Preclinical Development of SHR-1819, a Potent Humanized IL-4Rα Antibody for Treating Type 2 Inflammatory Diseases.

Background: Interleukin (IL)-4 and IL-13 are critical pathogenic factors for type 2 inflammation-related allergic diseases, sharing the mutual receptor subunit IL-4Rα. However, it was ineffective for certain type 2 inflammation diseases by targeting IL-4, IL-13 ligand alone or both in clinical studies. The work presented herein aimed to evaluate the preclinical efficacy and pharmacokinetics profile of a novel monoclonal antibody against IL-4Rα, SHR-1819, as a promising therapy for type 2 inflammation diseases. Methods: SHR-1819 was generated through immunization by C57BL/6 mice with recombinant hIL-4Rα protein, followed by humanization and affinity maturation. Then, its binding properties with IL-4Rα were determined using surface plasmon resonance (SPR) and ELISA. In vitro inhibitory effects of SHR-1819 were assessed on hIL-4-/hIL-13-induced cell proliferation and signal transducer and activator of transcription 6 (STAT6) signaling activation. In vivo efficacy of SHR-1819 was evaluated in several type 2 inflammatory diseases models, including asthma, atopic dermatitis (AD), and allergic rhinitis (AR) by using hIL-4/hIL-4Rα transgenic mice. Furthermore, the pharmacokinetic (PK) profiles of SHR-1819 were characterized. Results: SHR-1819 showed high binding affinity to human IL-4Rα and effectively blocked IL-4Rα at sub-nanomolar concentration. In vitro assays indicated that SHR-1819 significantly inhibited TF-1 cell proliferation and STAT6 activation induced by hIL-4/hIL-13. In the asthma model, SHR-1819 could reduce airway hyperresponsiveness, decrease serum IgE levels, and alleviated inflammatory lung cell infiltration. In the AD model, SHR-1819 could significantly alleviate inflammatory and skin symptoms. In the AR model, it could remarkably decrease the frequencies of nasal rubbing and sneezing, and inflammatory cell infiltration in nasal tissues. These in vivo efficacy studies demonstrated the therapeutic potential of SHR-1819 in preclinical disease models. Moreover, subcutaneous administration of SHR-1819 exhibited favorable bioavailability in mice. Conclusion: The results supported SHR-1819 as a promising preclinical candidate for the treatment of type 2 inflammatory diseases, including asthma, AD and AR.

Transarterial chemoembolization combined with sintilimab and lenvatinib for the treatment of unresectable hepatocellular carcinoma: a retrospective study.

BACKGROUND: The treatment of unresectable hepatocellular carcinoma (uHCC) challenging due to unfulfilled clinical requirements. OBJECTIVE: To evaluate the safety and efficacy of combining transarterial chemoembolization (TACE) with sintilimab and lenvatinib in the treatment of uHCC. METHODS: We retrospectively analyzed the data of patients with uHCC who were treated with a combination of TACE, sintilimab, and lenvatinib between May 2019 and December 2021 at the Chinese PLA General Hospital. Systemic treatment was started 1 week after TACE was performed. Sintilimab was administered intravenously at a dosage of 200 mg every three weeks, and lenvatinib was given orally at dosages of 8 mg or 12 mg daily, contingent upon the weight of the patients. The primary endpoint was the objective response rate (ORR) as per the mRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (tr-AEs). RESULTS: A total of 32 patients were enrolled in the study. Among them, 9 patients were classified as Barcelona Clinic Liver Cancer-B (BCLC-B), 23 patients were classified as BCLC-C, 14 patients diagnosed with portal vein tumors, and 12 patients were diagnosed with extra hepatic metastases. The ORR and DCR were 75% and 90.6% respectively, with 4 patients exhibiting (12.5%) complete response, 20 patients exhibiting (62.5%) partial response, 5 patients exhibiting (15.6%) stable disease, and 3 patients exhibiting (9.4%) progressive disease. With a median follow-up time of 19.6 months, the median PFS was 9.9 months, and the median OS was 33.3 months. A total of 31 patients experienced different degrees of tr-AEs, of which 2 were grade 3 tr-AEs. CONCLUSION: The combination therapy of TACE, sintilimab, and lenvatinib demonstrates satisfactory efficacy in the treatment of uHCC with manageable tr-AEs.

The dynamic roles of intracellular vacuoles in heavy metal detoxification by Rhodotorula mucilaginosa.

AIMS: Rhodotorula mucilaginosa (Rho) can develop a range of strategies to resist the toxicity of heavy metals. This study aimed to investigate the physiological responses and transcriptomic regulation of the fungus under different heavy metal stresses. METHODS AND RESULTS: This study applied transmission electron microscopy and RNA-seq to investigate the fungal resistance to Pb, Cd, and Cu stresses. Under Pb stress, the activated autophagy-related genes, vesicle-fusing ATPase, and vacuolar ATP synthase improved vacuolar sequestration. This offsets the loss of lipids. However, the metal sequestration by vacuoles was not improved under Cd stress. Vacuolar fusion was also inhibited following the interference of intravacuolar Ca2+ due to their similar ionic radii. Cu2+ showed the maximum toxic effects due to its lowest cellular sorption (as low as 7%) with respect to Pb2+ and Cd2+, although the efflux pumps and divalent metal ion transporters partially contributed to the detoxification. CONCLUSIONS: Divalent cation transporters and vacuolar sequestration are the critical strategies for Rho to resist Pb stress. SOD is the main strategy for Cd resistance in Rho. The intracellular Cu level was decreased by efflux pump and divalent metal ion transporters.

Organic-Inorganic Interfacial Dipole Induced by Energy Level Alignment for Efficient Photocatalytic Sterilization.

Photocatalytic molecules are considered to be one of the most promising substitutions of antibiotics against multidrug-resistant bacterial infections. However, the strong excitonic effect greatly restricts their efficiency in antibacterial performance. Inspired by the interfacial dipole effect, a Ti3C2 MXene modified photocatalytic molecule (MTTTPyB) is designed and synthesized to enhance the yield of photogenerated carriers under light irradiation. The alignment of the energy level between Ti3C2 and MTTTPyB results in the formation of an interfacial dipole, which can provide an impetus for the separation of carriers. Under the role of a dipole electric field, these photogenerated electrons can rapidly migrate to the side of Ti3C2 for improving the separation efficiency of photogenerated electrons and holes. Thus, more electrons can be utilized to produce reactive oxygen species (ROS) under light irradiation. As a result, over 97.04% killing efficiency can be reached for Staphylococcus aureus (S. aureus) when the concentration of MTTTPyB/Ti3C2 was 50 ppm under 660 nm irradiation for 15 min. A microneedle (MN) patch made from MTTTPyB/Ti3C2 was used to treat the subcutaneous bacterial infection. This design of an organic-inorganic interface provides an effective method to minimize the excitonic effect of molecules, further expanding the platform of inorganic/organic hybrid materials for efficient phototherapy.

Momentum-space spin texture induced by strain gradient in nominally centrosymmetric SrIrO3 films.

Spin texture in k-space is a consequence of spin splitting due to strong spin-orbit coupling and inversion symmetry breaking. It underlies fertile spin transport phenomena and is of crucial importance for spintronics. Here, we observe the spin texture in k-space of nominally centrosymmetric SrIrO3 grown on NdGaO3 (110) substrates, using non-linear magnetotransport measurements. We demonstrate that the spin texture is not only induced by the interface, which inherently breaks the inversion symmetry in strong spin-orbit coupled SrIrO3 films, but also originates from the film bulk. Structural analysis reveals that thicker SrIrO3 films exhibit a strain gradient, which could be considered as a continuous change in the lattice constant across different layers and breaks the inversion symmetry throughout the entire SrIrO3 films, giving rise to the spin texture in k-space. First-principles calculations reveal that the strain gradient creates large spin-splitting bands, inducing the spin texture with anisotropy, which is consistent with our experimental observations. Our results offer an efficient method for inducing the spin textures in k-space.

Quantitative assessment of rotator cuff injuries using synthetic MRI and IDEAL-IQ imaging techniques.

Purpose: To evaluate synthetic magnetic resonance imaging (SyMRI) and iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL-IQ) imaging for a comprehensive evaluation of rotator cuff injuries (RCI). Methods: Ninety-seven patients with RCI were classified into four groups based on the arthroscopic results: (grade II), partial tear (grade III), complete tear (grade IV), and controls (grade I). T1 (Transverse Relaxation Time 1), T2 (Transverse Relaxation Time 2), proton density (PD), and fat fraction (FF) were evaluated using SyMRI and IDEAL-IQ. Measurement reliability was assessed using intraclass correlation coefficients (ICC). The diagnostic potential for grading RCI was evaluated using ordinal regression and ROC analyses. Results: A high measurement reliability (ICC > 0.7) was observed across subregions. T1 and T2 significantly varied across grades, particularly T2 in the lateral subregion between grades III and IV (P < 0.001) and the central subregion between grades II and III (P < 0.001). ROC analyses yielded valuable diagnostic accuracy, including T2 in the lateral subregion with an AUC of 0.891, distinguishing grade I from grade IV. Positive correlations were found between T2 values in specific shoulder subregions and injury grade (r = 0.615 for lateral, r = 0.542 for medial, both P < 0.001). In grade IV, FF was notably increased in the supraspinatus, infraspinatus, and subscapularis muscles compared with grades I-III. There were no significant FF variations in the teres minor muscle among grades. Conclusions: Quantitative MRI parameters from SyMRI and IDEAL-IQ, especially T2 and FF, may classify and assess RCI severity. The results could help improve the accuracy of diagnosing different grades of RCI, offering clinicians additional tools for improving patient outcomes through personalized medicine.

Study on the mechanism of Shenling Baizhu powder on the pathogenesis of pregnancy complicated with non-alcoholic fatty liver, based on PI3K/AKT/mTOR signal pathway.

This study investigates the effectiveness of Shenlin Baizhu powder in managing non-alcoholic fatty liver disease (NAFLD) during pregnancy and its mechanism through the PI3K/AKT/mTOR signaling pathway. Eight healthy male and 24 female Sprague-Dawley rats were used. After acclimatization, 6 female rats were fed normal chow, and 18 female rats were fed high-fat chow to induce NAFLD. After 8 weeks, female rats were mated with males to create a pregnant NAFLD model. The rats were divided into four groups: normal feeding, high-fat diet with saline, high-fat diet with 1.6 g/kg Shenlin Baizhu powder, and high-fat diet with 4.8 g/kg Shenlin Baizhu powder. Maternal body weight, serum and liver levels of aspartate aminotransferase (AST), alanine transaminase (ALT), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), related inflammatory indexes interleukin-1 ß (IL-1 ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. Liver tissue was examined using hematoxylin and oil red O staining, and protein expression related to the PI3K/AKT/mTOR pathway was assessed via Western blotting, immunohistochemistry and RT-PCR. Results showed significant weight gain and increases in ALT, AST, TG, TC, LDL-C, IL-1ß, TNF-α, and IL-6, along with decreased HDL-C in NAFLD rats compared to controls. The high and low-dose Shenlin Baizhu powder groups exhibited improvements in body weight, liver histopathology, and reductions in serum TG, TC, LDL-C, ALT, AST, IL-1ß, TNF-α, and IL-6, with increased HDL-C levels. Notably, the high-dose group showed greater efficacy in reducing hepatic fat accumulation, liver function markers, blood lipids, and inflammatory indexes, and decreased expression of hepatic PPARγ mRNA, SREBP1 mRNA, AKT mRNA, and related proteins. Shenlin Baizhu powder demonstrates potential in ameliorating high-fat diet-induced NAFLD in pregnant rats, likely through modulation of the PI3K/AKT/mTOR pathway, suggesting its therapeutic potential for gestational NAFLD.

Improvement of luminescence properties in Zn2.1Mg0.9Ta2O8:Cr3+ by the cation substitution and its application in biological nondestructive testing and night vision lighting.

Recently, it is of great significance to explore near-infrared (NIR) phosphor with more application prospects. In this work, a series of Zn2.1 Mg(0.9 - y)GaySnyTa(2 - y)O8:0.003Cr3+ NIR broadband phosphors with high quantum yields and high thermal stability are discovered by uniquely replacing [Mg2+-Ta5+] in Zn2.1Mg0.9Ta2O8 with [Ga3+-Sn4+]. Under 460 nm excitation, Zn2.1Mg0.85Ga0.05Sn0.05Ta1.95O8: 0.003Cr3+ depicts the 600-1100 nm broadband emission with a full-width at half maximum (FWHM) of 210 nm, and the quantum yields can reach 61.2%. Finally, the phosphor was mixed with epoxy resin and encapsulated in a 460 nm blue light emitting diode (LED) chip to convert the NIR LED by phosphor (NIR pc-LED), which was applied in the field of biological nondestructive testing and night vision lighting.

Effects of temperature and lactic acid Bacteria additives on the quality and microbial community of wilted alfalfa silage.

This study investigated the influence of different temperatures (35℃ High temperature and average indoor ambient temperature of 25℃) and lactic acid bacterial additives (Lactiplantibacillus plantarym, Lentilactobacillus buchneri, or a combination of Lactiplantibacillus plantarym and Lentilactobacillus buchneri) on the chemical composition, fermentation quality, and microbial community of alfalfa silage feed. After a 60-day ensiling period, a significant interaction between temperature and additives was observed, affecting the dry matter (DM), crude protein (CP), acid detergent fiber (ADF), and neutral detergent fiber (NDF) of the silage feed (p < 0.05). Temperature had a highly significant impact on the pH value of the silage feed (p < 0.0001). However, the effect of temperature on lactic acid, acetic acid, propionic acid, and butyric acid was not significant (p > 0.05), while the inoculation of additives had a significant effect on lactic acid, acetic acid, and butyric acid (p > 0.05). As for the dynamic changes of microbial community after silage, the addition of three kinds of bacteria increased the abundance of lactobacillus. Among all treatment groups, the treatment group using complex bacteria had the best fermentation effect, indicating that the effect of complex lactic acid bacteria was better than that of single bacteria in high temperature fermentation. In summary, this study explained the effects of different temperatures and lactic acid bacterial additives on alfalfa fermentation quality and microbial community, and improved our understanding of the mechanism of alfalfa related silage at high temperatures.

Evidence for Two-Dimensional Weyl Fermions in Air-Stable Monolayer PtTe1.75.

The Weyl semimetals represent a distinct category of topological materials wherein the low-energy excitations appear as the long-sought Weyl Fermions. Exotic transport and optical properties are expected because of the chiral anomaly and linear energy-momentum dispersion. While three-dimensional Weyl semimetals have been successfully realized, the quest for their two-dimensional (2D) counterparts is ongoing. Here, we report the realization of 2D Weyl Fermions in monolayer PtTe1.75, which has strong spin-orbit coupling and lacks inversion symmetry, by combined angle-resolved photoemission spectroscopy, scanning tunneling microscopy, second harmonic generation, X-ray photoelectron spectroscopy measurements, and first-principles calculations. The giant Rashba splitting and band inversion lead to the emergence of three pairs of critical Weyl cones. Moreover, monolayer PtTe1.75 exhibits excellent chemical stability in ambient conditions, which is critical for future device applications. The discovery of 2D Weyl Fermions in monolayer PtTe1.75 opens up new possibilities for designing and fabricating novel spintronic devices.

Research Note: Metabolomics revealed the causes of the formation of chicken structural blue earlobes.

The earlobes of chickens exhibit a range of colors, but there has been relatively little research on the formation of structural blue earlobes. Previous results showed that the structural color earlobes were related to the interplay between melanin and collagen in light reflection. To investigate the metabolic differences in these earlobe colors, we conducted nontargeted liquid chromatograph mass spectrometer (LC-MS) for metabolomic sequencing on structural blue (Green and Blue groups) and nonstructural color (Black group) earlobes tissue of Jiangshan black-bone chickens. The content detection in earlobe tissues of different groups shows that there were significant differences in melanin and collagen content between the Black and Green group. The metabolome identified a total of 6,102 mass spectroscopic peaks and ultimately identified 919 annotated metabolites. Variable importance in the projection (VIP) analysis identified the common differential expressed metabolites (DMs) "Tyr Thr Ala Glu" among the 3 groups. By combining those DMs with differentially expressed genes (DEGs) in our previous transcriptome data from the same sample, and associated with KEGG pathway analysis, multiple pathways related to melanogenesis and collagen metabolism were enriched across the 3 groups. By analyzing the metabolites and genes in these pathways, as well as the interaction network diagram of DEGs, we identified some key genes, Wnt Family Member 6 (WNT6), Transcription Factor 7 (TCF7), Proopiomelanocortin (POMC) and Calcium/Calmodulin Dependent Protein Kinase II Alpha (CAMK2A), and some key DMs like DG (11M3/9M5/0:0) and gentisic acid. The differential gene expression and metabolic levels affect the production of melanin and collagen, leading to differences in the content in melanin and the thickness of the collagen layer between earlobe colors, while the thickness of the collagen layer could affect light scattering, ultimately resulting in different colored earlobes in Jiangshan black-bone chickens.

Platinum Cluster Decoration on Hollow Carbon Spheres for High-Efficiency Hydrogen Evolution Reaction.

Currently, platinum (Pt)/carbon support composite materials have tremendous application prospects in the hydrogen evolution reaction (HER). However, one of the primary challenges for boosting their performance is designing a substrate with the desired microstructure. Herein, the intact hollow carbon spheres (HCSs) were prepared via template method. Based on the morphology variation of the as-prepared HCSs-x, we conjectured that the polydopamine (PDA) core was generated first and then slowly grew into a complete overburden (SiO2@PDA). Afterward, Pt atomic clusters were anchored on the outer shells of HCSs-4 to construct composite electrocatalysts (Pty/HCSs-4) by a chemical reduction method. Due to the low charge-transfer resistance, the HCSs have a large electrochemical surface area and provide a continuous electron transport pathway, boosting the atom utilization efficiency during hydrogen production and release. The synthesized Pt2.5/HCSs-4 electrocatalysts exhibit excellent HER activity in acidic media, which can be ascribed to the compositional modulation and delicate structural design. Specifically, when the overpotential is 10 A g-1, the overpotential can achieve 92 mV. This work opens a new route to fabricate Pt-based electrocatalysts and brings a new understanding of the formation mechanism of HCSs.

Periodic spinodal decomposition in double-strengthened medium-entropy alloy.

Achieving an optimal balance between strength and ductility in advanced engineering materials has long been a challenge for researchers. In the field of material strengthening, most approaches that prevent or impede the motion of dislocations involve ductility reduction. In the present study, we propose a strengthening approach based on spinodal decomposition in which Cu and Al are introduced into a ferrous medium-entropy alloy. The matrix undergoes nanoscale periodic spinodal decomposition via a simple one-step aging procedure. Chemical fluctuations within periodic spinodal decomposed structures induce spinodal hardening, leading to a doubled strengthening effect that surpasses the conventional precipitation strengthening mechanism. Notably, the periodic spinodal decomposed structures effectively overcome strain localization issues, preserving elongation and doubling their mechanical strength. Spinodal decomposition offers high versatility because it can be implemented with minimal elemental addition, making it a promising candidate for enhancing the mechanical properties of various alloy systems.

Transcriptome and proteome revealed the differences in 3 colors of earlobe in Jiangshan Black-bone chicken.

The earlobe is a featherless, exposed thickening located beneath the ear canal of chickens, which plays a visual signaling role in age, performance, mental vitality, reproduction, and other aspects. However, despite its importance, there have been few studies on the color differences and formation mechanisms of chicken earlobes, particularly the structurally blue earlobes characteristic of the Jiangshan black-bone chicken. In this study, we explored the physiological mechanisms that may influence the formation of differently colored earlobes using 3 types of earlobes from Jiangshan black-bone chickens: light peacock green (Green group), dark peacock green (Blue group), and dark reddish purple (Black group). All 3 earlobe colors exhibited positive melanin Masson-Fontana staining, and the thickness of collagen fibers in the dermis decreased in the order of Green, Blue, and Black groups. A total of 1,953 differentially expressed genes (DEGs) were detected in the 3 earlobes through mRNA sequencing, among which the GO term "collagen trimer" was significantly enriched in DEGs between groups. Additionally, 716 differentially expressed proteins (DEPs) were identified in the 3 earlobes using 4D-DIA proteomics, with the term "collagen fibril organization" being significantly enriched in DEPs between the Green and Black groups. Integrated analysis of transcriptome and proteome data revealed that 12 DEGs and DEPs were commonly differentially expressed between the Green and Black groups, including the gene LUM (corneal keratan sulfate proteoglycan), which was significantly enriched in the "collagen fibril organization" GO term. In conclusion, our study suggests that LUM plays a crucial role in the formation of peacock green earlobes in Jiangshan black-bone chickens. The high level of LUM in peacock green (Green and Blue groups) may affect collagen nanostructures, leading to a stronger effect of melanin-supported dermal collagen on the production of non-iridescent structural colors through coherent scattering, resulting in a bright structural blue color in Jiangshan black-bone chickens. In contrast, the low expression of LUM in dark reddish purple (Black group) reduces the reflection of non-iridescent structural colors, making the earlobe color appear almost black, similar to melanin.

Effects of selenium enrichment on fermentation characteristics, selenium content and microbial community of alfalfa silage.

BACKGROUND: Selenium is essential for livestock and human health. The traditional way of adding selenium to livestock diets has limitations, and there is a growing trend to provide livestock with a safe and efficient source of selenium through selenium-enriched pasture. Therefore, this study was conducted to investigate the effects of selenium enrichment on fermentation characteristics, selenium content, selenium morphology, microbial community and in vitro digestion of silage alfalfa by using unenriched (CK) and selenium-enriched (Se) alfalfa as raw material for silage. RESULTS: In this study, selenium enrichment significantly increased crude protein, soluble carbohydrate, total selenium, and organic selenium contents of alfalfa silage fresh and post-silage samples, and it significantly decreased neutral detergent fiber and acid detergent fiber contents (p < 0.05). Selenium enrichment altered the form of selenium in plants, mainly in the form of SeMet and SeMeCys, which were significantly higher than that of CK (p < 0.05). Selenium enrichment could significantly increase the lactic acid content, reduce the pH value, change the diversity of bacterial community, promote the growth of beneficial bacteria such as Lactiplantibacillus and inhibit the growth of harmful bacteria such as Pantoea, so as to improve the fermentation quality of silage. The in vitro digestibility of dry matter (IVDMD), in vitro digestibility of acid detergent fibers (IVADFD) and in vitro digestibility of acid detergent fibers (IVNDFD) of silage after selenium enrichment were significantly higher than those of CK (p < 0.05). CONCLUSION: This study showed that the presence of selenium could regulate the structure of the alfalfa silage bacterial community and improve alfalfa silage fermentation quality. Selenium enrichment measures can change the morphology of selenium in alfalfa silage products, thus promoting the conversion of organic selenium.

Impact of excessive daytime sleepiness on attention impairment in obstructive sleep apnea: a cross-sectional observational study.

PURPOSE: This study aims to examine the relationship between excessive daytime sleepiness (EDS) and attention impairment in Chinese individuals with obstructive sleep apnea (OSA). METHODS: A total of 1996 OSA patients with an apnea-hypopnea index (AHI) of ≥ 5 events per hour were included in this study. EDS was measured using the Epworth Sleepiness Scale (ESS), while cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: OSA patients with EDS demonstrated higher body mass index (BMI), comorbidities of hypertension and diabetes, decreased N3 sleep, increased AHI and ODI, as well as lower minimum oxygen saturation. Despite no significant differences in total cognitive scores assessed by MMSE and MoCA, individuals with comorbid sleepiness exhibited more evident attention deficits in the subdomains of MoCA. Stratified analysis indicated that regardless of age, educational level was the primary factor influencing attention in the AHI < =20 group. In the AHI > 20 group, attention impairment in patients younger than 40 remained significantly associated with education level, whereas for individuals aged 40 and above, attention deficits were associated with education level, age, and daytime sleepiness. The interaction analysis indicated that OSA severity modulated the impact of sleepiness on attention in patients aged 40 and above. CONCLUSION: A significant correlation was observed between EDS and attention deficits in Chinese individuals diagnosed with OSA, with a particular emphasis on patients aged 40 and above. The severity of OSA modulates the impact of sleepiness on attention in patients aged 40 and above.

Regio- and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Utilisation of Lactiplantibacillus plantarum and propionic acid to improve silage quality of amaranth before and after wilting: fermentation quality, microbial communities, and their metabolic pathway.

Objective: The aim of this study was to investigate the effects of Lactiplantibacillus plantarum (L. plantarum) and propionic acid (PA) on fermentation characteristics and microbial community of amaranth (Amaranthus hypochondriaus) silage with different moisture contents. Methods: Amaranth was harvested at maturity stage and prepared for ensiling. There were two moisture content gradients (80%: AhG, 70%: AhS; fresh material: FM) and three treatments (control: CK, L. plantarum: LP, propionic acid: PA) set up, and silages were opened after 60 d of ensiling. Results: The results showed that the addition of L. plantarum and PA increased lactic acid (LA) content and decreased pH of amaranth after fermentation. In particular, the addition of PA significantly increased crude protein content (p < 0.05). LA content was higher in wilted silage than in high-moisture silage, and it was higher with the addition of L. plantarum and PA (p < 0.05). The dominant species of AhGLP, AhSCK, AhSLP and AhSPA were mainly L. plantarum, Lentilactobacillus buchneri and Levilactobacillus brevis. The dominant species in AhGCK include Enterobacter cloacae, and Xanthomonas oryzae was dominated in AhGPA, which affected fermentation quality. L. plantarum and PA acted synergistically after ensiling to accelerate the succession of dominant species from gram-negative to gram-positive bacteria, forming a symbiotic microbial network centred on lactic acid bacteria. Both wilting and additive silage preparation methods increased the degree of dominance of global and overview maps and carbohydrate metabolism, and decreased the degree of dominance of amino acid metabolism categories. Conclusion: In conclusion, the addition of L. plantarum to silage can effectively improve the fermentation characteristics of amaranth, increase the diversity of bacterial communities, and regulate the microbial community and its functional metabolic pathways to achieve the desired fermentation effect.