Lewis Base-Boryl Radicals Enabled Borylation Reactions and Selective Activation of Carbon-Heteroatom Bonds.

ConspectusThe past decades have witnessed tremendous progress on radical reactions. However, in comparison with carbon, nitrogen, oxygen, and other main group element centered radicals, the synthetic chemistry of boron centered radicals was less studied, mainly due to the high electron-deficiency and instability of such 3-center-5-electron species. In the 1980s, Roberts and co-workers found that the coordination of a Lewis base (amines or phosphines) with the boron center could form 4-center-7-electron boryl radicals (Lewis base-boryl radicals, LBRs) that are found to be more stable. However, only limited synthetic applications were developed. In 2008, Curran and co-workers achieved a breakthrough with the discovery of N-heterocyclic carbene (NHC) boryl radicals, which could enable a range of radical reduction and polymerization reactions. Despite these exciting findings, more powerful and valuable synthetic applications of LBRs would be expected, given that the structures and reactivities of LBRs could be easily modulated, which would provide ample opportunities to discover new reactions. In this Account, a summary of our key contributions in LBR-enabled radical borylation reactions and selective activation of inert carbon-heteroatom bonds will be presented.Organoboron compounds have shown versatile applications in chemical society, and their syntheses rely principally on ionic borylation reactions. The development of mechanistically different radical borylation reactions allows synthesizing products that are inaccessible by traditional methods. For this purpose, we progressively developed a series of NHC-boryl radical mediated chemo-, regio-, and stereoselective radical borylation reactions of alkenes and alkynes, by which a wide variety of structurally diverse organoboron molecules were successfully prepared. The synthetic utility of these borylated products was also demonstrated. Furthermore, we disclosed a photoredox protocol for oxidative generation of NHC-boryl radicals, which enabled useful defluoroborylation and arylboration reactions.Selective bond activation is an ideal way to convert simple starting materials to value-added products, while the cleavage of inert chemical bonds, in particular the chemoselectivity control when multiple identical bonds are present in similar chemical environments, remains a long-standing challenge. We envisaged that finely tuning the properties of LBRs might provide a new solution to address this challenge. Recently, we disclosed a 4-dimethylaminopyridine (DMAP)-boryl radical promoted sequential C-F bond functionalization of trifluoroacetic acid derivatives, in which the α-C-F bonds were selectively snipped via a spin-center shift mechanism. This strategy enables facile conversion of abundantly available trifluoroacetic acid to highly valuable mono- and difluorinated molecules. Encouraged by this finding, we further developed a boryl radical enabled three-step sequence to construct all-carbon quaternary centers from a range of trichloromethyl groups, where the three C-Cl bonds were selectively cleaved by the rational choice of suitable boryl radical precursors in each step. Furthermore, a boryl radical promoted dehydroxylative alkylation of α-hydroxy carboxylic acid derivatives was achieved, allowing for the efficient conversion of some biomass platform molecules to high value products.

Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3.

Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI.

Research and application of a novel selective stacking ensemble model based on error compensation and parameter optimization for AQI prediction.

With the ongoing process of industrialization, the issue of declining air quality is increasingly becoming a critical concern. Accurate prediction of the Air Quality Index (AQI), considered as an all-inclusive measure representing the extent of pollutants present in the atmosphere, is of paramount importance. This study introduces a novel methodology that combines stacking ensemble and error correction to improve AQI prediction. Additionally, the reptile search algorithm (RSA) is employed for optimizing model parameters. In this study, four distinct regional AQI data containing a collection of 34864 data samples are collected. Initially, we perform cross-validation on ten commonly used single models to obtain prediction results. Then, based on evaluation indices, five models are selected for ensemble. The results of the study show that the model proposed in this paper achieves an improvement of around 10% in terms of accuracy when compared to the conventional model. Thus, the model introduced in this study offers a more scientifically grounded approach in tackling air pollution.

Chemokines and Their Receptors: Predictors of Therapeutic Potential in Tumor Microenvironment on Esophageal Cancer.

Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.

Skeleton-Based Activity Recognition for Process-Based Quality Control of Concealed Work via Spatial-Temporal Graph Convolutional Networks.

Computer vision (CV)-based recognition approaches have accelerated the automation of safety and progress monitoring on construction sites. However, limited studies have explored its application in process-based quality control of construction works, especially for concealed work. In this study, a framework is developed to facilitate process-based quality control utilizing Spatial-Temporal Graph Convolutional Networks (ST-GCNs). To test this model experimentally, we used an on-site collected plastering work video dataset to recognize construction activities. An ST-GCN model was constructed to identify the four primary activities in plastering works, which attained 99.48% accuracy on the validation set. Then, the ST-GCN model was employed to recognize the activities of three extra videos, which represented a process with four activities in the correct order, a process without the activity of fiberglass mesh covering, and a process with four activities but in the wrong order, respectively. The results indicated that activity order could be clearly withdrawn from the activity recognition result of the model. Hence, it was convenient to judge whether key activities were missing or in the wrong order. This study has identified a promising framework that has the potential to the development of active, real-time, process-based quality control at construction sites.

Enantioselective formal total synthesis of dihydrospirotryprostatin B.

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

Antinociceptive C19-diterpenoid alkaloids from the roots of Aconitum nagarum.

Three new C19-diterpenoid alkaloids, nagarumines A-C (1-3), together two known alkaloids, deoxyaconitine (4) and N-deethyldeoxyaconitine (5), were isolated from the roots of Aconitum nagarum. The structures of the new compounds were elucidated by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, as well as high resolution mass spectrometry. The in vivo pharmacological studies revealed that nagarumine C (3) possessed comparable antinociceptive activity (ED50 = 76.0 µmol/kg) with the positive control drugs aspirin and acetaminophen.

Antinociceptive diterpenoid alkaloids from the roots of Aconitum austroyunnanense.

A phytochemical investigation on the roots of Aconitum austroyunnanense afforded three undescribed aconitine-type C19-diterpenoid alkaloids, austroyunnanines A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The isolated alkaloids were tested in vivo for their antinociceptive properties. Consequently, austroyunnanine B (2) exhibited significant antinociceptive effect and its ID50 value (48.0 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

Antibacterial lanostane triterpenoids from Ganoderma tsugae.

A phytochemical investigation on the 80% EtOH extract of the fruiting bodies of Ganoderma tsugae resulted into the isolation of two previously undescribed lanostane triterpenoids, 7,11-dioxo-3ß-acetyloxy-26,27-dihydroxy-lanosta-8,24-diene (1) and 7,20-dioxo-3ß-acetyloxy-11ß,15α-dihydroxy-22,23,24,25,26,27-hexanorlanosta-8-ene (2), togeher with one known lanostane triterpenoid ganodermanontriol (3). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. All the triterpenoids were in vitro evaluated for their antibacterial activities against six pathogenic microorganisms. Compound 3 exhibited some activities against three Gram positive bacteria with MIC values less than 30 µg/ml.

Sustained over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice through aberrant autophagy.

Calpains have been implicated in heart diseases. While calpain-1 has been detrimental to the heart, the role of calpain-2 in cardiac pathology remains controversial. In this study we investigated whether sustained over-expression of calpain-2 had any adverse effects on the heart and the underlying mechanisms. Double transgenic mice (Tg-Capn2/tTA) were generated, which express human CAPN2 restricted to cardiomyocytes. The mice were subjected to echocardiography at age 3, 6, 8 and 12 months, and their heart tissues and sera were collected for analyses. We showed that transgenic mice over-expressing calpain-2 restricted to cardiomyocytes had normal heart function with no evidence of cardiac pathological remodeling at age 3 months. However, they exhibited features of dilated cardiomyopathy including increased heart size, enlarged heart chambers and heart dysfunction from age 8 months; histological analysis revealed loss of cardiomyocytes replaced by myocardial fibrosis and cardiomyocyte hypertrophy in transgenic mice from age 8 months. These cardiac alterations closely correlated with aberrant autophagy evidenced by significantly increased LC3BII and p62 protein levels and accumulation of autophagosomes in the hearts of transgenic mice. Notably, injection of 3-methyladenine, a well-established inhibitor of autophagy (30 mg/kg, i.p. once every 3 days starting from age 6 months for 2 months) prevented aberrant autophagy, attenuated myocardial injury and improved heart function in the transgenic mice. In cultured cardiomyocytes, over-expression of calpain-2 blocked autophagic flux by impairing lysosomal function. Furthermore, over-expression of calpain-2 resulted in lower levels of junctophilin-2 protein in the heart of transgenic mice and in cultured cardiomyocytes, which was attenuated by 3-methyladenine. In addition, blockade of autophagic flux by bafilomycin A (100 nM) induced a reduction of junctophilin-2 protein in cardiomyocytes. In summary, transgenic over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice, which may be mediated through aberrant autophagy and a reduction of junctophilin-2. Thus, a sustained increase in calpain-2 may be detrimental to the heart.

A multi-scale evolutionary deep learning model based on CEEMDAN, improved whale optimization algorithm, regularized extreme learning machine and LSTM for AQI prediction.

With the rapid development of economy, air pollution occurs frequently, which has a huge negative impact on human health and urban ecosystem. Air quality index (AQI) can directly reflect the degree of air pollution. Accurate AQI trend prediction can provide reliable information for the prevention and control of air pollution, but traditional forecasting methods have limited performance. To this end, a dual-scale ensemble learning framework is proposed for the complex AQI time series prediction. First, complete ensemble empirical mode decomposition adaptive noise (CEEMDAN) and sample entropy (SE) are used to decompose and reconstruct AQI series to reduce the difficulty of direct modeling. Then, according to the characteristics of high and low frequencies, the high-frequency components are predicted by the long short-term memory neural network (LSTM), and the low-frequency items are predicted by the regularized extreme learning machine (RELM). At the same time, the improved whale optimization algorithm (WOA) is used to optimize the hyper-parameters of RELM and LSTM models. Finally, the hybrid prediction model proposed in this paper predicts the AQI of four cities in China. This work effectively improves the prediction accuracy of AQI, which is of great significance to the sustainable development of the cities.

Antinociceptive C19-diterpenoid alkaloids from the root of Aconitum episcopale.

A chemical investigation on the roots of Aconitum episcopale afforded three undescribed aconitine-type C19-diterpenoid alkaloids, episcopalines A-C (1-3). The structures of the new compounds were elucidated by spectroscopic analysis (NMR, IR, UV, and MS). The isolated alkaloids were tested in vivo for their antinociceptive properties. As a result, episcopaline B (2) showed potent antinociceptive effect and its ID50 value (55.0 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

[Relationship between Blood Glucose and Lipid Levels and Intestinal Bifidobacteriumin Middle-Aged and Older Adults in Chengdu].

Objective: To explore characteristics of the species structure of the genus Bifidobacterium at different levels of blood glucose and lipid in middle-aged and older adults in Chengdu so as to provide research basis for applying bifidobacteria in the prevention and treatment of hyperglycemia and dyslipidemia. Methods: A total of 289 middle-aged and older adults of 45 and older were recruited in Chengdu between April and August 2018. They were divided into the healthy group, the dyslipidemia group, the hyperglycemia group, and the combination group (of subjects with both dyslipidemia and hyperglycemia). The levels of their fasting blood glucose (GLU), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were examined. In addition, stool samples were collected and real-time fluorescence quantitative PCR was used for quantitative analysis of the genus Bifidobacteriumand the 8 bifidobacteria most commonly found in human intestines, the results of which were then examined to identify their correlation to blood glucose and lipid levels. Results: A total of 289 samples were collected and findings of inter-group comparison of the species structure of Bifidobacterium were as follows: 1) findings regarding the Bifidobacterium species examined--there was no significant difference between groups in the detection rate and the number of species detected; the quantity of B. angulatum was significantly higher in the dyslipidemia group than that in the healthy group and that in the combination group, the quantify of B. catenulatum was significantly higher in the hyperglycemia group than that in the healthy group, and the quantity of B. dentium was significantly higher in the dyslipidemia group than that in the combination group. 2) Findings regarding the correlation between the quantity of bifidobacteria and blood glucose and lipid--at the genus level, only the dyslipidemia group showed negative correlation (r=-0.346) between Bifidobacterium and TC. At the species level, B. bifidum was negatively correlated with TG (r=-0.761), B. breve was negatively correlated with GLU, TC, and LDL-C (r=-0.256, r=-0.261, and r=-0.362), B.dentium was positively correlated with GLU (r=0.206), and B. infantis was negatively correlated with TC (r=-0.334) in the healthy group. In the hyperglycemia group, B. catenulatum and B. infantis were both positively correlated with HDL-C (r=0.307 and r=0.525). In the combination group, B. bifidum was negatively correlated with HDL-C (r=-0.828), while B. breve was positively correlated with TG and HDL-C (r=0.427 and r=0.375). Conclusion: Middle-aged and older adults with dyslipidemia and/or hyperglycemia were significantly different from healthy subjects in their testing results for Bifidobacterium. Compared with the structure of Bifidobacterium species, the changes in the number of Bifidobacterium species detected were more closely correlated to the levels of blood glucose and blood lipid, showing unique characteristics in different situations, which may indicate potential application as indicators for glucose and lipid metabolism.

Dehydroxylative Alkylation of α-Hydroxy Carboxylic Acid Derivatives via a Spin-Center Shift.

A strategically distinct dehydroxylative alkylation reaction of α-hydroxy carboxylic acid derivatives with alkenes is developed. The reaction starts with the attack of a 4-dimethylaminopyridine (DMAP)-boryl radical to the carbonyl oxygen atom, followed by a spin-center shift (SCS) to trigger the C-O bond scission. The resulting α-carbonyl radicals couple with a wide range of alkenes to furnish various alkylated products. This strategy allows for the efficient conversion of a wide array of α-hydroxy amides and esters derived from several biomass molecules and natural products to value-added compounds. Experimental and computational studies verified the reaction mechanism.

Leveraging sequence-based faecal microbial community survey data to identify alterations in gut microbiota among patients with Parkinson's disease.

Parkinson's disease is a common degenerative disease of the elderly. Although the majority of studies have focused on the central nervous system (CNS) features of Parkinson's disease, recent findings suggest there is a functional link between the gut microbiome and the hallmarks of the disease. PubMed, Web of Science, EMBASE and other Chinese and English databases were searched for relevant literature. Studies on changes to intestinal microbiota in Parkinson's patients were retrieved and systematically reviewed. Quality filtering, clustering and species annotation were performed on 16s sequencing raw data from retrieved studies to achieve comparability across studies. Alpha-diversity indices and a random effect model were used to analyse significantly altered microbiota. A total of nine studies were included in this retrospective analysis, four of which contained raw data. Alpha diversity was significantly different between control and Parkinson's disease patients in two of the four studies. Using the raw data from four individual studies, we observed differences in the phlya Bacteroidetes and Actinobacteria. Additionally, differences were observed between control and Parkinson's disease patients at the level of family (Prevotellacaea and Lactobacillaceae) and genus (Bifidobacterium and Clostridium). This study confirmed that changes in the microbiome are a consistent feature of Parkinson's disease patients and, therefore, may contribute to the onset of disease.

Mutant Zp1 impedes incorporation of ZP3 and ZP4 in the zona pellucida, resulting in zona absence and female infertility in rats†.

The zona pellucida (ZP) plays vital roles in reproductive processes including oogenesis, fertilization, and preimplantation development. Both human and rat ZP consist of four glycoproteins, called ZP1, ZP2, ZP3, and ZP4. Our previous research reported a novel Zp1 mutation in cases of human infertility, associated with an abnormal phenotype involving the absence of the ZP. Here, we developed a homologous rat strain to investigate the pathogenic effect. The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully grown oocytes; the oocytes completely lacked a ZP, but ZP1 was detectable inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of superovulated Zp1MT/MT females, while an average of 21 eggs were recovered from superovulated Zp1WT/WT per female. The eggs of Zp1MT/MT females were not surrounded by a ZP and lost their fertilization capacity in vitro. Zp1MT/MT females mated with wild-type males failed to become pregnant. Studies in 293T cells showed that mutant Zp1 resulted in a truncated ZP1 protein, which might be intracellularly sequestered and interacted with wild-type ZP3 or ZP4. Our results suggest that the Zp1 point mutation led to infertility and loss of the ZP in oocytes in rats.

Targeted inhibition of calpain in mitochondria alleviates oxidative stress-induced myocardial injury.

The protein levels and activities of calpain-1 and calpain-2 are increased in cardiac mitochondria under pathological conditions including ischemia, diabetes, and sepsis, and transgenic overexpression of mitochondrial-targeted calpain-1 induces dilated heart failure, which underscores an important role of increased calpain in mitochondria in mediating myocardial injury. However, it remains to be determined whether selective inhibition of calpain in mitochondria protects the heart under pathological conditions. In this study, we generated transgenic mice overexpressing mitochondrial-targeted calpastatin in cardiomyocytes. Their hearts were isolated and subjected to global ischemia/reperfusion. Hyperglycemia was induced in the transgenic mice by injections of STZ. We showed that transgenic calpastatin was expressed exclusively in mitochondria isolated from their hearts but not from other organs including skeletal muscle and lung tissues. Transgenic overexpression of mitochondrial-targeted calpastatin significantly attenuated mitochondrial oxidative stress and cell death induced by global ischemia/reperfusion in isolated hearts, and ameliorated mitochondrial oxidative stress, cell death, myocardial remodeling and dysfunction in STZ-treated transgenic mice. The protective effects of mitochondrial-targeted calpastatin were correlated with increased ATP5A1 protein expression and ATP synthase activity in isolated hearts subjected to global ischemia/reperfusion and hearts of STZ-treated transgenic mice. In cultured rat myoblast H9c2 cells, overexpression of mitochondrial-targeted calpastatin maintained the protein levels of ATP5A1 and ATP synthase activity, prevented mitochondrial ROS production and decreased cell death following hypoxia/reoxygenation, whereas upregulation of ATP5A1 or scavenging of mitochondrial ROS by mito-TEMPO abrogated mitochondrial ROS production and decreased cell death. These results confirm the role of calpain in myocardial injury, suggesting that selective inhibition of calpain in myocardial mitochondria by mitochondrial-targeted calpastatin is an effective strategy for alleviating myocardial injury and dysfunction in cardiac pathologies.

Role of Sensors in Error Propagation with the Dynamic Constrained Observability Method.

The inverse problem of structural system identification is prone to ill-conditioning issues; thus, uniqueness and stability cannot be guaranteed. This issue tends to amplify the error propagation of both the epistemic and aleatory uncertainties, where aleatory uncertainty is related to the accuracy and the quality of sensors. The analysis of uncertainty quantification (UQ) is necessary to assess the effect of uncertainties on the estimated parameters. A literature review is conducted in this paper to check the state of existing approaches for efficient UQ in the parameter identification field. It is identified that the proposed dynamic constrained observability method (COM) can make up for some of the shortcomings of existing methods. After that, the COM is used to analyze a real bridge. The result is compared with the existing method, demonstrating its applicability and correct performance by a reinforced concrete beam. In addition, during the bridge system identification by COM, it is found that the best measurement set in terms of the range will depend on whether the epistemic uncertainty involved or not. It is concluded that, because the epistemic uncertainty will be removed as the knowledge of the structure increases, the optimum sensor placement should be achieved considering not only the accuracy of sensors, but also the unknown structural part.

Antinociceptive C19-diterpenoid alkaloids isolated from Aconitum pseudostapfianum.

Phytochemical investigation on the roots of Aconitum pseudostapfianum resulted in the isolation of three new aconitine-type C19-diterpenoid alkaloids, pseudostapines A-C (1-3). Their structures were determined by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, NOESY and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated alkaloids were tested in vivo for their antinociceptive potential. As a result, pseudostapine C (3) showed 2-fold more potent antinociceptive effect (ID50 = 60.3 µmol/kg) than the positive control drugs aspirin and acetaminophen.

[Surgical intervention in adult varicocele: An update].

Varicocele is one of the common causes of infertility in adult males. Surgical intervention can improve the semen quality of some of the patients and significantly increase the pregnancy rate, but fails to benefit them all. Therefore, it is of great practical significance to identify the patients who can significantly benefit from surgical interventions to maximize the effectiveness of surgery and avoid medical waste. This article summarizes the recent progress in surgical indications and strategies for varicocele in adult males, and provides some reference for the management of the disease.