arsenic-induced hepatotoxicity in rats.

Arsenic (As) is a highly toxic environmental toxicant and a known human carcinogen. Long-term exposure to As can cause liver injury. Dictyophora polysaccharide (DIP) is a biologically active natural compound found in the Dictyophora with excellent antioxidation, anti-inflammation, and immune protection properties. In this study, the Sprague-Dawley (SD) rat model of As toxicity was established using a feeding method, followed by DIP treatment in rats with As-induced liver injury. The molecular mechanisms of As toxicity to the rat liver and the protective effect of DIP were investigated by proteomic studies. The results showed that 172, 328 and 191 differentially expressed proteins (DEPs) were identified between the As-exposed rats versus control rats (As/Ctrl), DIP treated rats versus As-exposed rats (DIP+As/As), and DIP treated rats versus control rats (DIP+As /Ctrl), respectively. Among them, the expression of 90 DEPs in the As/Ctrl groups was reversed by DIP treatment. As exposure caused dysregulation of metabolic pathways, mitochondria, oxidative stress, and apoptosis-related proteins in the rat liver. However, DIP treatment changed or restored the levels of these proteins, which attenuated the damage to the livers of rats caused by As exposure. The results provide new insights into the mechanisms of liver injury induced by As exposure and the treatment of DIP in As poisoning.

Effects of arsenic exposure on blood trace element levels in rats and sex differences.

Arsenic (As) is a widespread environmental metalloid and human carcinogen, and its exposure is associated with a wide range of toxic effects, leading to serious health hazards. As poisoning is a complex systemic multi-organ and multi-system damage disease. In this study, a rat model of As poisoning was established to investigate the levels of trace elements in the blood of rats and sex differences in the effect of As on every trace elements in rat blood. Twenty 6-week-old SD (Sprague Dawley) rats were randomly divided into the control group and the As-exposed group. After 3 months, the contents of 19 elements including As in the blood were detected in these two groups by inductively coupled plasma mass spectrometry (ICP-MS). As levels in the blood of As-exposed rats were significantly higher than those in the control group, with increased levels of Rb, Sr, Cs and Ce, and decreased levels of Pd. As showed a significant positive correlation with Rb. There were significant sex differences in blood Se, Pd, Eu, Dy, Ho, and Au levels in the As-exposed group. The results showed that As exposure can lead to an increase of As content in blood and an imbalance of some elements. There were sex differences in the concentration and the correlation between elements of some elements. Elemental imbalances may affect the toxic effects of As and play a synergistic or antagonistic role in As toxicity.

Association between graded subchorionic hematoma and adverse pregnancy outcomes in singleton pregnancies: a prospective observational cohort study.

OBJECTIVE: To investigate whether different grades of subchorionic hematoma (SCH) are involved in the timing of birth and the development of adverse pregnancy outcomes in singleton pregnant women. METHODS: A total of 171 women with singleton pregnancies, 72 of whom had SCH before 20 weeks and between 12 and 20 weeks of gestational age (GA), were included in this study conducted between January 2018 and December 2021. These patients were divided into three subgroups based on the size of the subchorionic hematoma on ultrasound imaging. Baseline demographic data, obstetric outcomes, and risk factors for subchorionic hematoma were compared for the two groups. RESULTS: A higher number of pregnancies from the SCH group resulted in miscarriage (30.56% versus 2.02%, p < 0.0001), early preterm birth (8.33% versus 1.01%, p = 0.0035), premature rupture of membranes (15.28% versus 4.04%, p = 0.0103), fetal growth restriction (9.72% versus 0%, p = 0.0015), and delivery 13.18 days earlier (274.34 ± 11.25 versus 261.16 ± 29.80, p = 0.0013) than those from the control group. Compared with SCH detected before 12 weeks of GA, the rate of miscarriage increased, and the live birth rate decreased significantly in patients with SCH caught between 12 and 20 weeks of GA. With the increase in hematoma size, the likelihood of miscarriage increased significantly. Further analysis found that delivery occurred earlier in the medium/large SCH group (271.49 ± 23.61 versus 253.28 ± 40.68/261.77 ± 22.11, p = 0.0004/0.0073) but not in the small SCH group (274.34 ± 11.25 versus 267.85 ± 21.01, p = 0.2681) compared to the control group. Our results also showed that the anterior placenta (52.04% versus 33.33%, p = 0.0005, OR = 0.3137, 95% CI [0.1585, 0.601]) is a protective factor for subchorionic hematoma. CONCLUSION: Our study shows that women with SCH are at a higher risk of adverse pregnancy outcomes and are independently associated with miscarriage, early preterm birth, premature rupture of membranes, and fetal growth restriction. A subchorionic hematoma, especially detected between 12 and 20 weeks of GA, is very likely to cause miscarriage or preterm birth in women with a medium or large subchorionic hematoma.

Eu3+-functionalized covalent organic framework for ratiometric fluorescence detection and adsorption of tetracycline and information steganography.

Functional materials with organic/inorganic composites as the main matrix and rare earth ion complexes as the guest have shown a very broad application prospect for antibiotic sensors. However, Eu3+-complex often relies on a single fluorescence response signal, which is susceptible to changes in the detection environment and cannot simultaneously detect and remove tetracycline (TC). Herein, green fluorescent covalent two-dimensional organic framework (COF-TD) is synthesized, followed by modification of Eu3+ to synthesize COF-TD@Eu3+. In the ratiometric sensor, Eu3+ serves as the recognition site and specific response probe for TC, while COF-TD is the fluorescence reference and carrier for Eu3+. Due to the antenna effect, TC enhances the red fluorescence of Eu3+, while the green fluorescence of COF-TD remains almost stable. Based on the change of fluorescence intensity and fluorescence color from green to red, the efficient ratiometric sensing can be finished in 1 min. The developed method shows high sensitivity with a detection limit of 0.3 µM and high selectivity to TC which makes the method applicable to detect TC in traditional Chinese medicine preparations. In addition, due to the high specific surface area of COFs and specific adsorption sites, COF-TD@Eu3+ also shows good performance for TC removal. The findings show that the maximum adsorption capacity is 137.3 mg g-1 and the adsorption equilibrium is reached in 30 min. Smartphone assisted COF-TD@Eu3+ for both ratiometric fluorescence detection and detecting the absorption of TC is proposed for the first time. The molecular cryptosteganography that transforms the selective response of COF-TD@Eu3+ to binary strings is anticipated to advance utilization of nanomaterials in logic sensing and information safety.

Synthesis, Structural Characterization, and Hirschfeld Surface Analysis of a New Cu(II) Complex and Its Role in Photocatalytic CO2 Reduction.

A new Cu(II) complex, [CuL1L2(CH3COO)2(H2O)]·H2O, was synthesized by the reaction of Cu(CH3COO)2·H2O, 6-phenylpyridine-2-carboxylic acid (HL1), and 4-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]pyridine (L2) in ethanol-water (v:v = 1:1) solution. The Cu(II) complex was characterized using elemental analysis, IR, UV-vis, TG-DTA, and single-crystal X-ray analysis. The fluorescence properties of the copper complex were also evaluated. The structural analysis results show that the Cu(II) complex crystallizes in the triclinic system with space group P-1. The Cu(II) ion in the complex is five-coordinated with one O atom (O2) and one N atom (N1) from one 6-phenylpyridine-2-carboxylate ligand (L1), one N atom (N2) from 4-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]pyridine ligand (L2), one O atom (O4) from acetate, and one O atom (O5) from a coordinated water molecule, and it adopts a distorted trigonal bipyramidal geometry. Cu(II) complex molecules form a two-dimensional layer structure through intramolecular and intermolecular O-H…O hydrogen bonding. The two-dimensional layer structures further form a three-dimensional network structure by π-π stacking interactions of aromatic rings. The analysis of the Hirschfeld surface of the Cu(II) complex shows that the H…H contacts made the most significant contribution (46.6%) to the Hirschfeld surface, followed by O…H/H…O, N…H/H…N and C…H/H…C contacts with contributions of 14.2%, 13.8%, and 10.2%, respectively. In addition, the photocatalytic CO2 reduction using Cu(II) complex as a catalyst is investigated under UV-vis light irradiation. The findings reveal that the main product is CO, with a yield of 10.34 µmol/g and a selectivity of 89.4% after three hours.

The Synthesis, Structural Characterization, and DFT Calculation of a New Binuclear Gd(III) Complex with 4-Aacetylphenoxyacetic Acid and 1,10-Phenanthroline Ligands and Its Roles in Catalytic Activity.

A new binuclear Gd(III) complex, [Gd2(L)6(Phen)2]·4H2O, was synthesized via the reaction of gadolinium(III) nitrate hexahydrate, 4-acetylphenoxyacetic acid (HL), NaOH, and 1,10-phenanthroline (Phen) in a solution of water-ethanol (v:v = 1:1). The Gd(III) complex was characterized using IR, UV-vis, TG-DSC, fluorescence, and single-crystal X-ray diffraction analyses. The results showed that the Gd(III) complex crystallizes in the triclinic system, space group P-1, and each Gd(III) ion was coordinated with two nitrogen atoms (N1, N2, or N1a, and N2a) from two Phen ligands and seven oxygen atoms (O1, O2, O7a, O9, O8, O8a, O10a, or O1a, O2a, O7, O8, O8a, O9a, and O10) from six L ligands, respectively, forming a nine-coordinated coordination mode. The Gd(III) complex molecules formed a one-dimensional chained and three-dimensional network structure via benzenering π-π stacking. The Hirschfeld surface analysis and the calculations of the electron density distributions of the frontier molecular orbitals of the Gd(III) complex were performed. The catalytic activities of the photocatalytic CO2 reduction and benzyl alcohol oxidation using the Gd(III) complex as a catalyst were performed. The results of the photocatalytic CO2 reduction showed that the yield and the selectivity of CO reached 41.5 µmol/g and more than 99% after four hours, respectively. The results of the benzyl alcohol oxidation showed that the yield of benzaldehyde was 45.7% at 120 °C with THF as the solvent under 0.5 MPa O2 within 2 h.

[Type â £ Hiatal Hernia With Severe Anemia as the Main Clinical Manifestation:Report of One Case].

Type Ⅳ hiatal hernia with a high risk usually presents sudden or suddenly worsening epigastric pain,vomiting,and dysphagia.It is not conducive to early diagnosis and treatment when symptoms are atypical.Type Ⅳ hiatal hernia with severe anemia is rare.This article reports an atypical case of type Ⅳ hiatal hernia with melena and severe anemia as the main manifestations,aiming to improve clinicians' identification of the atypical clinical presentations of type Ⅳ hiatal hernia.

[Two new glycosides from Hypericum elatoides].

The column chromatography with silica gel, reversed-phase C_(18), and Sephadex LH-20 was employed to separate the methanol extract of the aerial parts of Hypericum elatoides. The compounds were identified by the comprehensive analysis of IR, NMR, and MS data as methyl 8-O-ß-D-glucopyranosyl-(Z)-5-octenoate(1), methyl 3-O-ß-D-glucopyranosyl-4-methylhexanoate(2), byzantionoside B(3), 9-epi-blumenol C glucoside(4), corchoionoside C(5),(6S,9R)-roseoside(6), cis-p-coumaric acid 4-O-ß-D-glucopyranoside(7), trans-p-coumaric acid 4-O-ß-D-glucopyranoside(8), methyl 3-(4-hydroxyphenyl)propanoate(9),(E)-chlorogenic acid methyl ester(10), quercetin-3-O-ß-D-glucopyranoside(11), ß-sitosterol(12), stigmasterol(13), stigmast-4-en-3-one(14), ß-amyrin(15), daucosterol(16), sitoindoside Ⅰ(17), oleic acid(18), methyl α-linolenate(19), trilinolein(20), and cassipourol(21). Among them, compounds 1 and 2 were identified as new glycosides and named hyperelatosides G and H. Compounds 3-5, 7-9, 17, and 20-21 were isolated from the genus Hypericum for the first time. The remaining compounds were isolated from H. elatoides for the first time. The results of biological assays revealed that compound 11 exhibited significant anti-neuroinflammatory activity, and compounds 1, 3, and 19 displayed certain neuroprotective effects.

Molecular Engineering of Methylated Sulfone-Based Covalent Organic Frameworks for Back-Reaction Inhibited Photocatalytic Overall Water Splitting.

Solar-to-hydrogen (H2) and oxygen (O2) conversion via photocatalytic overall water splitting (OWS) holds great promise for a sustainable fuel economy, but has been challenged by the backward O2 reduction reaction (ORR) with favored proton-coupled electron transfer (PCET) dynamics. Here, we report that molecular engineering by methylation inhibits the backward ORR of molecular photocatalysts and enables efficient OWS process. As demonstrated by a benchmark sulfone-based covalent organic framework (COF) photocatalyst, the precise methylation of its O2 adsorption sites effectively blocks electron transfer and increases the barrier for hydrogen intermediate desorption that cooperatively obstructs the PCET process of ORR. Methylation also repels electrons to the neighboring photocatalytic sulfone group that promotes the forward H2 evolution. The resultant DS-COF achieves an impressive inhibition of about 70 % of the backward reaction and a three-fold enhancement of the OWS performance with a H2 evolution rate of 124.7 µmol h-1 g-1, ranking among the highest reported for organic-based photocatalysts. This work provides insights for engineering photocatalysts at the molecular level for efficient solar-to-fuel conversion.

Coupling Electron Transfer and Redox Site in Boranil Covalent Organic Framework Toward Boosting Photocatalytic Water Oxidation.

The efficient polymeric semiconducting photocatalyst for solar-driven sluggish kinetics with multielectron transfer oxygen evolution has spurred scientific interest. However, existing photocatalysts limited by π-conjugations, visible-light harvest, and charge transfer often compromise the O2 production rate. Herein, we introduced an alternative strategy involving a boranil functionalized-based fully π-conjugated ordered donor and acceptor (D-A) covalent organic frameworks (Ni-TAPP-COF-BF2 ) photocatalyst. The co-catalyst-free Ni-TAPP-COF-BF2 exhibits an excellent ~11-fold photocatalytic water oxidation rate, reaching 1404 µmol g-1 h-1 under visible light irradiation compared to pristine Ni-TAPP-COF (123 µmol g-1 h-1 ) alone and surpasses to reported organic frameworks counterpart. Both experimental and theoretical results demonstrate that the push/pull mechanism (metalloporphyrin/BF2 ) is responsible for the appropriate light-harvesting properties and extending π-conjugation through chelating BF2 moieties. This strategy benefits in narrowing band structure, improving photo-induced charge separation, and prolonged charge recombination. Further, the lower spin magnetic moment of M-TAPP-COF-BF2 and the closer d-band center of metal sites toward the Fermi level lead to a lower energy barrier for *O intermediate. Reveal the potential of the functionalization strategy and opens up an alternative approach for engineering future photocatalysts in energy conversion applications.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.