ABSTRACT
BACKGROUND: Increasing evidence shows the pivotal significance of miRNAs in the pathogenesis of osteoporosis. miR-381-3p has been identified as an inhibitor of osteogenesis. This study explored the role and mechanism of miR-381-3p in postmenopausal osteoporosis (PMOP), the most common type of osteoporosis. METHODS: Bilateral ovariectomy (OVX) rat model was established and miR-381-3p antagomir was administrated through the tail vein in vivo. The pathological changes in rats were assessed through the evaluation of serum bone turnover markers (BALP, PINP, and CTX-1), hematoxylin and eosin (H&E) staining, as well as the expression of osteoblast differentiation biomarkers. Moreover, isolated bone marrow mesenchymal stem cells from OVX-induced rats (OVX-BMMSCs) were utilized to explore the impact of miR-381-3p on osteoblast differentiation. In addition, the target gene and downstream pathway of miR-381-3p were further investigated both in vivo and in vitro. RESULTS: miR-381-3p expression was elevated, whereas KLF5 was suppressed in OVX rats. miR-381-3p antagomir decreased serum levels of bone turnover markers, improved trabecular separation, promoted osteoblast differentiation biomarker expression in OVX rats. ALP activity and mineralization were suppressed, and levels of osteoblast differentiation biomarkers were impeded after miR-381-3p overexpression during osteoblast differentiation of OVX-BMMSCs. While contrasting results were found after inhibition of miR-381-3p. miR-381-3p targets KLF5, negatively affecting its expression as well as its downstream Wnt/ß-catenin pathway, both in vivo and in vitro. Silencing of KLF5 restored Wnt/ß-catenin activation induced by miR-381-3p antagomir. CONCLUSION: miR-381-3p aggravates PMOP by inhibiting osteogenic differentiation through targeting KLF5/Wnt/ß-catenin pathway. miR-381-3p appears to be a promising candidate for therapeutic intervention in PMOP.
Subject(s)
Cell Differentiation , Kruppel-Like Transcription Factors , MicroRNAs , Osteogenesis , Osteoporosis, Postmenopausal , Ovariectomy , Wnt Signaling Pathway , Animals , Female , Humans , Rats , Cells, Cultured , Disease Models, Animal , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mesenchymal Stem Cells/metabolism , MicroRNAs/genetics , Osteoblasts/metabolism , Osteogenesis/genetics , Osteogenesis/physiology , Osteoporosis/genetics , Osteoporosis/etiology , Osteoporosis/metabolism , Osteoporosis, Postmenopausal/genetics , Osteoporosis, Postmenopausal/metabolism , Ovariectomy/adverse effects , Rats, Sprague-Dawley , Wnt Signaling Pathway/physiology , Wnt Signaling Pathway/geneticsABSTRACT
MOTIVATION: Recent frameworks based on deep learning have been developed to identify cancer subtypes from high-throughput gene expression profiles. Unfortunately, the performance of deep learning is highly dependent on its neural network architectures which are often hand-crafted with expertise in deep neural networks, meanwhile, the optimization and adjustment of the network are usually costly and time consuming. RESULTS: To address such limitations, we proposed a fully automated deep neural architecture search model for diagnosing consensus molecular subtypes from gene expression data (DNAS). The proposed model uses ant colony algorithm, one of the heuristic swarm intelligence algorithms, to search and optimize neural network architecture, and it can automatically find the optimal deep learning model architecture for cancer diagnosis in its search space. We validated DNAS on eight colorectal cancer datasets, achieving the average accuracy of 95.48%, the average specificity of 98.07%, and the average sensitivity of 96.24%, respectively. Without the loss of generality, we investigated the general applicability of DNAS further on other cancer types from different platforms including lung cancer and breast cancer, and DNAS achieved an area under the curve of 95% and 96%, respectively. In addition, we conducted gene ontology enrichment and pathological analysis to reveal interesting insights into cancer subtype identification and characterization across multiple cancer types. AVAILABILITY AND IMPLEMENTATION: The source code and data can be downloaded from https://github.com/userd113/DNAS-main. And the web server of DNAS is publicly accessible at 119.45.145.120:5001.
Subject(s)
Breast Neoplasms , Deep Learning , Humans , Female , Neural Networks, Computer , Algorithms , SoftwareABSTRACT
Golden 2-Like (GLK) transcription factors play a crucial role in chloroplast development and chlorophyll synthesis in many plant taxa. To date, no systematic analysis of GLK transcription factors in tree species has been conducted. In this study, 40 EgrGLK genes in the Eucalyptus grandis genome were identified and divided into seven groups based on the gene structure and motif composition. The EgrGLK genes were mapped to 11 chromosomes and the distribution of genes on chromosome was uneven. Phylogenetic analysis of GLK proteins between E. grandis and other species provided information for the high evolutionary conservation of GLK genes among different species. Prediction of cis-regulatory elements indicated that the EgrGLK genes were involved in development, light response, and hormone response. Based on the finding that the content of chlorophyll in mature leaves was the highest, and leaf chlorophyll content of triploid Eucalyptus urophylla was higher than that of the diploid control, EgrGLK expression pattern in leaves of triploid and diploid E. urophylla was examined by means of transcriptome analysis. Differential expression of EgrGLK genes in leaves of E. urophylla of different ploidies was consistent with the trend in chlorophyll content. To further explore the relationship between EgrGLK expression and chlorophyll synthesis, co-expression networks were generated, which indicated that EgrGLK genes may have a positive regulatory relationship with chlorophyll synthesis. In addition, three EgrGLK genes that may play an important role in chlorophyll synthesis were identified in the co-expression networks. And the prediction of miRNAs targeting EgrGLK genes showed that miRNAs might play an important role in the regulation of EgrGLK gene expression. This research provides valuable information for further functional characterization of GLK genes in Eucalyptus.
ABSTRACT
We describe a multicenter study using the European Spine Phantom (ESP) to compare the accuracy, linearity and precision of QCT measurements of spine vBMD between different brands of scanner, different models of the same brand and identical units of the same model. Ten scans of the same ESP with repositioning were performed on forty CT scanners from five manufacturers in different hospitals across China, all calibrated with the Mindways QCT system. The three ESP vertebral bodies simulating low (L1), medium (L2) and high (L3) vBMD and their average (L1-3 vBMD) were compared with phantom values. Linearity was assessed using the standard error of the estimate derived from linear regression. Precision errors were expressed as the standard deviation of the ten measurements on each scanner. Median (IQR) vBMD over all forty CT scanners compared with phantom values were: L1: 52.2 (49.9-56.4) vs 51.0; L2: 104.4 (101.2-108.6) vs 102.2; L3: 201.4 (195.0-204.9) vs 200.4; L1-3: 119.3 (116.6-123.2) vs 117.9 mg/cm3. Statistically significant differences in L1-3 vBMD were found between different brands (p= 0.005) and between different models of the same brand and identical units of the same model (both p< 0.001). Cross-calibration using linear regression gave a good fit for all forty systems with a median standard error of the estimate of 1.7 mg/cm3. The median precision error for L1-3 vBMD was 0.61 mg/cm3. Statistically significant differences in spine vBMD measurements between different scanners reinforce the importance of cross-calibration in multi-center studies. Cross-calibration can be reliably performed using linear regression equations.
Subject(s)
Bone Density , Tomography, X-Ray Computed , Humans , Phantoms, Imaging , Spine/diagnostic imaging , Tomography Scanners, X-Ray ComputedABSTRACT
tert-Butoxide unlocks new reactivity patterns embedded in nitroarenes. Exposure of nitrostilbenes to sodium tert-butoxide was found to produce N-hydroxyindoles at room temperature without an additive. Changing the counterion to potassium changed the reaction outcome to yield solely oxindoles through an unprecedented dioxygen-transfer reaction followed by a 1,2-phenyl migration. Mechanistic experiments established that these reactions proceed via radical intermediates and suggest that counterion coordination controls whether an oxindole or N-hydroxyindole product is formed.
Subject(s)
Butanols/chemistry , Indoles/chemistry , Nitro Compounds/chemistry , Oxindoles/chemistry , Stilbenes/chemistry , Electron Transport , Molecular StructureABSTRACT
Ascorbate peroxidase (APX) is an important antioxidant enzyme. APXs in maize are encoded by multiple genes and exist as isoenzymes. The evolutionary history and functional divergence of the maize APX gene family were analyzed through comparative genomic and experimental data on the Internet in this paper. APX genes in higher plants were divided into classes A, B, and C. Each type of APX gene in angiosperms only had one ancestral gene that was duplicated along with the genome duplication or local (or tandem) duplication of the angiosperm. A total of eight genes were retained in maize and named APXa1, APXa2, APXa3, APXb1, APXb2, APXc1.1, APXc1.2, and APXc2. The APX genes of class A were located in the chloroplasts or mitochondria, and the class B and C genes were localized in the peroxisomes and cytoplasm, respectively. The expression patterns of eight APXs were different in vegetative and reproductive organs at different growth and development stages. APXa1 and APXb1 of maize may participate in the antioxidant metabolism of vegetative organs under normal conditions. APXa2, APXb2, APXc1.1, and APXc1.2 may be involved in the stress response, and APXb2 and APXc2 may participate in the senescence response. These results provide a basis for cultivating high-yield and resistant maize varieties.
Subject(s)
Ascorbate Peroxidases/genetics , Evolution, Molecular , Gene Expression Regulation, Plant , Plant Proteins/genetics , Plant Proteins/metabolism , Zea mays/enzymology , Zea mays/genetics , Ascorbate Peroxidases/metabolism , Multigene Family , Phylogeny , Zea mays/growth & developmentABSTRACT
We herein establish a multicomponent annulation method for the synthesis of valuable iminocoumarins using aryl thiocarbamates, internal alkynes, and sulfonamides as starting materials, which are safe and readily available. The key step is a Rh-catalyzed and sulfur-directed C-H bond activation. Preliminary mechanistic investigations suggested that the nucleophilic attack of the sulfonamide on an active iminium cation finally completes the imine segment.
ABSTRACT
Cross-coupling reactions involving metal carbene intermediates play an increasingly important role in C-C bond formation. Expanding the carbene precursors to a broader range of starting materials and more diverse products is an ongoing challenge in synthetic organic chemistry. Herein, we report a Suzuki-Miyaura coupling reaction of in situ-generated Pd-carbene complexes via desulfurization of thioureas or thioamides. This strategy enables the preparation of a broad array of substituted amidinium salts and unsymmetrical diaryl ketones. The reaction is readily scalable, compatible with bromo groups on aromatic rings, tolerant to moisture and air and has a broad substrate scope. Furthermore, a single crystal structure of Pd-diaminocarbene complex is obtained and proven to be the key intermediate in both catalytic and stoichiometric reactions. Preliminary mechanistic studies demonstrate the dual role of the silver salt as a desulfurating reagent assisting the elimination of sulfur and as oxidant facilitating the PdII/Pd0/PdII catalytic cycle.
ABSTRACT
Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.
Subject(s)
Crush Injuries/metabolism , Crush Injuries/pathology , Cytokines/metabolism , Inflammation Mediators/metabolism , Neuroprotective Agents/pharmacology , Nicotine/pharmacology , Sciatic Nerve/metabolism , Sciatic Nerve/pathology , Animals , Disease Models, Animal , GAP-43 Protein/metabolism , Interleukin-1beta/metabolism , Male , Motor Activity/drug effects , Nerve Regeneration/drug effects , Rats, Wistar , Sciatic Nerve/drug effects , Sensory Receptor Cells/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
This paper investigates the attitude estimation errors caused by the deflections of vertical (DOV) in the case of a rotational inertial navigation system (INS) integrated with a global satellite navigation system (GNSS). It has been proved theoretically and experimentally that the DOV can introduce a tilt error to the INS/GNSS integration, whereas less attention has been given to its effect to the heading estimation. In fact, due to the intercoupling characteristic of attitude errors, the heading estimation of an INS/GNSS integrated navigation system can also be affected. In this paper, first, the attitude estimation errors caused by DOV were deduced based on the INS's error propagation functions. Then, the corresponding simulations were conducted and the results were well consistent with the theoretical analysis. Finally, a real shipborne marine test was organized with the aimed to verify the effect of DOV on attitude estimation in the rotational INS/GNSS integration, whereas the global gravity model was used for DOV compensation. The results with DOV compensation were compared with the corresponding results where the compensation was not used and showed that the heading estimation errors caused by DOV could exceed 20 arcsecs, which must be considered in high-precision application cases.
ABSTRACT
As little as 2 mol % of (XPhos)AuNTf2 catalyzes the transformation of a broad range of o-acetylene-substituted styrenes into 1,2-dihydronaphthalenes. Our data suggests that this transformation occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The relative rates of these migrations can be controlled by the identity of the ligand or by stabilizing the mesomeric cation.
ABSTRACT
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly abundant in the brain and confers protection against numerous neurological diseases, yet the fundamental mechanisms regulating the enrichment of DHA in the brain remain unknown. Here, we have discovered that a member of the long-chain acyl-CoA synthetase family, Acsl6, is required for the enrichment of DHA in the brain by generating an Acsl6-deficient mouse (Acsl6-/-). Acsl6 is highly enriched in the brain and lipid profiling of Acsl6-/- tissues reveals consistent reductions in DHA-containing lipids in tissues highly abundant with Acsl6. Acsl6-/- mice demonstrate motor impairments, altered glutamate metabolism, and increased astrogliosis and microglia activation. In response to a neuroinflammatory lipopolysaccharide injection, Acsl6-/- brains show similar increases in molecular and pathological indices of astrogliosis compared with controls. These data demonstrate that Acsl6 is a key mediator of neuroprotective DHA enrichment in the brain.
Subject(s)
Brain/enzymology , Coenzyme A Ligases/metabolism , Docosahexaenoic Acids/metabolism , Animals , Brain/metabolism , Coenzyme A Ligases/genetics , Gene Expression Regulation , Gene Expression Regulation, Enzymologic , Male , Mice , Mice, Knockout , Microglia , Motor ActivityABSTRACT
Due to the temperature delay effect, the coefficients of the traditional ring laser gyroscope's (RLG) bias temperature model usually change with environmental temperature. In order to improve the applicability of the temperature model in complex temperature-varying environments, a modified RLG bias modeling method based on the temperature delay effect is proposed. The time series model (TSM), whose coefficients are independent of the environmental temperature variation, is established through theoretical analysis according to the temperature delay effect. The forecasting accuracy of the proposed method is compared with the conventional stepwise regression model (SRM) when both the temperature and temperature-varying rate exceed their boundaries. The experimental results indicate that the proposed TSM can overcome the defect that the compensation accuracy will decline or even diverge when outside the boundaries of temperature and temperature-varying rate. Therefore, the TSM is more suitable for the RLG bias temperature modeling in complex temperature-varying environments.
ABSTRACT
A palladium-catalyzed dual ortho C-H bond activation of aryl thiocarbamates is developed. This tandem reaction initiates by thiocarbamate-directed ortho C-H palladation, which leads to favorable olefin insertion rather than reductive elimination. The oxidative Heck reaction followed by another C-H activation and sulfuration affords the dual-functionalized products. This reaction provides a concise route to the S,O,C multisubstituted benzene skeleton which could be successfully applied for the synthesis of a COX-2 inhibitor.
Subject(s)
Thiocarbamates/chemistry , Alkenes , Catalysis , Cyclooxygenase 2 Inhibitors , Molecular Structure , PalladiumABSTRACT
C-N bond formation via a copper-catalyzed aerobic oxidative decarboxylative tandem protocol was realized. The phenylacetic acids which contain ortho-X (X = F or Br) on the aromatic ring will render a fused five-membered heterocycle via a tandem aromatic nucleophilic substitution and aerobic oxidative decarboxylative acylation at the C(sp(2))-H bond of benzimidazoles under the Cu(OAc)2/K2CO3/BF3·Et2O catalytic system, while with CuBr as the catalyst and pyridine as the base, N-acylation occurred and tertiary amides were obtained.
ABSTRACT
The palladium-catalyzed Sonogashira-type aerobic oxidative coupling of arylhydrazines with terminal alkynes via C-N bond cleavage has been developed; internal alkynes were afforded with a broad substrate scope. This reaction proceeds under copper- and base-free conditions with molecular oxygen as the sole oxidant and nitrogen and water as the only by-products.
Subject(s)
Alkynes/chemical synthesis , Hydrazines/chemistry , Oxidation-Reduction , Catalysis , PalladiumABSTRACT
A Rh-catalyzed annulation of aryl thiocarbamates with internal alkynes via C-H bond activation has been developed. This protocol provides a new route to 3,4-disubstituted coumarins.
Subject(s)
Alkynes/chemistry , Coumarins/chemical synthesis , Rhodium/chemistry , Thiocarbamates/chemistry , Catalysis , Coumarins/chemistry , Cyclization , Molecular Structure , Oxidation-ReductionABSTRACT
Spherical ß-CD-silica hybrid materials have been prepared successfully by simple one-pot polymerization, which provide a new strategy to construct new type of HPLC chiral stationary phases. Various ß-CD, ethane, triazinyl and 3,5-dimethylphenyl functional groups that can provide multiple interactions were introduced into the pore channels and pore wall framework of mesoporous materials, respectively. The materials towards some chiral, acidic, anilines and phenols compounds showed multiple chromatographic separation functions including racemic resolution, anion exchange and achiral separations with a typical feature of normal/reversed phase chromatography. Multi-tasking including racemic resolution and achiral separations for selected compounds were performed simultaneously on a chiral chromatographic column. The multifunctional character of materials arises from the multiple interactions including hydrophobic interaction, π-π interaction, anion exchange, inclusion interaction and hydrogen bonding interaction.
Subject(s)
Chromatography, High Pressure Liquid/methods , Silicon Dioxide/chemistry , beta-Cyclodextrins/chemistry , Benzyl Alcohols/analysis , Benzyl Alcohols/isolation & purification , Chromatography, High Pressure Liquid/instrumentation , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ion Exchange , Propanolamines/analysis , Propanolamines/isolation & purification , StereoisomerismABSTRACT
OBJECTIVE: To establish inter-simple sequences repeat (ISSR) molecular makers based on (CAGCG)n repeat sequence in mycobacteria. METHODS: The distribution of pentanucleotide repeat sequence (CAGCG)n in mycobacterial genomes was analyzed by MICdb 2.0 software in the microsatellite database. ISSR primer MISP6 based on (CAGCG)n sequences was designed and tested in mycobacterial strains, which included 17 mycobacterial strains and 41 Mycobacterium tuberculosis clinical strains. RESULTS: The abundances of pentanucleotide repeat sequences (CAGCG)n were high in most of the mycobacterial genomes and they were mainly located in the coding regions. The results of ISSR analysis in mycobacteria showed that 15 reference strains from mycobacteria were clustered into 2 major clusters. The first cluster contained 2 subtypes and the second cluster contained 4 subtypes. Forty-one clinical strains from Mycobacterium tuberculosis were divided into 2 major clusters by the analysis of MISP6 primer, and each cluster had 2 subtypes. CONCLUSION: ISSR primer MISP6 based on (CAGCG)n sequences can be used as a genetic marker to genotype mycobacterial strains.
Subject(s)
Genome, Bacterial , Mycobacterium/genetics , Repetitive Sequences, Nucleic Acid , Bacterial Typing Techniques , DNA Primers/genetics , DNA, Bacterial/genetics , Genetic Markers , Genotype , Mycobacterium/classificationABSTRACT
The nucleophilic addition of thiocarbamate imidazolium ylide to aldehyde triggered sequential intramolecular N to O migration of thiocarbonyl amide group and reversible oxygen-sulfur rearrangement to afford 2-imidazolium alkylcarbamothioate. The ortho group on phenyl of aldehyde strongly affects the balance of the O- to S-rearrangement.