Atroposelective Synthesis of Biaryl N-Oxides via Cu-Catalyzed De Novo Heteroaromatic N-Oxide Ring Formation.

Heteroaromatic N-oxides, renowned for their highly polar N─O bond and robust structure, exhibit significant bioactivities and have played a pivotal role in various drug development projects since the discovery of Minoxidil. Moreover, heteroaromatic N-oxides, featuring axially chiral biaryl frameworks, are indispensable as Lewis base catalysts and ligands in organic synthesis. Despite their importance, synthesizing these chiral compounds is challenging, necessitating chiral starting materials or resolution processes. Catalytic strategies rely on the functionalization of heteroaromatic N-oxide compounds, leading to products with a relatively limited skeletal diversity. This study introduces a Cu-catalyzed atroposelective method for synthesizing biaryl N-oxides via de novo heteroaromatic N-oxide ring formation. This mild and efficient approach achieves excellent stereoselectivities (up to 99:1 er), enabling the production of a wide array of N-oxides with novel heteroaromatic scaffolds. The axially chiral N-oxide product 3f demonstrates high stereoselectivity and recyclability as a Lewis base catalyst. Additionally, product 3e exhibits promising therapeutic efficacy against triple-negative breast cancer, with IC50 values of 4.8 and 5.2 µm in MDA-MB-231 and MDA-MB-468 cells, respectively. This research not only advances the synthesis of challenging chiral heteroaromatic N-oxides but also encourages further exploration of N-oxide entities in the discovery of bioactive small molecules.

Effect of Cotesia ruficrus Parasitization on Diversity and Community Composition of Intestinal Bacteria in Spodoptera frugiperda.

Parasitoids have the potential to alter the gut microbiota of their host insects post-parasitization, thereby influencing the host's physiological functions and creating a more favorable environment for the survival of the parasitoid's progeny. Cotesia ruficrus is a native enemy of the important invasive fall armyworm (FAW) pest, Spodoptera frugiperda, in China, exhibiting significant pest control capabilities. To investigate the impact of C. ruficrus on the gut bacteria of FAW caterpillars following parasitism, we used 16S rRNA sequencing technology to analyze the diversity and richness of gut bacteria in both long-term laboratory and short-term laboratory FAW caterpillars. The results revealed Enterococcus as the predominant bacteria across all treatments, while no significant differences were observed in the diversity and richness of gut bacteria between non-parasitized and parasitized long-term laboratory FAW caterpillars. Similarly, while the diversity of gut bacteria in non-parasitized and parasitized short-term laboratory FAWs showed no significant variance, a marked discrepancy in richness was noted. Moreover, the richness of gut bacteria in short-term laboratory FAW caterpillars surpassed that of their long-term laboratory counterparts. In addition, it was found that Corynebacterium existed only in the intestinal tract of FAW caterpillars that were parasitized by C. ruficrus. These results substantiate that C. ruficrus parasitization can alter the gut microbiota of FAW caterpillars, providing valuable insights into the interplay between gut microbiota and the dynamics of parasitoid-host interactions.

More is different: progressive ß-thiolation induced-porphyrin aggregation switches singlet oxygen photosensitization.

Incorporating sulfur atoms into photosensitizers (PSs) has been well-established to populate triplet states and increase singlet oxygen (1O2) production when exposed to light. In this work, we found that progressive thiolation of porphyrin ß-periphery does promote intersystem crossing (ISC) between triplets and singlets, as seen in the excited state dynamics in dichloromethane or PS nanoparticles in water. However, in the latter case, more sulfur substitution deactivates 1O2 photosensitization, in contrast to the expected trend observed in dichloromethane. This observation was further supported by photocytotoxicity studies, where 1O2 photosensitization was switched off in living cells and multicellular spheroids despite being switched on in in vivo mice models. To understand the inconsistency, we performed molecular dynamics simulation and time-dependent density functional theory calculations to investigate possible aggregation and related excited states. We found that the extent of thiolation could regulate molecular packing inside nanoparticles, which gradually lowers the energy levels of triplet states even lower than that of 1O2 and, in turn, alters their energy dissipation pathways. Therefore, this study provides new insights into the design of metal-free PSs and sheds light on the excited state dynamics in aqueous media beyond the molecular level.

Magnetic manipulation of the reactivity of singlet oxygen: from test tubes to living cells.

Although magnetism undoubtedly influences life on Earth, the science behind biological magnetic sensing is largely a mystery, and it has proved challenging, especially in the life sciences, to harness the interactions of magnetic fields (MFs) with matter to achieve specific ends. Using the well-established radical pair (RP) mechanism, we here demonstrate a bottom-up strategy for the exploitation of MF effects in living cells by translating knowledge from studies of RP reactions performed in vitro. We found an unprecedented MF dependence of the reactivity of singlet oxygen (1O2) towards electron-rich substrates (S) such as anthracene, lipids and iodide, in which [S ˙+ O2 ˙-] RPs are formed as a basis for MFs influencing molecular redox events in biological systems. The close similarity of the observed MF effects on the biologically relevant process of lipid peroxidation in solution, in membrane mimics and in living cells, shows that MFs can reliably be used to manipulate 1O2-induced cytotoxicity and cell-apoptosis-related protein expression. These findings led to a 'proof-of-concept' study on MF-assisted photodynamic therapy in vivo, highlighting the potential of MFs as a non-invasive tool for controlling cellular events.

Association of serum uric acid with male sexual hormones and erectile dysfunction: a bidirectional 2-sample Mendelian randomization analysis.

Background: Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous. Aim: This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED. Methods: Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone-binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes. Outcomes: The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier). Results: UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (ß = -0.10, P = 1.70 × 10-7) and testosterone (ß = -0.10, P = 5.94 × 10-3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (ß = -0.06, P = 4.82 × 10-4) and E2 (ß = -0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P < .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study. Clinical Implications: Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED. Strengths and Limitations: This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors. Conclusion: Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.

CM082 suppresses hypoxia-induced retinal neovascularization in larval zebrafish.

Retinal neovascularization is a common feature of several ocular neovascular diseases, which are the leading cause of blindness in the world. Current treatments are administered through invasive intravitreal injections, leading to poor patient compliance, serious ocular complications and heavy economic burdens. Thus, an alternative less or non-invasive therapeutic strategy is in demand. Here, a non-invasive oral tyrosine kinase inhibitor, CM082, was evaluated in a retinal neovascularization model induced by hypoxia in zebrafish larvae. We found that CM082 effectively suppressed retinal neovascularization, rescued cell loss in the retinal ganglion cell layer, and rescued the visual function deficiency. Our results elucidated that CM082 mediated its therapeutic efficacy primarily through the inhibition of Vegfr2 phosphorylation. The findings demonstrated that CM082 possessed strong antiangiogenic effects and may serve as a potential treatment for angiogenesis in ocular neovascular diseases.

Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis.

The molecular editing of ketones represents an appealing strategy due to its ability to maximize the structural diversity of ketone compounds in a straightforward manner. However, developing efficient methods for the arbitrary modification of ketonic molecules, particularly those integrated within complex skeletons, remains a significant challenge. Herein, we present a unique strategy for ketone recasting that involves radical acylation of pre-functionalized ketones facilitated by N-heterocyclic carbene and photo dual catalysis. This protocol features excellent substrate tolerance and can be applied to the convergent synthesis and late-stage functionalization of structurally complex bioactive ketones. Mechanistic investigations, including experimental studies and density functional theory (DFT) calculations, shed light on the reaction mechanism and elucidate the basis of the regioselectivity.

Effect of bile duct resection on the prognosis of patients with hepatocellular carcinoma combined with extrahepatic bile duct tumor thrombus.

BACKGROUND: Surgical therapy is the most optimal treatment for hepatocellular carcinoma (HCC) combined with bile duct tumor thrombus (BDTT) patients. However, whether to perform bile duct resection (BDR) is still controversial. The purpose of this multicenter research is to compare the effect of BDR on the prognosis of extrahepatic BDTT patients. METHODS: We collected the data of 111 HCC patients combined with extrahepatic BDTT who underwent radical hepatectomy from June 1, 2004 to December 31, 2021. Those patients had either received hepatectomy with extrahepatic bile duct resection (BDR group) or hepatectomy without bile duct resection (NBDR group). Inverse probability of treatment weighting (IPTW) was used to reduce the potential bias between two groups and balance the influence of confounding factors in baseline data. Then compare the prognosis between the two groups of patients. Cox regression model was used for univariate and multivariate analysis to further determine the independent risk factors that influence the prognosis of HCC-BDTT patients. RESULTS: There were 38 patients in the BDR group and 73 patients in the NBDR group. Before and after IPTW, there were no statistical significance in OS, RFS and intraoperative median blood loss between the two groups (all P > 0.05). Before IPTW, the median postoperative hospital stay in the NBDR group was shorter (P = 0.046) and the grade of postoperative complications was lower than BDR group (P = 0.014). After IPTW, there was no difference in postoperative hospital stay between the two groups (P > 0.05). The complication grade in the NBDR group was still lower than that in the BDR group (P = 0.046). The univariate analysis showed that TNM stage and portal vein tumor thrombus (PVTT) were significantly correlated with OS (both P < 0.05). Preoperative AFP level, TNM stage and prognostic nutritional index (PNI) were significantly correlated with postoperative RFS (all P < 0.05). Multivariate analysis showed that tumor TNM stage was an independent risk factor for the OS rate (P = 0.014). TNM stage, PNI and AFP were independent predictors of RFS after radical hepatectomy (all P < 0.05). CONCLUSIONS: For HCC-BDTT patients, hepatocellular carcinoma resection combined with choledochotomy to remove the tumor thrombus may benefit more.

N-Heterocyclic carbene catalytic 1,2-boron migrative acylation accelerated by photocatalysis.

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent ß-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of ß-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.

Seven New Noroleanane Triterpenoids from Mastic and their NO Inhibitory and Cytotoxic Activities.

Mastic is a natural resin produced by Pistacia lentiscus L. (Anacardiaceae) with high medicinal value and have been traditionally used as Uighur imported medicine for centuries. In this study, 16 triterpenoids including seven new norleanane triterpenoids (1-7), along with nine known oleanane triterpenoids (8-16), were isolated from the mastic. Their chemical structures were determined on the basis of extensive spectroscopic analyses (including IR, UV, ESI-HR-MS and NMR spectroscopy) and single-crystal X-ray diffraction. Compounds 4-7, 11, 14 and 16 showed strong inhibitory NO production in LPS-induced RAW264.7 cells with IC50 values 7.44-9.76 µM, respectively (positive control dexamethasone, 9.93 ± 1.17 µM). Furthermore, compounds 3 and 12 significantly inhibited the growth of SW480 cells, compound 3 showed the most pronounced inhibitory effect with an  IC50 of 2.30 ± 0.38 µM.

Glioma-Stem-Cell-Derived Exosomes Remodeled Glioma-Associated Macrophage via NEAT1/miR-125a/STAT3 Pathway.

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma.

Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy.

Immunogenic cell death (ICD) often results in the production and accumulation of adenosine (ADO), a byproduct that negatively impacts the therapeutic effect as well as facilitates tumor development and metastasis. Here, an innovative strategy is elaborately developed to effectively activate ICD while avoiding the generation of immunosuppressive adenosine. Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

[Characteristics of leaf stoichiometry and the driving factors of Ammopiptanthus mongolicus, China]. / æ²™å†¬é’å¶ç‰‡åŒ–å­¦è®¡é‡ç‰¹å¾åŠå ¶é©±åŠ¨å› ç´ .

The stoichiometric characteristics of leaves can reflect environmental adaptation of plants, and thus the study of the relationship between them is helpful for exploring plant adaptation strategies. In this study, taking the national second-level key protection species, Ammopiptanthus mongolicus, as the research object, we set up 26 plots to collect samples, and measured the content of carbon (C), nitrogen (N), phosphorus (P) and water use efficiency (WUE) of leaves. We analyzed the relationship between leaf stoichiometric characteristics and WUE, and quantified the contributions of soil, climate, and water use efficiency to the variations of leaf stoichiometry. The results showed that C, N, and P contents in the leaves were (583.99±27.93), (24.31±2.09), and (1.83±0.06) mg·g-1, respectively. The coefficients of variation were 4.8%, 8.6%, and 3.2%, respectively, all belonging to weak variability, indicating that foliar contents of C, N and P tended to a certain stable value. The average value of N:P was 13.3, indicating that the growth of A. mongolicus was mainly limited by N. WUE was not correlated with leaf C content, but was significantly positively correlated with leaf N and P contents and N:P, and significantly negatively correlated with C:N and C:P, indicating that there was a linear synergistic trend between WUE and leaf nutrient content. The main factors influencing leaf C content and C:P were climatic factors, the leaf N content and N:P were mainly affected by soil factors, and the water use efficiency mainly affected leaf P content and C:N, indicating that the driving factors of different stoichiometric characteristics were different. The results could help eva-luate the habitat adaptation of desert plants, which would provide a theoretical basis for the conservation and management of A. mongolicus.

Microplastics weaken the digestion and absorption functions in the golden pompano (Trachinotus blochii) by affecting the intestinal structure, bacteria and metabolites.

Microplastics are difficult to degrade and widespread environmental pollutants. Coastal areas are hardest hit of microplastic pollution as they receive significant amounts of microplastics discharged from inland sources. Golden pompano (Trachinotus blochii) is a high commercial valuable marine aquaculture fish species, most of the golden pompano are raised in coastal areas, which means they are at significant risk of exposure to microplastics. Therefore, we exposed golden pompano to 10 µg/L, 100 µg/L and 1000 µg/L of 5 µm spherical polystyrene microplastics and conducted a 14-day stress experiment. Histopathology results showed the intestinal villi shrank. The 16s sequencing analysis revealed that microplastics significantly impacted the abundance and community structure of intestinal microorganisms, which may affect the metabolic function of the gastrointestinal tract. Metabolomics sequencing of the intestinal contents showed that microplastics caused disruptions in lipid, glucose, and amino acid metabolism, thus compromising the normal digestion and absorption functions in the intestinal system. In addition, the activation of various pathways, including the intestinal endocrine system, proline metabolism, and signal transduction, which can lead to the occurrence of several diseases. This study combined various methods to investigate the adverse effects of microplastics on intestinal digestion and absorption, and provided new insights into the toxic mechanisms of microplastics.

Atroposelective N-N Axes Synthesis via Electrochemical Cobalt Catalysis.

Here, we disclosed an unprecedented cobalt electrocatalyzed atroposelective C-H activation and annulation for the efficient construction of diversely functionalized N-N axes in an undivided cell. A broad range of allene substrates and benzamides bearing different functionalities are compatible with generating axially chiral products with good yields and excellent enantioselectivities (up to 92% yield and 99% ee). A series of synthetic applications and control experiments were also performed, which further expanded the practicality of this strategy.

Different machine learning methods based on maxillary sinus in sex estimation for northwestern Chinese Han population.

BACKGROUND & OBJECTIVE: Sex estimation is a critical aspect of forensic expertise. Some special anatomical structures, such as the maxillary sinus, can still maintain integrity in harsh environmental conditions and may be served as a basis for sex estimation. Due to the complex nature of sex estimation, several studies have been conducted using different machine learning algorithms to improve the accuracy of sex prediction from anatomical measurements. MATERIAL & METHODS: In this study, linear data of the maxillary sinus in the population of northwest China by using Cone-Beam Computed Tomography (CBCT) were collected and utilized to develop logistic, K-Nearest Neighbor (KNN), Support Vector Machine (SVM) and random forest (RF) models for sex estimation with R 4.3.1. CBCT images from 477 samples of Han population (75 males and 81 females, aged 5-17 years; 162 males and 159 females, aged 18-72) were used to establish and verify the model. Length (MSL), width (MSW), height (MSH) of both the left and right maxillary sinuses and distance of lateral wall between two maxillary sinuses (distance) were measured. 80% of the data were randomly picked as the training set and others were testing set. Besides, these samples were grouped by age bracket and fitted models as an attempt. RESULTS: Overall, the accuracy of the sex estimation for individuals over 18 years old on the testing set was 77.78%, with a slightly higher accuracy rate for males at 78.12% compared to females at 77.42%. However, accuracy of sex estimation for individuals under 18 was challenging. In comparison to logistic, KNN and SVM, RF exhibited higher accuracy rates. Moreover, incorporating age as a variable improved the accuracy of sex estimation, particularly in the 18-27 age group, where the accuracy rate increased to 88.46%. Meanwhile, all variables showed a linear correlation with age. CONCLUSION: The linear measurements of the maxillary sinus could be a valuable tool for sex estimation in individuals aged 18 and over. A robust RF model has been developed for sex estimation within the Han population residing in the northwestern region of China. The accuracy of sex estimation could be higher when age is used as a predictive variable.

Correlations of dynamic changes in lipid and protein of salted large yellow croaker during storage.

Protein and lipid are two major components that undergo significant changes during processing of aquatic products. This study focused on the protein oxidation, protein conformational states, lipid oxidation and lipid molecule profiling of salted large yellow croaker during storage, and their correlations were investigated. The degree of oxidation of protein and lipid was time-dependent, leading to an increase in carbonyl content and surface hydrophobicity, a decrease in sulfhydryl groups, and an increase in conjugated diene, peroxide value and thiobarbituric acid reactive substances value. Oxidation caused protein structure denaturation and aggregation during storage. Lipid composition and content changed dynamically, with polyunsaturated phosphatidylcholine (PC) was preferentially oxidized compared to polyunsaturated triacylglycerol. Correlation analysis showed that the degradation of polyunsaturated key differential lipids (PC 18:2_20:5, PC 16:0_22:6, PC 16:0_20:5, etc.) was closely related to the oxidation of protein and lipid. The changes in protein conformation and the peroxidation of polyunsaturated lipids mutually promote each other's oxidation process.

Expression of genes related to gonadal development and construction of gonadal DNA methylation maps of Trachinotus blochii under hypoxia.

Chronic hypoxia can affect the growth and metabolism of fish and potentially impact gonadal development through epigenetic regulation. Trachinotus blochii (Golden pompano) is widely cultured near the coast and is sensitive to low oxygen conditions. We found that hypoxia and reoxygenation processes acted on multiple targets on the HPG axis, leading to endocrine disorders. Changes in the expression of key genes in the brain (gnrh), pituitary (fsh and lh), ovaries (cyp19a1a, foxl2, and er), and testes (dmrt1, ar, sox9, and gsdf) were associated with significant decreases in estrogen and testosterone levels. Hypoxia and reoxygenation lead to changes in DNA methylation levels in the gonads. Hypoxia upregulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in females and dnmt3a and dnmt3b in males, while reoxygenation down-regulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in males. Whole genome methylation sequencing showed that the number of differentially methylated regions was highest on chromosome 10 (5192) and lowest on chromosome 24 (275). Differentially methylated genes in females and males, as well as between males and females, were enriched in the oxytocin signaling pathway, fatty acid metabolism pathway, and HIF-1a pathway. In summary, hypoxia and reoxygenation can induce endocrine disorders, affect the expression of HPG axis genes, change the methylation pattern and modification pattern of gonad DNA, and then have potential effects on gonad development.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e ., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Strategies to Enhance the Electrochromic Properties of Conjugated Polymers Bearing Pyromellitic Diimide Acceptors.

A series of conjugated polymers bearing thiophene-based donors and pyromellitic diimide (PMDI) acceptor were prepared, and their electrochromic (EC) properties were studied via using fabricated thin-film EC devices. It was observed that structurally regular alternating polymers with fewer (1 and 2) thiophene donors do not exhibit any EC properties while increasing the number of donors eventually led to the emergence of orange-red-to-green colour switching. On this basis, two more random co-polymers containing higher donor-to-acceptor ratios were synthesized to further improve EC switching properties. The two polymers, which bear a PMDI-to-thiophene ratio of ca. 1 : 7 and 1 : 8, revealed orange red-to-blue colour switching and generally improved optical contrasts and switching speeds in both the visible and near infra-red (NIR) region. In addition, the subtle modulation of polymer colour and hue via variation of the number of thiophene donors was evident through colorimetric study. This work therefore demonstrates the potential and possibility of using the PMDI acceptor unit to construct EC-active conjugated polymers, and considerations for future tuning of colour and switching performances.