Sensory circuitry controls cytosolic calcium-mediated phytochrome B phototransduction.

Although Ca2+ has long been recognized as an obligatory intermediate in visual transduction, its role in plant phototransduction remains elusive. Here, we report a Ca2+ signaling that controls photoreceptor phyB nuclear translocation in etiolated seedlings during dark-to-light transition. Red light stimulates acute cytosolic Ca2+ increases via phyB, which are sensed by Ca2+-binding protein kinases, CPK6 and CPK12 (CPK6/12). Upon Ca2+ activation, CPK6/12 in turn directly interact with and phosphorylate photo-activated phyB at Ser80/Ser106 to initiate phyB nuclear import. Non-phosphorylatable mutation, phyBS80A/S106A, abolishes nuclear translocation and fails to complement phyB mutant, which is fully restored by combining phyBS80A/S106A with a nuclear localization signal. We further show that CPK6/12 function specifically in the early phyB-mediated cotyledon expansion, while Ser80/Ser106 phosphorylation generally governs phyB nuclear translocation. Our results uncover a biochemical regulatory loop centered in phyB phototransduction and provide a paradigm for linking ubiquitous Ca2+ increases to specific responses in sensory stimulus processing.

CO2-mediated organocatalytic chlorine evolution under industrial conditions.

During the chlor-alkali process, in operation since the nineteenth century, electrolysis of sodium chloride solutions generates chlorine and sodium hydroxide that are both important for chemical manufacturing1-4. As the process is very energy intensive, with 4% of globally produced electricity (about 150 TWh) going to the chlor-alkali industry5-8, even modest efficiency improvements can deliver substantial cost and energy savings. A particular focus in this regard is the demanding chlorine evolution reaction, for which the state-of-the-art electrocatalyst is still the dimensionally stable anode developed decades ago9-11. New catalysts for the chlorine evolution reaction have been reported12,13, but they still mainly consist of noble metal14-18. Here we show that an organocatalyst with an amide functional group enables the chlorine evolution reaction; and that in the presence of CO2, it achieves a current density of 10 kA m-2 and a selectivity of 99.6% at an overpotential of only 89 mV and thus rivals the dimensionally stable anode. We find that reversible binding of CO2 to the amide nitrogen facilitates formation of a radical species that plays a critical role in Cl2 generation, and that might also prove useful in the context of Cl- batteries and organic synthesis19-21. Although organocatalysts are typically not considered promising for demanding electrochemical applications, this work demonstrates their broader potential and the opportunities they offer for developing industrially relevant new processes and exploring new electrochemical mechanisms.

Structure-based design of bitopic ligands for the µ-opioid receptor.

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology.

Commensal bacteria direct selective cargo sorting to promote symbiosis.

Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.

Photo-affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids.

The opioids are powerful analgesics yet possess contingencies that can lead to opioid-use disorder. Chemical probes derived from the opioid alkaloids can provide deeper insight into the molecular interactions in a cellular context. Here, we designed and developed photo-click morphine (PCM-2) as a photo-affinity probe based on morphine and dialkynyl-acetyl morphine (DAAM) as a metabolic acetate reporter based on heroin. Application of these probes to SH-SY5Y, HEK293T, and U2OS cells revealed that PCM-2 and DAAM primarily localize to the lysosome amongst other locations inside the cell by confocal microscopy and chemical proteomics. Interaction site identification by mass spectrometry revealed the mitochondrial phosphate carrier protein, solute carrier family 25 member 3, SLC25A3, and histone H2B as acylation targets of DAAM. These data illustrate the utility of chemical probes to measure localization and protein interactions in a cellular context and will inform the design of probes based on the opioids in the future.

Blood transcriptome analysis uncovered COVID-19-myocarditis crosstalk.

BACKGROUND: The condition of COVID-19-related myocarditis has emerged as a prominent contributor to COVID-19 mortality. As the epidemic persists, its incidence continues to rise. Despite ongoing efforts, the elucidation of COVID-19-related myocarditis underlying molecular mechanisms still requires further investigation. METHODS: Hub genes for COVID-19-related myocarditis were screened by integrating gene expression profile analysis via differential expression in COVID-19 (GSE196822) and myocarditis (GSE148153 and GSE147517). After verification with independent datasets (GSE211979, GSE167028, GSE178491 and GSE215865), the hub genes were studied using a range of systems-biology approaches, such as ceRNA, TF-mRNA networks and PPI networks, as well as gene ontology, pathway enrichment, immune infiltration analysis and drug target identification. RESULTS: TBKBP1 and ERGIC1 were identified as COVID-19-related myocarditis hub genes via integrated bioinformatics analysis. In addition, receiver operating characteristic curves constructed based on the expression levels of TBKBP1 and ERGIC1 could effectively distinguish healthy control individuals from patients with COVID-19. Functional enrichment analysis suggested several enriched biological pathways related to inflammation and immune response. Immune cell changes correlated with TBKBP1 and ERGIC1 levels in patients with COVID-19 or patients with COVID-19 and myocarditis. Tamibarotene, methotrexate and theophylline were identified as a potential drug targeting TBKBP1 and ERGIC1. CONCLUSION: TBKBP1 and ERGIC1 were identified as crucial genes in the development of COVID-19-related myocarditis and have demonstrated a strong association with innate antiviral immunity. The present work may be helpful for further investigation of the molecular mechanisms and new therapeutic drug targets correlated with myocarditis in COVID-19.

Visible light-driven photocatalytic sulfonative oxidation of benzyl secondary amines.

A method for the α-oxidation and sulfonation of benzyl secondary amines was developed utilizing Ir(III) or Eosin Y as the photocatalyst in the presence of O2 as a green oxidant. Using commercial substrates, 37 products from cyclic and acyclic benzylamines were achieved with good functional group compatibility in 48-87% yields. Furthermore, tetrahydroisoquinoline protected by an Ac or a Boc group was oxidized under standard conditions.

Associations of Digital Ulcers in Patients with Systemic Sclerosis: An 8-Year Retrospective Study.

INTRODUCTION: This study aimed to investigate the associations of digital ulcers (DUs) in patients with systemic sclerosis (SSc). METHODS: This retrospective study investigated the demographic characteristics, specific autoantibodies, organ involvement, and laboratory tests in patients with SSc from our hospital. RESULTS: This study enrolled 144 patients with SSc. The DU+ group consisted of 15 (10.4%) patients. Patients with SSc having DUs have longer disease duration, higher fibrinogen, higher fibrin degradation product, and lower cholesterol. None of the patients used cholesterol-lowering drugs before onset of DUs. The study also demonstrated a higher prevalence of anti-dsDNA and anti-histone antibodies in patients with SSc with DUs. Anti-dsDNA antibody is a specific antibody for SLE with a specificity of 96-99%. A total of 86.1% (124/144) of patients suffered from diffuse cutaneous SSc, and 28.5% (41/144) of patients suffered from overlap syndrome. CONCLUSION: Our study indicated that patients with SSc with fibrinogen of >2.895 g/L (p = 0.043) and cholesterol of <3.340 mmol/L (p = 0.036), which is equal to 129.258 mg/dL, are at high risk of developing DUs.

The pederin-producing bacteria density dynamics in Paederus fuscipes at different developmental stages.

Pederin, a defensive toxin in Paederus fuscipes, is produced by an uncultured Gram-negative symbiont, which establishes a stable symbiotic relationship with a female host before completion of metamorphosis. However, the transmission process of pederin-producing bacteria (PPB) in P. fuscipes at different life stages remains unknown. Herein, the PPB population dynamics and transcriptome atlas for P. fuscipes development (egg, first-instar larva, second-instar larva, pupa, and newly emerged female and male) were characterised. We found that a microbial layer containing PPB covered the eggshell, which could be sterilised by smearing the eggshell with streptomycin. Maternal secretions over the eggshell are likely the main PPB acquisition route for P. fuscipes offspring. The PPB density in eggs was significantly higher than that in other life stages (p < 0.05), which demonstrated that the beetle mothers gave more PPB than the larvae acquired. Physiological changes (hatching and eclosion) led to a decreased PPB density in P. fuscipes. Pattern recognition receptors related to Gram-negative bacteria recognition were identified from P. fuscipes transcriptomes across various life stages, which might be used to screen genes involved in PPB regulation. These results will help advance future efforts to determine the molecular mechanisms of PPB colonisation of P. fuscipes.

Incomplete tuberculosis reporting and registration to the surveillance system in southwestern China of Yunnan Province: an inventory survey.

BACKGROUND: The real-world tuberculosis (TB) surveillance data was generally incomplete due to underreporting and underdiagnosis. The inventory study aimed to assess and quantify the incompletion of surveillance systems in southwestern China. METHODS: The inventory study was conducted at randomly selected health facilities (HF) by multi-stage stratified cluster sampling. The participants were included in the period between August of 2020 in province-level and prefecture-level HF, and in the period between June to December of 2020 in other categories of HF respectively. The clinical committee confirmed medical records were matched to the National Notifiable Disease Reporting System (NNDRS) and the Tuberculosis Information Management System (TBIMS) to define the report and register status. The underreporting and under-register rates were evaluated based on the matched data, and factors associated with underreport and under-register were assessed by the 2-level logistic multilevel model (MLM). RESULTS: We enrolled 7,749 confirmed TB cases in the analysis. The province representative overall underreport rate to NNDRS was 1.6% (95% confidence interval, 95% CI, 1.3 - 1.9), and the overall under-register rate to TBIMS was 9.6% (95% CI, 8.9-10.3). The various underreport and under-register rates were displayed in different stratifications of background TB disease burden, HF level, HF category, and data source of the medical record in HF among prefectures of the province. The intraclass correlation coefficient (ICC) was 0.57 for the underreporting null MLM, indicating the facility-level cluster effect contributes a great share of variation in total variance. The two-level logistic MLM showed the data source of medical records in HF, diagnostic category of TB, and type of TB were associated with underreporting by adjusting other factors (p < 0.05). The ICC for under-register was 0.42, and the HF level, HF category, data source of medical records in HF, diagnostic category of TB and type of TB were associated with under-register by adjusting other factors (p < 0.05). CONCLUSION: The inventory study depicted incomplete TB reporting and registering to NNDRS and TBIMS in southwestern China. It implied that surveillance quality improvement would help advance the TB prevention and control strategy.

Fluoroquinolone antibiotics in the aquatic environment: environmental distribution, the research status and eco-toxicity.

The increasing presence of fluoroquinolone (FQ) antibiotics in aquatic environments is a growing concern due to their widespread use, negatively impacting aquatic organisms. This paper provides an overview of the environmental distribution, sources, fate, and both single and mixed toxicity of FQ antibiotics in aquatic environments. It also examines the accumulation of FQ antibiotics in aquatic organisms and their transfer into the human body through the food chain. The study identifies critical factors such as metabolism characteristics, physiochemical characteristics, light, temperature, dissolved oxygen, and environmental compatibility that influence the presence of FQ antibiotics in aquatic environments. Mixed pollutants of FQ antibiotics pose significant risks to the ecological environment. Additionally, the paper critically discusses advanced treatment technologies designed to remove FQ antibiotics from wastewater, focusing on advanced oxidation processes (AOPs) and electrochemical advanced oxidation processes (EAOPs). The discussion also includes the benefits and limitations of these technologies in degrading FQ antibiotics in wastewater treatment plants. The paper concludes by proposing new approaches for regulating and controlling FQ antibiotics to aid in the development of ecological protection measures.

Corosolic acid inhibits metastatic response of human renal cell carcinoma cells by modulating ERK/MMP2 signaling.

Corosolic acid (CA), a plant-derived pentacyclic triterpenoid, has potent anti-inflammatory, anti-metabolic, and anti-neoplastic actions against a variety of human cancers. However, the specific mechanism by which CA inhibits the progression of renal cell carcinoma (RCC) is yet unclear. We found that CA (≤8 µM) had no influence on either the growth or viability of RCC cell lines (786-O, ACHN, and Caki-1) or normal HK2 cells. However, in a dose-dependent manner, CA prevented the invasion and migration of RCC cells. Human protease array analysis showed that CA reduced MMP2 expression. At increasing concentrations of CA, the expression of MMP2 was dose-dependently reduced, as shown by western blot and RT-PCR analyses as well as immunofluorescence staining. CA also stimulated ERK1/2 phosphorylation in 786-O and Caki-1 cells. Transfection of CA-treated RCC cells with siRNA-ERK restored MMP2 protein expression and the motility and invasion capabilities of RCC cells. Molecular docking study results showed that CA and MMP2 interact strongly. These findings elucidate the mechanism by which CA prevents RCC cells from migrating and invading, and these findings indicate that CA may be a potential anti-metastatic therapy for RCC.

Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. METHODS: 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. RESULTS: In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. CONCLUSIONS: FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

Non-trade-off Changes in Soil Conservation Service and Soil Loss on the Tibetan Plateau Underlying the Impacts of Climate Change and human activities.

Climate change and human activities have significantly influenced soil loss and the soil conservation service, posed threats to regional ecological sustainability. However, the relationships and underlying driving forces between potential soil loss, actual soil loss, and soil conservation service have not been well understood. Utilizing the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model, we evaluated the soil conservation service on the Tibetan plateau from 1990 to 2020. We analyzed the spatial and temporal trends and examined the driving factors using linear regression, Pearson correlation, and random forest regression. The soil conservation service exhibited a complex pattern of increase followed by a decrease, with a turning point around 2010. Soil conservation service and soil loss demonstrated non-trade-off changes. The potential soil loss dominated the spatiotemporal patterns of soil conservation service on the Tibetan Plateau. Climatic factors significantly influenced the spatiotemporal patterns of soil conservation service, with annual precipitation emerging as the dominant driving factor, contributing approximately 20%. However, the impacts of human activities became more pronounced since 2010, and the contribution of vegetation to changes in soil conservation service was increased. The impact of the Normalized Difference Vegetation Index (NDVI) on soil conservation service for the grades I, II, and III increased by 13.19%, 3.08%, and 3.41%, respectively. Conversely, in northern Tibet before 2010 and eastern Three-River-Source after 2010, soil conservation service exhibited an increasing trend driven by both climate factors and human activities. Which indicates that the implementation of ecological restoration measures facilitated vegetation improvement and subsequently reduced actual soil loss. This study provides a scientific basis for resource management, land development strategies, and the formulation of ecological restoration measures on the Tibetan Plateau.

[Analysis of constituents in different parts of Forsythia suspensa by UPLC-Q-TOF-MS and evaluation of their anti-inflammatory activity].

This study aims to characterize and identify the chemical constituents in 11 parts of Forsythia suspensa by using ultra-performance liquid chromatography-quadrupole time of flight-mass spectrometry(UPLC-Q-TOF-MS) combined with a self-established chemical constituent database, including leaves, flowers, fruits, green F. suspensa, old F. suspensa, and seeds. The quality attributes and differences of different parts of F. suspensa were evaluated by principal component analysis, partial least square discriminant analysis, and other stoichiometric methods. A total of 79 compounds were identified, including 13 phenylethanol glycosides, 10 lignans, 12 flavonoids, 10 organic acids, 14 terpenoids, and 20 other types of compounds. Among them, 34 compounds were the main variables of difference between the different parts of F. suspensa, and the content of each component was relatively higher in the leaves and green F. suspensa. The LPS-induced inflammation model of RAW264.7 cells was applied to study the anti-inflammatory activity of the extracts of the different parts of F. suspensa and the main constituents. The results show that the extracts of green F. suspensa, flower, twig, and stem exhibited anti-inflammatory activity, and the constituents such as forsythoside A, phyllyrin, phillygenin, and(+)-pinoresinol-ß-D-glucopyranoside could significantly inhibit anti-inflammatory activity released by NO. The chemical constituent in different parts of F. suspensa is analyzed comprehensively, and the anti-inflammatory activity is evaluated in this study, which provides a reference for the development and comprehensive utilization of F. suspensa resources.

Single-Atom Manganese-Catalyzed Oxygen Evolution Drives the Electrochemical Oxidation of Silane to Silanol.

The oxygen evolution reaction (OER), characterized by a four-electron transfer kinetic process, represents a significant bottleneck in improving the efficiency of hydrogen production from water electrolysis. Consequently, extensive research efforts have been directed towards identifying single-atom electrocatalysts with exceptional OER performance. Despite the comprehensive understanding of the OER mechanism, its application to other valuable synthetic reactions has been limited. Herein, we leverage the MOOH intermediate, a key species in the Mn-N-C single-atom catalyst (Mn-SA@NC), which can be cyclically delivered in the OER. We exploit this intermediate' s capability to facilitate electrophilic transfer with silane, enabling efficient silane oxidation under electrochemical conditions. The SAC electrocatalytic system exhibits remarkable performance with catalyst loadings as low as 600 ppm and an exceptional turnover number of 9132. Furthermore, the catalytic method demonstrates stability under a 10 mmol flow chemistry setup. By serving as an OER electrocatalyst, the Mn-SA@NC drives the entire reaction, establishing a practical Mn SAC-catalyzed organic electrosynthesis system. This synthesis approach not only presents a promising avenue for the utilization of electrocatalytic OER but also highlights the potential of SACs as an attractive platform for organic electrosynthesis investigations.

Single-Atom Iron Catalyst as an Advanced Redox Mediator for Anodic Oxidation of Organic Electrosynthesis.

Homogeneous electrocatalysts can indirect oxidate the high overpotential substrates through single-electron transfer on the electrode surface, enabling efficient operation of organic electrosynthesis catalytic cycles. However, the problems of this chemistry still exist such as high dosage, difficult recovery, and low catalytic efficiency. Single-atom catalysts (SACs) exhibit high atom utilization and excellent catalytic activity, hold great promise in addressing the limitations of homogeneous catalysts. In view of this, we have employed Fe-SA@NC as an advanced redox mediator to try to change this situation. Fe-SA@NC was synthesized using an encapsulation-pyrolysis method, and it demonstrated remarkable performance as a redox mediator in a range of reported organic electrosynthesis reactions, and enabling the construction of various C-C/C-X bonds. Moreover, Fe-SA@NC demonstrated a great potential in exploring new synthetic method for organic electrosynthesis. We employed it to develop a new electro-oxidative ring-opening transformation of cyclopropyl amides. In this new reaction system, Fe-SA@NC showed good tolerance to drug molecules with complex structures, as well as enabling flow electrochemical syntheses and gram-scale transformations. This work highlights the great potential of SACs in organic electrosynthesis, thereby opening a new avenue in synthetic chemistry.

Utilization of natural alleles for heat adaptability QTLs at the flowering stage in rice.

BACKGROUND: Heat stress threatens rice yield and quality at flowering stage. In this study, average relative seed setting rate under heat stress (RHSR) and genotypes of 284 varieties were used for a genome-wide association study. RESULTS: We identified eight and six QTLs distributed on chromosomes 1, 3, 4, 5, 7 and 12 in the full population and indica, respectively. qHTT4.2 was detected in both the full population and indica as an overlapping QTL. RHSR was positively correlated with the accumulation of heat-tolerant superior alleles (SA), and indica accession contained at least two heat-tolerant SA with average RHSR greater than 43%, meeting the needs of stable production and heat-tolerant QTLs were offer yield basic for chalkiness degree, amylose content, gel consistency and gelatinization temperature. Chalkiness degree, amylose content, and gelatinization temperature under heat stress increased with accumulation of heat-tolerant SA. Gel consistency under heat stress decreased with polymerization of heat-tolerant SA. The study revealed qHTT4.2 as a stable heat-tolerant QTL that can be used for breeding that was detected in the full population and indica. And the grain quality of qHTT4.2-haplotype1 (Hap1) with chalk5, wx, and alk was better than that of qHTT4.2-Hap1 with CHALK5, WX, and ALK. Twelve putative candidate genes were identified for qHTT4.2 that enhance RHSR based on gene expression data and these genes were validated in two groups. Candidate genes LOC_Os04g52830 and LOC_Os04g52870 were induced by high temperature. CONCLUSIONS: Our findings identify strong heat-tolerant cultivars and heat-tolerant QTLs with great potential value to improve rice tolerance to heat stress, and suggest a strategy for the breeding of yield-balance-quality heat-tolerant crop varieties.

Protective effect of L-pipecolic acid on constipation in C57BL/6 mice based on gut microbiome and serum metabolomic.

BACKGROUND: Functional constipation (FC) in children affects their growth, development and quality of life. L-pipecolic acid (L-PA) was decreased in FC children based on gut microbiome and serum metabolomic. In this study, loperamide-induced constipation in mice was used to evaluate the effects of L-PA on constipated mice. METHOD: 26 FC and 28 healthy children were recruited. Stool samples and serum samples were subjected to 16S rDNA sequencing and ultra-performance liquid chromatography/quadrupole time of flight (UPLC-Q/TOF-MS) approach, respectively. A loperamide-induced mouse constipation model was developed, and all mice were randomly divided into control (Con), loperamide (Lop) and L-PA (Lop + L-PA) treatment groups (6 mice per group). The mice in the Lop + L-PA group were given L-PA (250 mg/kg, once a day) and loperamide; the Lop group was given loperamide for 1 week, and the Con group was given saline. The fecal parameters and intestinal motility of mice in each group were detected. serum 5-HT levels and colon 5-HT expression were detected by ELISA and immunohistochemistry, respectively; qRT-PCR was used to detect the expression of AQP3 and 5-HT4R mRNA in each group. RESULTS: 45 differential metabolites and 18 significantly different microbiota were found in FC children. The α and ß diversity of gut microbiota in FC children was significantly reduced. Importantly, serum L-PA was significantly reduced in FC children. The KEGG pathway enrichment were mainly enriched in fatty acid biosynthesis, lysine degradation, and choline metabolism. L-PA was negatively associated with Ochrobactrum, and N6, N6, N6-trimethyl-l-lysine was positively associated with Phascolarcrobacterium. In addition, L-PA improved the fecal water content, intestinal transit rate, and increased the serum 5-HT levels in constipated mice. Moreover, L-PA increased the expression of 5-HT4R, reduced AQP3, and regulated constipation-associated genes. CONCLUSIONS: Gut microbiota and serum metabolites were significantly altered in children with FC. The abundance of Phascolarctobacterium and Ochrobactrum and serum L-PA content were decreased in FC children. L-PA was found to alleviate the fecal water content, increase intestinal transit rate and the first black stool defecation time. L-PA improved constipation by increasing 5-HT and 5-HT4R expression while down-regulating AQP3 expression.

Three-Component Electrochemical Aminoselenation of 1,3-Dienes.

Azoles and organoselenium compounds are pharmacologically important scaffolds in medicinal chemistry and natural products. We developed an efficient regioselective electrochemical aminoselenation reaction of 1,3-dienes, azoles, and diselenide derivatives to access selenium-containing allylazoles skeletons. This protocol is more economical and environmentally friendly and features a broad substrate scope; pyrazole, triazole, and tetrazolium were all tolerated under the standard conditions, which could be applied to the expedient synthesis of bioactive molecules and in the pharmaceutical industry.