Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

High stocking rates effects in continuous season long grazing reduces the contribution of microbial necromass to soil organic carbon in a semi-arid grassland in Inner Mongolia.

Livestock grazing strongly influences the accumulation of soil organic carbon (SOC) in grasslands. However, whether the changes occurring in SOC content under different intensities of continuous summer long grazing are associated with the changes in microbially-derived necromass C remains unclear. Here, we established a sheep grazing experiment in northern China in 2004 with four different stocking rates. Soil samples were collected after 17 years of grazing and analyzed for physical, chemical, and microbial characteristics. Grazing decreased SOC and microbial necromass carbon (MNC). Notably, grazing also diminished contributions of MNC to SOC. MNC declined with decreasing plant carbon inputs with degradation of the soil environment. Direct reductions in microbial necromass C, which indirectly reduced SOC, resulted from reduced in plant C inputs and microbial abundance and diversity. Our study highlights the key role of stocking rate in governing microbial necromass C and SOC and the complex relationships these variables.

Novel PDI-NH/PDI-COOH Supramolecular Junction for Enhanced Visible-Light Photocatalytic Phenol Degradation.

The development of efficient and environmentally friendly photocatalysts is crucial for addressing global energy and environmental challenges. Perylene diimide, an organic supramolecular material, holds great potential for applications in mineralized phenol. In this study, through the integration of different mass ratios of unmodified perylenimide (PDI-NH) into the self-assembly of amino acid-substituted perylenimide (PDI-COOH), a novel supramolecular organic heterojunction (PDICOOH/PDINH) was fabricated. The ensuing investigation focuses on its visible-light mineralized phenol properties. The results show that the optimal performance is observed with a composite mass fraction of 10%, leading to complete mineralization of 5 mg/L phenol within 5 h. The reaction exhibits one-stage kinetics with rate constants 13.80 and 1.30 times higher than those of PDI-NH and PDI-COOH, respectively. SEM and TEM reveal a heterogeneous interface between PDI-NH and PDI-COOH. Photoelectrochemical and Kelvin probe characterization confirm the generation of a built-in electric field at the interface, which is 1.73 times stronger than that of PDI-COOH. The introduction of PDI-NH promotes π-π stacking of PDI-COOH, while the built-in electric field facilitates efficient charge transfer at the interface, thereby enhancing phenol decomposition. The finding demonstrates that supramolecular heterojunctions have great potential as highly effective photocatalysts for environmental remediation applications.

Recent Advances in Catalytic Asymmetric Construction of Atropisomers.

Atropisomerism is a stereochemical behavior portrayed by three-dimensional molecules that bear rotationally restricted σ bond. Akin to the well-represented point-chiral molecules, atropisomerically chiral compounds are finding increasing utilities in many disciplines where molecular asymmetry is influential. This provides steady demand on atroposelective synthesis, where numerous synthetic pursuits have been rewarded with conceptually novel and streamlined methods while expanding the structural diversity of atropisomers. This review summarizes key achievements in stereoselective preparation of biaryl, heterobiaryl, and nonbiaryl atropisomers documented between 2015 and 2020. Emphasis is placed on the synthetic strategies for each structural class, while examples are cited to illustrate the potential applications of the accessed atropochiral targets.

Biodiversity and soil pH regulate the recovery of ecosystem multifunctionality during secondary succession of abandoned croplands in northern China.

The 'Grain-for-Green' program in China provides a valuable opportunity to investigate whether spontaneous restoration can reverse the deterioration of grassland ecosystem functions. Previous studies have focused on individual ecosystem functions, but the response of and mechanisms driving variation in ecosystem multifunctionality (EMF) during restoration are poorly understood. Here, we quantified EMF using productivity, nutrient cycling, and water regulation functions along abandoned croplands in a recovery chronosequence (5, 15 and 20 years) and in natural grasslands in the desert steppe and typical steppe. We also analyzed the effects of plant and microbial diversity and an abiotic factor (soil pH) on EMF. Our results showed that EMF increased gradually concomitant with recovery time, shifting toward EMF values comparable to those in natural grasslands in both desert and typical steppe. Similar results were found for the productivity function, the water regulation function, and soil organic carbon. However, even after 20 years of restoration, EMF did not reach the levels observed in natural grasslands. Structural equation modeling showed that the driving mechanisms of EMF differed between the two steppe types. Specifically, in the desert steppe, plant diversity, especially the diversity of perennial graminoids and perennial herbs, had a positive effect on EMF, but in the typical steppe, soil bacterial diversity had a negative effect, while soil pH had a positive effect on EMF. Our results demonstrated that spontaneous grassland restoration effectively enhanced EMF, and emphasized the importance of biodiversity and soil pH in regulating EMF during secondary succession. This work provides important insights for grassland ecosystem management in arid and semi-arid regions.

AMP-activated kinase regulates porcine reproductive and respiratory syndrome virus infection in vitro.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen in the pig industry worldwide. Many viruses manipulate their cellular metabolism to replicate themselves and cause infection. A conserved cellular energy sensor, 5'-AMP-activated protein kinase (AMPK), maintains cellular energy homeostasis. We found that PRRSV infection caused significant AMPK activation in a time-dependent manner via the ROS-calcium/calmodulin-dependent protein kinase-2 pathway. RNA interference-mediated AMPK knockdown could increase PRRSV replication in MARC-145 cells, suggesting that AMPK contributed to PRRSV infection regulation. Moreover, investigation of the effect of AMPK activity on PRRSV replication showed that PRRSV replication could be suppressed by the pharmacological agonists 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside and A769662. Conversely, an AMPK inhibitor, compound C, markedly enhanced PRRSV infection. Furthermore, the AMPK agonist A769662 was found to exert no effect on PRRSV entry, assembly, and release, suggesting that A769662 may hinder the PRRSV genome replication in MARC-145 cells. In conclusion, AMPK may be a promising antiviral drug target against PRRSV infection.

Tim-3/Galectin-9 signaling pathway is involved in the cytokine changes in mice with alveolar echinococcosis.

BACKGROUND: Tim-3/Galectin-9 is involved in the immune escape of many pathogens. However, the role of Tim-3/Galectin-9 in persistent infection of Echinococcus multilocularis (Em), which is related to immune escape, is still unclear. OBJECTIVE: To investigate the role of Tim-3/Galectin-9 and related cytokines in mice with persistent infection of Em. METHODS: Em infection model was established by injecting the protoscoleces. Serum was collected at days 2, 8, 30, 60, 90, 180 and 270 after infection. Lymphocytes were isolated from liver tissue samples with Ficoll. Tim-3 + CD4 + T percentage was analyzed by flow cytometry. CD4 + T cells were isolated from liver tissues of Em infected mice and cultured in vitro. The mRNA levels of Tim-3, Galectin-9, IFN-γ and IL-4 were detected by qRT-PCR. Cytokine levels in serum and culture supernatant (IFN-γ and IL-4) were analyzed by cytometric bead array. RESULTS: The expression of Tim-3 and Galectin-9 mRNA significantly increased after 30 days of infection, reached peak on day 90, and then decreased slightly on days 180-270. The expression of IFN-γ mRNA, increased on day 2 and 8 after infection, slightly decreased on days 30-60, and obvious decreased on days 90-270, but were still higher than those of the control group. The expression of IL-4 mRNA gradually increased along with the time of infection. In serum of Em infected mice, level of IFN-γ peaked at day 30 and then gradually decreased; whereas IL-4 level peaked at day 90 and then gradually decreased. In vitro experiment found that Tim-3/Galectin-9 directly caused the changes in the levels of IFN-γ and IL-4. CONCLUSIONS: Tim-3/Galectin-9 signaling pathway may be involved in the development of persistent infection of Em by regulating the production of Th1 and Th2 cytokines.

Asymmetric Pnictogen-Bonding Catalysis: Transfer Hydrogenation by a Chiral Antimony(V) Cation/Anion Pair.

Pnictogen-bonding catalysis based on σ-hole interactions has recently attracted the attention of synthetic chemists. As a proof-of-concept for asymmetric pnictogen-bonding catalysis, we report herein an enantioselective transfer hydrogenation of benzoxazines catalyzed by a novel chiral antimony cation/anion pair. The chiral pnictogen catalyst library could be rapidly accessed from triarylstibine with readily available mandelic acid analogues, and the catalyst displays remarkable efficiency and enantiocontrol potency even at 0.05 mol % loading. Moreover, the properties of the catalyst and the mechanistic insights have been investigated by nonlinear effect studies, 1H NMR, LC-MS, and control experiments.

Chiral Phosphoric Acid-Catalyzed Remote Control of Axial Chirality at Boron-Carbon Bond.

The previously elusive catalytic enantioselective construction of axially chiral B-aryl-1,2-azaborines with a C-B stereogenic axis has been realized through a chiral phosphoric acid-catalyzed desymmetrization strategy reported herein. The electrophilic aromatic substitution reaction of 3,5-disubsituted phenols with diazodicarboxamides could afford these axially chiral structures in good efficiency with excellent enantiocontrol. The efficient long-range stereochemical control is achieved by multiple well-defined H-bonding interactions between chiral phosphoric acid and both substrates. Meanwhile, the reaction duration could be markedly shortened with weakly acidic N-H in 1,2-azaborine acting as H-bond donor. The scalability of the reaction and facile cleavage of the N-N bond in the product further demonstrated the practicality of this method.

Copper-Catalyzed Synthesis of Axially Chiral Biaryls with Diaryliodonium Salts as Arylation Reagents.

NOBIN and BINAM derivatives harboring biaryl frameworks are recognized as a class of important atropisomers with versatile applications. Here, we present an efficient synthetic route to access such compounds through copper-catalyzed domino arylation of N-arylhydroxylamines or N-arylhydrazines with diaryliodonium salts and [3,3]-sigmatropic rearrangement. This reaction features mild conditions, good substrate compatibility, and excellent efficiency. The practicality of this protocol was further extended by the synthesis of biaryl amino alcohols.

Robust network-based regularization and variable selection for high-dimensional genomic data in cancer prognosis.

In cancer genomic studies, an important objective is to identify prognostic markers associated with patients' survival. Network-based regularization has achieved success in variable selections for high-dimensional cancer genomic data, because of its ability to incorporate the correlations among genomic features. However, as survival time data usually follow skewed distributions, and are contaminated by outliers, network-constrained regularization that does not take the robustness into account leads to false identifications of network structure and biased estimation of patients' survival. In this study, we develop a novel robust network-based variable selection method under the accelerated failure time model. Extensive simulation studies show the advantage of the proposed method over the alternative methods. Two case studies of lung cancer datasets with high-dimensional gene expression measurements demonstrate that the proposed approach has identified markers with important implications.

An optimal kernel-based U-statistic method for quantitative gene-set association analysis.

Single-variant-based genome-wide association studies have successfully detected many genetic variants that are associated with a number of complex traits. However, their power is limited due to weak marginal signals and ignoring potential complex interactions among genetic variants. The set-based strategy was proposed to provide a remedy where multiple genetic variants in a given set (e.g., gene or pathway) are jointly evaluated, so that the systematic effect of the set is considered. Among many, the kernel-based testing (KBT) framework is one of the most popular and powerful methods in set-based association studies. Given a set of candidate kernels, the method has been proposed to choose the one with the smallest p-value. Such a method, however, can yield inflated Type 1 error, especially when the number of variants in a set is large. Alternatively one can get p values by permutations which, however, could be very time-consuming. In this study, we proposed an efficient testing procedure that cannot only control Type 1 error rate but also have power close to the one obtained under the optimal kernel in the candidate kernel set, for quantitative trait association studies. Our method, a maximum kernel-based U-statistic method, is built upon the KBT framework and is based on asymptotic results under a high-dimensional setting. Hence it can efficiently deal with the case where the number of variants in a set is much larger than the sample size. Both simulation and real data analysis demonstrate the advantages of the method compared with its counterparts.

Michael Reaction Inspired Atroposelective Construction of Axially Chiral Biaryls.

The first copper-catalyzed atroposelective Michael-type addition between azonaphthalenes and arylboronic acids for the construction of biaryl atropisomers was established using a novel BINOL-derived phosphoramidite as a chiral ligand. A broad range of atropisomeric biaryls were obtained with good efficiency, and the practicality of this approach was verified by versatile transformations toward axially chiral ligands, catalysts, and other functional atropisomers. This set of catalytic systems successfully inhibited the routine 1,2-addition and promoted the formation of an aryl-aryl chiral axis. Meanwhile, this strategy bypassed the use of an oxidant as well as the harsh conditions normally necessary for transition-metal-mediated arene C-H coupling with arylboronic acids as an arylation counterpart, offering a straightforward alternative to access optically active biaryls.

Effectiveness of a Theory-Based mHealth Intervention for High-Risk Drinking in College Students.

Background: College students are among the most vulnerable groups to problems associated with high-risk drinking consequences such as illness, injury, sexual abuse, and death. Promising mobile health (mHealth) approaches, such as smartphone (SP) apps, can be used in interventions to address or prevent excessive drinking. Method: The aim of the investigation was to examine the efficacy of a theoretically based mHealth SP app for alcohol intervention in two independent samples (N = 379): Mandated participants (Study 1) and voluntary participants (Study 2). Study 1 included a controlled trial with Mandated participants randomized into either an in-person Brief Motivational Interviewing BMI (n = 70) or BMI + SP app intervention (n = 71). Study 2 included Voluntary participants who participated in either a Control group (n = 157) or the BMI + SP app intervention (n = 81). Participants in both studies completed baseline and 6-week assessments. Results: In Study 1, peak Blood Alcohol Concentration (BAC) of participants in the in-person BMI group had increased slightly at six weeks, while it had decreased for the app-based BMI + SP group. Study 2 participants using the BMI + SP app reported significant reductions in drinking and consequences; there were no changes in the (AO) Control group. Conclusions: The BMI + SP app was effective with both Mandated and Voluntary participants. Future testing with the BMI + SP app is needed to assess whether reach, adoptability, portability, and sustainability are greater with the mHealth smartphone app for alcohol intervention than in-person approaches.

Organocatalytic Enantioselective Synthesis of Atropisomeric Aryl-p-Quinones: Platform Molecules for Diversity-Oriented Synthesis of Biaryldiols.

Presented here is a class of novel axially chiral aryl-p-quinones as platform molecules for the preparation of non-C2 symmetric biaryldiols. Two sets of aryl-p-quinone frameworks were synthesized with remarkable enantiocontrol by means of chiral phosphoric acid catalyzed enantioselective arylation of p-quinones by central-to-axial chirality conversion. These aryl-p-quinones were then used to access a wide spectrum of highly functionalized non-C2 symmetric biaryldiols with excellent retention of the enantiopurity.

Chiral Phosphoric Acid Catalyzed Atroposelective C-H Amination of Arenes.

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C-H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C-N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C-N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.

miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2.

Colon cancer stem cells (CCSCs) stand for a critical subpopulation of colon cancer cells that possess self-renewal and multilineage differentiation potentials and drive tumorigenicity. Due to their impact on treatment tolerance, CCSCs have been a hot research topic in the past few years. We have previously reported that miR-139-5p is a vital tumor repressive noncoding RNA whose level decreases in the clinical colon cancer samples with the increase of tumor malignancy. This research discovered that miR-139-5p targets the Wnt/ß-catenin/TCF7L2 downstream effector E2-2 in CCSCs. E2-2 is a pivot molecule in the negative feedback loop of miR-139-5p/Wnt/ß-catenin/TCF7L2. Its small interfering RNA reverses the stemness maintenance and epithelial-mesenchymal transition of colon cancer CSCs. This study provides a theoretical foundation for the clinical diagnosis and medical treatment of recurrent or metastatic colon cancer with miR-139-5p and its target E2-2.

Predicting disease trait with genomic data: a composite kernel approach.

With the advancement of biotechniques, a vast amount of genomic data is generated with no limit. Predicting a disease trait based on these data offers a cost-effective and time-efficient way for early disease screening. Here we proposed a composite kernel partial least squares (CKPLS) regression model for quantitative disease trait prediction focusing on genomic data. It can efficiently capture nonlinear relationships among features compared with linear learning algorithms such as Least Absolute Shrinkage and Selection Operator or ridge regression. We proposed to optimize the kernel parameters and kernel weights with the genetic algorithm (GA). In addition to improved performance for parameter optimization, the proposed GA-CKPLS approach also has better learning capacity and generalization ability compared with single kernel-based KPLS method as well as other nonlinear prediction models such as the support vector regression. Extensive simulation studies demonstrated that GA-CKPLS had better prediction performance than its counterparts under different scenarios. The utility of the method was further demonstrated through two case studies. Our method provides an efficient quantitative platform for disease trait prediction based on increasing volume of omics data.

EpCAM Aptamer-Functionalized Cationic Liposome-Based Nanoparticles Loaded with miR-139-5p for Targeted Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. MicroRNAs (miRNAs) play a vital role in a variety of biology processes. Our previous work identified miR-139-5p as a tumor suppressor gene overexpressed in CRC that assisted in inhibiting progression of cancer. The main challenge of miRNAs as therapeutic agents is their rapid degradation in plasma, poor uptake, and off-target effects. Therefore, the development of miRNA-based therapies is necessary. In this study, we developed a cationic liposome-based nanoparticle loaded with miR-139-5p (miR-139-5p-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MNPs) and surface-decorated with epithelial cell adhesion molecule (EpCAM) aptamer (Apt) (miR-139-5p-EpCAM Apt-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MANPs) for the targeted treatment of CRC. The size of MANPs was 150.3 ± 8.8 nm, which had a round-shaped appearance and functional dispersion capabilities. It also showed negligible hemolysis in the blood. MANPs markedly inhibited the proliferation, migration, and invasion of one or more CRC cell lines in vitro. Furthermore, we demonstrated the uptake and targeting ability of MANPs in vivo and in vitro. MANPs inhibit the growth of HCT8 cells in vitro and have a significant tumor suppressive effect on subcutaneous HCT8 colorectal tumor mice. Our results demonstrated that MANPs were an effective carrier approach to deliver therapeutic miRNAs to CRC.

Effect of stocking density and alpha-lipoic acid on the growth performance, physiological and oxidative stress and immune response of broilers.

OBJECTIVE: The study was conducted to evaluate the effect of stocking density and alpha-lipoic acid (ALA) on the growth performance, feed utilization, carcass traits, antioxidative ability and immune response of broilers. METHODS: A total of 1530 22-day-old male broilers (Arbor Acres) with comparable body weights (731.92 ± 5.26) were placed into 18 cages (2.46 × 2.02 m) in groups of 75 birds (15 birds/m2, 37.5 kg/m2; LD, low stocking density), 90 birds (18 birds/m2, 45.0 kg/m2; HD, high stocking density) and 90 birds with 300 mg/kg ALA added to the basal diet (18 birds/m2, 45.0 kg/m2; HD+ALA, high stocking density + -lipoic acid); each treatment was represented by 6 replicates. The experimental period was 3 weeks. RESULTS: The results showed that the high stocking density regimen resulted in a decreased growth, feed conversion ratio, carcass weight, thigh yield and bursa weight relative to body weight (P < 0.05) on d 42. The abdominal fat yield in the HD+ALA group was lower (P = 0.031) than that of the LD group at 42 d. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in serum were increased, and malondialdehyde (MDA) content decreased after adding ALA product (P < 0.05) on d 42. Additionally, the serum concentrations of IgA and IgG were decreased (P < 0.05) and the level of diamine oxidase (DAO) was higher (P < 0.01) in the HD group on d 42. CONCLUSION: The high stocking density significantly decreased broiler growth performance, feed utilization and carcass traits, increased physiological and oxidative stress and induced intestinal mucosal injury. The supplementation of ALA product in broiler diet at 300 mg/kg may reduce the adverse effects of high stocking density-mediated stress by maintaining the antioxidant system and humoral immune system.