Light-Driven Access to Selenium-Substituted Thiazole-2-imine Derivatives.

The thiazole-2-imine derivatives with interesting pharmacological activities have attracted significant attention. However, previously reported synthesis strategies usually suffered from some drawbacks, such as the use of metals/additive and harsh reaction conditions. Herein, we developed a metal- and photoinitiator-free photocatalytic strategy for the synthesis of various selenium-substituted thiazole-2-imine derivatives for the first time. The reaction displayed mild reaction conditions, simple operation, a broad substrate scope (37 examples), and good to excellent yields.

[Correlations between tanshinones and soil factors of Salviae Miltiorrhizae Radix et Rhizoma from different producing areas].

Soil nutrients and inorganic elements affect not only the growth and development of medicinal plants but also the formation and accumulation of active ingredients in traditional Chinese medicines. The content of tanshinones and 28 inorganic elements in Salviae Miltiorrhizae Radix et Rhizoma samples from 18 producing areas in 6 provinces was determined, and 35 physical and chemical properties of the corresponding soil samples were determined. The enrichment characteristics of inorganic elements in Salviae Miltiorrhizae Radix et Rhizoma were analyzed. The correlation analysis and stepwise regression analysis were performed to screen out the main soil factors affecting the content of tanshinones in Salviae Miltiorrhizae Radix et Rhizoma. The results showed that the content of tanshinones in the samples from different areas varied significantly, being the highest in the samples from Shandong, the second in the samples from Henan, and low in the samples from Shanxi and Sichuan. K, Mg, Ca, and Na were rich in Salviae Miltiorrhizae Radix et Rhizoma samples, among which Na and K had the highest enrichment coefficients. The results of correlation and regression analyses showed that soil K, Na, Ti, and total nitrogen were the main soil factors affecting the tanshinones in Salviae Miltiorrhizae Radix et Rhizoma. Specifically, the content of tanshinones was positively correlated with Ti and negatively correlated with Na, K, and total nitrogen in the soil. Therefore, during the planting of Salvia miltiorrhiza, the land should be selected with full consideration to the salinity and saline land should be avoided. Secondly, the application of nitrogen and potassium fertilizers can be appropriately reduced, and water-soluble elemental fertilizers for S. miltiorrhiza should be developed.

Transition-Metal-Free Synthesis of Polyfluoro-Polyarylmethanes via Direct Cross-Coupling of Polyfluoroarenes and Benzyl Chlorides.

The transition-metal-free direct cross-coupling between polyfluoroarenes and benzyl chlorides is reported. In this strategy, a variety of polyfluoro di-, tri- and tetra-arylmethanes was efficiently prepared with good to excellent yields in the presence of Mg turnings via a one-pot procedure. Significantly, this method provides a general approach for the synthesis of polyfluorinated polyarylmethanes.

Electrochemical Difunctionalization of Alkenes: Simultaneous Construction of C-Se and C-S Bonds.

Electrochemical oxidation of alkene difunctionalization with simultaneous construction of C-Se and C-S bonds is reported. The products of ß-selenylethyl dithiocarbamates are obtained with CS2, amines, alkenes, and diphenyl diselenides in the absence of any oxidant or metal. Furthermore, the transformation is compatible with various groups. In the preliminary mechanism studies, we propose three possible pathways.

Photoinduced Metal- and Photosensitizer-Free Decarbonylative C-H Alkylation of Cyclic Sulfamidate Imines.

Photoinduced decarbonylative C-C bond formation with readily accessible aldehydes as alkyl sources is described. This protocol provides a sustainable alternative for the effective construction of diverse valuable 4-alkylated sulfonyl ketimines under metal- and photosensitizer-free conditions. Significantly, in this reaction, air serves as the green oxidant, and cyclic sulfamidate imines play a dual role of substrate and photocatalyst, thus affording a concise reaction system for C-H alkylation of cyclic sulfamidate imines.

Ring-Opening Selenation of Cyclopropanol for the Selective Synthesis of ß-Hydroxy-Substituted Selenylated Ketones.

Ring opening of cycloalkanols has been employed as a commonly used strategy to prepare diverse distal functionalized ketones. However, most of these ketones obtained by this strategy belong to monofunctional ketones, while difunctional ketones with more potential application value have been rarely reported. Herein, we first reported a mild I2-promoted ring-opening selenation of cyclopropanol to synthesize various distal difunctional ketones. In the reaction, hydroxyl (-OH) derived from water and RSe+ from diselenide can be introduced into the α- and ß-positions, respectively, delivering ß-hydroxy selenylated ketones in good to excellent yields.

[3 + 2]-Annulation of gem-Difluoroalkenes and Pyridinium Ylides: Access to Functionalized 2-Fluoroindolizines.

A [3 + 2]-annulation of gem-difluoroalkenes and pyridinium ylides was developed employing ambient air as the sole oxidant in an open-vessel manner, affording a series of multifunctionalized 2-fluoroindolizines in moderate to good yields. In this reaction, gem-difluoroalkene acts as a C2 synthon and entirely avoids the competitive addition-elimination process, which provides facile access to 2-fluoroindolizines.

Selective divergent radical cyclization of 1,6-dienes with alkyl nitriles.

An efficient, selective, and step economical radical cyclization of 1,6-dienes with alkyl nitriles initiated by α-C(sp3)-H functionalization under the Sc(OTf)3 and Ag2CO3 system is described here. The selective divergent cyclization relies on the substitution effect at the α-position of the acrylamide moiety and nitriles, which is terminated by hydrogen abstraction, direct cyclization with the aryl ring, or further cyclization with the CN bond and hydrolysis, respectively.

Pd-Catalyzed Asymmetric Dearomative Cycloaddition for Construction of Optically Active Pyrroloindoline and Cyclopentaindoline Derivatives: Access to 3a-Aminopyrroloindolines.

Asymmetric dearomative [3 + 2] cycloaddition reactions of 3-nitroindoles with vinyl aziridine and vinyl cyclopropanes have been respectively successfully developed in the presence of a chiral box/Pd(0) complex. A series of enantiomerically enriched 3a-nitro-hexahydropyrrolo[2,3-b]indole and 8b-nitrohexahydrocyclopenta[b]indole derivatives containing three contiguous chiral centers are smoothly obtained in high yields with satisfactory regio-, chemo-, and enantioselectivity. Remarkably, the synthetic utility of this process was demonstrated through direct reductive amination and functionalization of the carbon-carbon double bond of the desired products.

Mild Pd-Catalyzed Decarboxylative Cross-Coupling of Zinc(II) Polyfluorobenzoates with Aryl Bromides and Nonaflates: Access to Polyfluorinated Biaryls.

We developed a Pd-catalyzed decarboxylative cross-coupling of zinc polyfluorobenzoates, which were used as precursors for producing zinc reagents in situ, with aryl bromides and nonaflates, providing a mild and efficient pathway for the synthesis of polyfluorinated biaryls. This protocol exhibits a broad substrate scope and excellent functional tolerance. Moreover, the versatility of this approach was demonstrated by the straightforward late-stage modification of drugs, biologically active molecules, and pesticides, indicating its potential significance in drug discovery.

Copper-Catalyzed Radical Relay 1,3-Carbocarbonylation across Two Distinct C═C Bonds.

The radical relay provides an effective paradigm for intermolecular assembly to achieve functionalization across remote chemical bonds. Herein, we report the first radical relay 1,3-carbocarbonylation of α-carbonyl alkyl bromides across two separate C═C bonds. The reaction is highly chemo- and regioselective, with two C(sp3)-C(sp3) bonds and one C═O bond formed in a single orchestrated operation. In addition, the synthesis method under mild conditions and using inexpensive copper as the catalyst allows facile access to structurally diverse 1,3-carbocarbonylation products. The plausible mechanism is investigated through a series of control experiments, including radical trapping, radical clock experiments, critical intermediate trapping, and 18O labeling experiment.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Application of convolutional neural network-based endoscopic imaging in esophageal cancer or high-grade dysplasia: A systematic review and meta-analysis.

BACKGROUND: Esophageal cancer is the seventh-most common cancer type worldwide, accounting for 5% of death from malignancy. Development of novel diagnostic techniques has facilitated screening, early detection, and improved prognosis. Convolutional neural network (CNN)-based image analysis promises great potential for diagnosing and determining the prognosis of esophageal cancer, enabling even early detection of dysplasia. AIM: To conduct a meta-analysis of the diagnostic accuracy of CNN models for the diagnosis of esophageal cancer and high-grade dysplasia (HGD). METHODS: PubMed, EMBASE, Web of Science and Cochrane Library databases were searched for articles published up to November 30, 2022. We evaluated the diagnostic accuracy of using the CNN model with still image-based analysis and with video-based analysis for esophageal cancer or HGD, as well as for the invasion depth of esophageal cancer. The pooled sensitivity, pooled specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUC) were estimated, together with the 95% confidence intervals (CI). A bivariate method and hierarchical summary receiver operating characteristic method were used to calculate the diagnostic test accuracy of the CNN model. Meta-regression and subgroup analyses were used to identify sources of heterogeneity. RESULTS: A total of 28 studies were included in this systematic review and meta-analysis. Using still image-based analysis for the diagnosis of esophageal cancer or HGD provided a pooled sensitivity of 0.95 (95%CI: 0.92-0.97), pooled specificity of 0.92 (0.89-0.94), PLR of 11.5 (8.3-16.0), NLR of 0.06 (0.04-0.09), DOR of 205 (115-365), and AUC of 0.98 (0.96-0.99). When video-based analysis was used, a pooled sensitivity of 0.85 (0.77-0.91), pooled specificity of 0.73 (0.59-0.83), PLR of 3.1 (1.9-5.0), NLR of 0.20 (0.12-0.34), DOR of 15 (6-38) and AUC of 0.87 (0.84-0.90) were found. Prediction of invasion depth resulted in a pooled sensitivity of 0.90 (0.87-0.92), pooled specificity of 0.83 (95%CI: 0.76-0.88), PLR of 7.8 (1.9-32.0), NLR of 0.10 (0.41-0.25), DOR of 118 (11-1305), and AUC of 0.95 (0.92-0.96). CONCLUSION: CNN-based image analysis in diagnosing esophageal cancer and HGD is an excellent diagnostic method with high sensitivity and specificity that merits further investigation in large, multicenter clinical trials.

Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3ß inhibition.

AIM: To identify the mechanisms underlying the elevation of intracellular Ca(2+) level ([Ca(2+)](i)) induced by lowering extracellular glucose in rat hypothalamic arcuate nucleus NPY neurons. METHODS: Primary cultures of hypothalamic arcuate nucleus (ARC) neurons were prepared from Sprague-Dawley rats. NPY neurons were identified with immunocytochemical method. [Ca(2+)](i) was measured using fura-2 AM. Ca(2+) current was recorded using whole-cell patch clamp recording. AMPK and GSK3ß levels were measured using Western blot assay. RESULTS: Lowering glucose level in the medium (from 10 to 1 mmol/L) induced a transient elevation of [Ca(2+)](i) in ARC neurons, but not in hippocampal and cortical neurons. The low-glucose induced elevation of [Ca(2+)](i) in ARC neurons depended on extracellular Ca(2+), and was blocked by P/Q-type Ca(2+)channel blocker ω-agatoxin TK (100 nmol/L), but not by L-type Ca(2+) channel blocker nifedipine (10 µmol/L) or N-type Ca(2+)channel blocker ω-conotoxin GVIA (300 nmol/L). Lowering glucose level increased the peak amplitude of high voltage-activated Ca(2+) current in ARC neurons. The low-glucose induced elevation of [Ca(2+)](i) in ARC neurons was blocked by the AMPK inhibitor compound C (20 µmol/L), and enhanced by the GSK3ß inhibitor LiCl (10 mmol/L). Moreover, lowering glucose level induced the phosphorylation of AMPK and GSK3ß, which was inhibited by compound C (20 µmol/L). CONCLUSION: Lowering glucose level enhances the activity of P/Q type Ca(2+)channels and elevates [Ca(2+)](i) level in hypothalamic arcuate nucleus neurons via inhibition of GSK3ß.

Bimetallic Metal-Organic Coordination Polymers Facilitated the Selective C-F Cleavage of Polyfluoroarenes.

Selective C-F bond cleavage of polyfluoroarenes has attracted tremendous interest due to its promising applications in introducing fluorinated building blocks into organic molecules. However, it remains a challenge to achieve highly site-selective C-F bond cleavage because of the intrinsic inertness of the C-F bond and the difficulty in distinguishing specific C-F bonds on the aromatic ring. Herein we report an efficient nucleophilic aromatic substitution (SNAr) reaction of polyfluoroarenes with Grignard reagents that employs MnFe-based bimetallic metal-organic coordination polymers (MOCPs) as recyclable and reusable heterogeneous catalysts. Significantly, in this reaction, the prepared MOCP (Mn-Fe) catalyst exhibited excellent activity in selective C-F bond cleavage and afforded a series of functionalized polyfluoroarenes in moderate to excellent yields (up to 96%). This work highlights the potential of MOCP catalysts to serve as a tunable platform in Lewis acid catalysis.

Rapid and Simple Access to α-(Hetero)arylacetonitriles from Gem-Difluoroalkenes.

A scalable cyanation of gem-difluoroalkenes to (hetero)arylacetonitrile derivatives was developed. This strategy features mild reaction conditions, excellent yields, wide substrate scope, and broad functional group tolerance. Significantly, in this reaction, aqueous ammonia offers a "N" source for the "CN" reagent and entirely avoids the use of toxic cyanating reagents or metal catalysis. Hence, we provide a green and alternative method for the synthesis of arylacetonitriles.

Electrochemical Selenium-Catalyzed N,O-Difunctionalization of Ynamides: Access to Polysubstituted Oxazoles.

A green and efficient approach for the difunctionalization of ynamides by merging the electrochemical and organoselenium-catalyzed processes is described. This strategy features mild reaction conditions, broad functional group tolerance and high atom-economy, and requires no external chemical oxidant. Hence, we provide a sustainable alternative for the synthesis of polysubstituted oxazoles.

The ctDNA-based postoperative molecular residual disease status in different subtypes of early-stage breast cancer.

Background: Breast cancer is a highly heterogeneous disease. Early-stage, non-metastatic breast cancer is considered curable after definitive treatment. Early detection of tumor recurrence and metastasis through sensitive biomarkers is helpful for guiding clinical decision-making and early intervention in second-line treatment, which could improve patient prognosis and survival. Methods: In this real-world study, we retrospectively analyzed 82 patients with stages I to III breast cancer who had been analyzed by molecular residual disease (MRD) assay. A total of 82 tumor tissues and 224 peripheral blood samples were collected and detected by next-generation sequencing (NGS) based on a 1,021-gene panel in this study. Results: MRD positivity was detected in 18 of 82 patients (22.0%). The hormone receptor-/human epidermal growth factor receptor 2+ (HR-/HER2+) subgroup had the highest postoperative MRD detection rate at 30.8% (4/13). The BRCA2 and SLX4 genes were significantly enriched in all patients in the MRD positive group and FGFR1 amplification was significantly enriched in the MRD negative group with HR+/HER2-. The number of single nucleotide variants (SNVs) in tissue samples of MRD-positive patients was higher than that of MRD-negative patients (11.94 vs. 8.50 SNVs/sample). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that there was a similar biological function of the tumor-mutated genes in the 2 MRD status groups. Conclusions: This real-world study confirmed that patient samples of primary tumor tissue with different MRD status and molecular subtypes had differential genetic features, which may be used to predict patients at high risk for recurrence.

Determination of protein-bound methionine oxidation in the hippocampus of adult and old rats by LC-ESI-ITMS method after microwave-assisted proteolysis.

Protein-bound methionine (Met) oxidation has been associated with normal aging and a variety of age-related diseases, including Alzheimer's disease and Parkinson's disease. Monitoring the changes of protein-bound methionine content in the brain in response to normal aging and oxidative stress is of great interest and could be used as an indicator of oxidative stress of rats in pathological conditions. We have developed a rapid analytical method for the determination of oxidized products of protein-bound methionine in rat brain. The assay involved rapid acid proteolysis with microwave irradiation and solid-phase extraction of the free amino acids followed by LC-ESI-ITMS analysis. Detection was achieved in positive ionization with an ion trap mass spectrometer operating in multiple-reaction monitoring mode. The calibration curves of the analytes were linear (r(2) > 0.99) in the range between 0.098 and 1.560 µg/mL. Intra- and inter-day relative standard deviation percentages were <9% and <8%, respectively. The assay performance was sufficient to support a rapid analytical tool for monitoring brain protein-bound methionine oxidation levels. The content of protein-bound Met and methionine sulfoxide (MetO) in the hippocampus of adult and old rats with or without H(2)O(2) treatment was determined by employing the new method. The content of protein-bound MetO was significantly increased in old rats after exposure to H(2)O(2). This result indicates increased sensitivity to Met oxidation in the hippocampus of old rats.

Sulfonyl radical triggered selective iodosulfonylation and bicyclization of 1,6-dienes.

A novel sulfonyl radical triggered selective iodosulfonylation and bicyclization of 1,6-dienes has been described for the first time. High selectivity and efficiency, mild reaction conditions, excellent functional group compatibility, and broad substrate scope are the attractive features of this synthetic protocol, which provides a unique platform for precise radical cyclization.