scGAL: unmask tumor clonal substructure by jointly analyzing independent single-cell copy number and scRNA-seq data.

BACKGROUND: Accurately deciphering clonal copy number substructure can provide insights into the evolutionary mechanism of cancer, and clustering single-cell copy number profiles has become an effective means to unmask intra-tumor heterogeneity (ITH). However, copy numbers inferred from single-cell DNA sequencing (scDNA-seq) data are error-prone due to technically confounding factors such as amplification bias and allele-dropout, and this makes it difficult to precisely identify the ITH. RESULTS: We introduce a hybrid model called scGAL to infer clonal copy number substructure. It combines an autoencoder with a generative adversarial network to jointly analyze independent single-cell copy number profiles and gene expression data from same cell line. Under an adversarial learning framework, scGAL exploits complementary information from gene expression data to relieve the effects of noise in copy number data, and learns latent representations of scDNA-seq cells for accurate inference of the ITH. Evaluation results on three real cancer datasets suggest scGAL is able to accurately infer clonal architecture and surpasses other similar methods. In addition, assessment of scGAL on various simulated datasets demonstrates its high robustness against the changes of data size and distribution. scGAL can be accessed at: https://github.com/zhyu-lab/scgal . CONCLUSIONS: Joint analysis of independent single-cell copy number and gene expression data from a same cell line can effectively exploit complementary information from individual omics, and thus gives more refined indication of clonal copy number substructure.

Highly selective and additive-free Pd(OAc)2/CPP catalyzed hydroaminocarbonylation of alkynes.

Herein, the synthesis of branched α,ß-unsaturated amides by a hydroaminocarbonylation reaction of alkynes with various amine substrates such as aromatic amines, aliphatic amines, solid amine sources like NH4HCO3, and even strongly basic piperidines is reported, using a Pd(OAc)2/hybrid N-heterocyclic carbene-phosphine-phosphine (CPP) catalytic system. The reactions feature no additives, wide substrate scope, high selectivity (b/l > 99 : 1) and excellent yields. Mechanistic studies have disclosed that the reaction takes place via a palladium hydride pathway. CPP adopts a hybrid bidentate ligand conformation with a carbene-phosphine coordination mode, wherein one phosphorus atom remains externally accessible, potentially serving as a stabilizing auxiliary during catalytic cycles.

Efficient and selective external activator-free cobalt catalyst for hydroboration of terminal alkynes enabled by BiPyPhos.

Herein, a robust catalyst system, composed of a bipyridine-based diphosphine ligand (BiPyPhos) and a cobalt precursor Co(acac)2, is successfully developed and applied in the hydroboration of terminal alkynes, exclusively affording various versatile ß-E-vinylboronates in high yields at room temperature.

Ketamine-induced 1-Hz oscillation of spontaneous neural activity is not directly visible in the hemodynamics.

The extent to which resting-state hemodynamics reflects the underlying neural activity is still under debate. Especially in the delta frequency band (0.5-4 Hz), it is unclear whether the hemodynamics can directly track the dynamics of underlying neural activity. Based on a recent report showing that ketamine administration induced a 1-Hz neural activity oscillation in the retrosplenial cortex, we conducted simultaneous recordings of the calcium signal and hemodynamics in mice and examined whether the hemodynamics tracked the oscillatory neural activity. Although we observed that the oscillation induced by ketamine appeared in the calcium signal, no sign of oscillation was detected in the simultaneously recorded hemodynamics. Consistently, there was a notable decrease in the correlation between simultaneously recorded calcium signal and hemodynamics. However, on a much longer time scale (10-60 min), we unexpectedly observed an ultraslow increase of hemodynamic signals specifically in the same cortical region exhibiting the neural activity oscillation. These results indicated that hemodynamics cannot track the 1-Hz oscillation in neural activity, although the presence of neural activity oscillation was detectable on a longer timescale. Such ultraslow hemodynamics may be useful for detecting abnormal neural activity induced by psychotic drugs or mental disorders.

Insulin Inhibits Autophagy by Inhibiting the Binding of FoXO1 to the Promoter Region of GABARAPL1.

Hyperinsulinemia and insulin resistance in T2D have a potent suppressive effect on hepatic autophagy, however, the underlying mechanisms remain unclear. To explore the effect of insulin on hepatic autophagy and its possible signaling pathways, HL-7702 cells were treated with insulin with or without insulin signaling inhibitors. The interaction between insulin and the promoter region of GABARAPL1 was assessed through luciferase assay and EMSA. There were significant dose-dependent decreases in the number of intracellular autophagosomes and the protein levels of GABARAPL1 and beclin1 in insulin-treated HL-7702 cells. Insulin signaling inhibitors reversed the inhibitory effect of insulin on rapamycin-induced autophagy and autophagy-related gene upregulation. Insulin blocks the binding of FoxO1 to putative insulin response elements in GABARAPL1 gene promoter, leading to the repressed transcription of GABARAPL1 gene and the suppression of hepatic autophagy. Our study identified GABARAPL1 as a novel target of insulin in suppressing hepatic autophagy.

Tandem Ring-Contraction/Regioselective C-H Iodination Reaction of Pyridinium Salts.

A facile route for direct access to the 4-iodopyrrole-2-carbaldehydes from pyridinium salts has been successfully developed, which undergoes cascade pyrrole-2-carbaldehydes construction/selective C4 position iodination process. Using Na2S2O8 as an oxidant and readily available sodium iodide as an iodine source, a variety of 4-iodopyrrole-2-carbaldehydes were obtained in good to excellent yields. Atom- and step-economy, good functional group tolerance, high regioselectivity, as well as mild conditions entail this transformation an alternative strategy for enriching pyrroles library.

Exogenous Electroactive Microbes Regulate Soil Geochemical Properties and Microbial Communities by Enhancing the Reduction and Transformation of Fe(III) Minerals.

Electroactive microbes can conduct extracellular electron transfer and have the potential to be applied as a bioresource to regulate soil geochemical properties and microbial communities. In this study, we incubated Fe-limited and Fe-enriched farmland soil together with electroactive microbes for 30 days; both soils were incubated with electroactive microbes and a common iron mineral, ferrihydrite. Our results indicated that the exogenous electroactive microbes decreased soil pH, total organic carbon (TOC), and total nitrogen (TN) but increased soil conductivity and promoted Fe(III) reduction. The addition of electroactive microbes also changed the soil microbial community from Firmicutes-dominated to Proteobacteria-dominated. Moreover, the total number of detected microbial species in the soil decreased from over 700 to less than 500. Importantly, the coexistence of N-transforming bacteria, Fe(III)-reducing bacteria and methanogens was also observed with the addition of electroactive microbes in Fe-rich soil, indicating the accelerated interspecies electron transfer of functional microflora.

Transcriptome analysis of immune-related genes of Asian corn borer (Ostrinia furnacalis [Guenée]) after oral bacterial infection.

The Asian corn borer (Ostrinia furnacalis) is an important agricultural pest causing serious damage to economic crops, such as corn and sorghum. The gut is the first line of defense against pathogens that enter through the mouth. Staphylococcus aureus was used to infect the O. furnacalis midgut to understand the midgut immune mechanism against exogenous pathogens to provide new ideas and methods for the prevention and control of O. furnacalis. A sequencing platform was used for genome assembly and gene expression. The unigene sequences were annotated and functionally classified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Significant differences were found in the induced expression profiles before and after infection. Some differentially expressed genes have important relations with lipid metabolism and immune mechanism, suggesting that they play an important role in the innate immune response of O. furnacalis. Furthermore, quantitative real-time polymerase chain reaction assay was used to identify the key genes involved in the signaling pathway, and the expression patterns of these key genes were confirmed. The results could help study the innate immune system of lepidopteran insects and provide theoretical support for the control of related pests and the protection of beneficial insects.

MVNMDA: A Multi-View Network Combing Semantic and Global Features for Predicting miRNA-Disease Association.

A growing body of experimental evidence suggests that microRNAs (miRNAs) are closely associated with specific human diseases and play critical roles in their development and progression. Therefore, identifying miRNA related to specific diseases is of great significance for disease screening and treatment. In the early stages, the identification of associations between miRNAs and diseases demanded laborious and time-consuming biological experiments that often carried a substantial risk of failure. With the exponential growth in the number of potential miRNA-disease association combinations, traditional biological experimental methods face difficulties in processing massive amounts of data. Hence, developing more efficient computational methods to predict possible miRNA-disease associations and prioritize them is particularly necessary. In recent years, numerous deep learning-based computational methods have been developed and have demonstrated excellent performance. However, most of these methods rely on external databases or tools to compute various auxiliary information. Unfortunately, these external databases or tools often cover only a limited portion of miRNAs and diseases, resulting in many miRNAs and diseases being unable to match with these computational methods. Therefore, there are certain limitations associated with the practical application of these methods. To overcome the above limitations, this study proposes a multi-view computational model called MVNMDA, which predicts potential miRNA-disease associations by integrating features of miRNA and diseases from local views, global views, and semantic views. Specifically, MVNMDA utilizes known association information to construct node initial features. Then, multiple networks are constructed based on known association to extract low-dimensional feature embedding of all nodes. Finally, a cascaded attention classifier is proposed to fuse features from coarse to fine, suppressing noise within the features and making precise predictions. To validate the effectiveness of the proposed method, extensive experiments were conducted on the HMDD v2.0 and HMDD v3.2 datasets. The experimental results demonstrate that MVNMDA achieves better performance compared to other computational methods. Additionally, the case study results further demonstrate the reliable predictive performance of MVNMDA.

Facile Synthesis of 2-Methylnicotinonitrile through Degenerate Ring Transformation of Pyridinium Salts.

Nucleophilic recyclization of pyridinium salts involving a CCN interchange ring transformation for the synthesis of 2-methylnicotinonitrile derivatives was herein developed. 3-Aminocrotononitrile (3-ACN) produced in situ from CH3CN acted as a C-nucleophile, as well as the source of CH3 and CN groups, which was supported by isotope-labeling and control experiments.

Acceptorless Dehydrogenative Cross-Coupling of Primary Alcohols Catalyzed by an N-Heterocyclic Carbene-Nitrogen-Phosphine Chelated Ruthenium(II) Complex.

The acceptorless dehydrogenative cross-coupling of primary alcohols to form cross-esters with the liberation of H2 gas was enabled using a [RuCl(η6-C6H6)(κ2-CNP)][PF6]Cl complex as the catalyst. This sustainable protocol is applicable to a broad range of primary alcohols, particularly for the sterically demanding ones, featuring good functional group tolerance and high selectivity. The good catalytic performance can be attributed to the nitrogen-phosphine-functionalized N-heterocyclic carbene (CNP) ligand, which adopts a facial coordination mode as well as the facile dissociation of coordinated benzene.

Practical Synthesis of (Z)-α,ß-Unsaturated Nitriles via a One-Pot Sequential Hydroformylation/Knoevenagel Reaction.

Herein, the synthesis of (Z)-α,ß-unsaturated nitriles by a sequential hydroformylation/Knoevenagel reaction has been first developed. A variety of crude α-olefins from Fischer-Tropsch synthesis, internal and special olefins, as well as alkynes could be transformed into value-added alkenyl nitriles (39 examples) up to 90% yield. Remarkably, compared with commonly used tedious multistep reactions, the one-pot protocol features cheap and easily available raw materials, excellent chemo-, regio-, and stereoselectivity, very mild reaction conditions, and easy scale-up production.

Iodination/Amidation of the N-Alkyl (Iso)quinolinium Salts.

The NaIO4-mediated sequential iodination/amidation reaction of N-alkyl quinolinium iodide salts has been first developed. This cascade process provides an efficient way to rapidly synthesize 3-iodo-N-alkyl quinolinones with high regioselectivity and good functional group tolerance. This protocol was also amenable to the isoquinolinium salts, thus providing a complementary method for preparing the 4-iodo-N-alkyl isoquinolinones.

Efficient Infrared-Light-Driven CO2 Reduction Over Ultrathin Metallic Ni-doped CoS2 Nanosheets.

Converting CO2 and H2 O into carbon-based fuel by IR light is a tough task. Herein, compared with other single-component photocatalysts, the most efficient IR-light-driven CO2 reduction is achieved by an element-doped ultrathin metallic photocatalyst-Ni-doped CoS2 nanosheets (Ni-CoS2 ). The evolution rate of CH4 over Ni-CoS2 is up to 101.8 µmol g-1 h-1 . The metallic and ultrathin nature endow Ni-CoS2 with excellent IR light absorption ability. The PL spectra and Arrhenius plots indicate that Ni atoms could facilitate the separation of photogenerated carriers and the decrease of the activation energy. Moreover, in situ FTIR, DFT calculations, and CH4 -TPD reveal that the doped Ni atoms in CoS2 could effectively depress the formation energy of the *COOH, *CHO and desorption energy of CH4 . This work manifests that element doping in atomic level is a powerful way to control the reaction intermediates, providing possibilities to realize high-efficiency IR-light-driven CO2 reduction.

The Clinical Significance of miR-135b-5p and Its Role in the Proliferation and Apoptosis of Hippocampus Neurons in Children with Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is the most familiar localized epilepsy in children. MicroRNAs (miRNAs) are essential for the inhibition or promotion of numerous diseases. This study aimed to detect the expression of miR-135b-5p and primarily uncover its underlying function and mechanism in children with TLE. Quantitative real-time polymerase chain reaction was used to evaluate the expression of miR-135b-5p in children with TLE and in a rat model of epilepsy. MTT assay and flow cytometric apoptosis assay were conducted to evaluate the effects of miR-135b-5p on cell viability and apoptosis. Additionally, the dual luciferase reporter assay was performed to confirm the direct target of miR-135b-5p. Our data showed that the expression of miR-135b-5p was significantly decreased in children with TLE and in the epileptic rat neuron model. The dysregulation of miR-135b-5p could serve as a promising diagnostic biomarker for children with TLE. The overexpression of miR-135b-5p moderated the adverse influence on cell viability and apoptosis induced by magnesium-free medium. SIRT1 was identified as a target gene of miR-135b-5p. These results proved that miR-135b-5p might serve as a potential diagnostic biomarker in children with TLE. Overexpression of miR-135b-5p alleviates the postepileptic influence on cell viability and apoptosis by targeting SIRT1.

Palladium-Catalyzed Direct Arylation of Alkylpyridine via Activated N-Methylpyridinium Salts.

An efficient Pd-catalyzed arylation of alkylpyridine based on the pyridinium activation strategy has been developed for synthesis of mixed aryl alkylpyridines. It was found that (1) the N-methyl group in the pyridinium salts acted as a transient activator and could be automatically departed after the reaction, (2) CuBr was an indispensable additive for achieving the C6-selective arylation, (3) the α-branched alkyl chain on the alkylpyridine greatly increased the yield of the product. Deuterium labelling experiment revealed that in the case of the α-branched alkylpyridine, the presence of CuBr completely inhibited the H/D exchange at the benzylic position and thus enabled the selective arylation at the C6 position. This protocol demonstrates a broad substrate scope, and with respect to both the aryl iodides and the α-branched alkylpyridine, the desired mixed aryl alkylpyridines were obtained in generally good to excellent yields.

Ginkgo biloba Extract EGb761 Attenuates Bleomycin-Induced Experimental Pulmonary Fibrosis in Mice by Regulating the Balance of M1/M2 Macrophages and Nuclear Factor Kappa B (NF-κB)-Mediated Cellular Apoptosis.

BACKGROUND The aim of this study was to show whether the standardized Ginkgo biloba extract EGb761, a traditional Chinese medicine, has a therapeutic effect on pulmonary fibrosis (PF). MATERIAL AND METHODS Bleomycin (BLM) was used for establishing the PF mouse model. The mice were treated with a gradient of EGb761 for 28 days to determine an appropriate drug dose. On day 28, the effect of EGb761 on lung injury and inflammation was confirmed by hematoxylin and eosin and Masson staining and evaluated by pulmonary alveolitis and Ashcroft score. The balance of M1/M2 macrophages was evaluated with the respective markers inducible nitric oxide synthase and and interleukin-10 by real-time polymerase chain reaction. Furthermore, the expressions of fibrosis-associated protein alpha-smooth muscle actin (SMA), related inflammatory protein transforming growth factor (TGF)-ß1, the apoptosis-related proteins B-cell lymphoma-associated X protein (Bax), B-cell lymphoma (Bcl)-2, caspase-3, caspase-9, and phosphorylated nuclear factor (NF)-kappaB (p65) were assessed by western blot. RESULTS On day 28, PF was induced by treating with BLM, whereas EGb761 suppressed the PF of lung tissue. The BLM-induced imbalance of M1/M2 macrophages was reduced by EGb761. Furthermore, the increasing amounts of alpha-SMA and TGF-ß1 induced by BLM were suppressed by EGb761. In addition, the protein or messenger ribonucleic acid expression levels of phosphorylated NF-kappaB (p65), caspase-3, and caspase-9 were upregulated, whereas Bax and Bcl-2 were downregulated. Treatment with EGb761 restored the levels of these proteins except for caspase-9. CONCLUSIONS This study illustrated the protective effect of EGb761 on BLM-induced PF by regulating the balance of M1/M2 macrophages and NF-kappaB (p65)-mediated apoptosis. The results demonstrated the potential clinical therapeutic effect of EGb761, providing a novel possibility for curing PF.

Route to Rheumatoid Arthritis by Macrophage-Derived Microvesicle-Coated Nanoparticles.

The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.

The Effect of Transcription Factor MYB14 on Defense Mechanisms in Vitis quinquangularis-Pingyi.

In the current study, we identified a transcription factor, MYB14, from Chinese wild grape, Vitis quinquangularis-Pingyi (V. quinquangularis-PY), which could enhance the main stilbene contents and expression of stilbene biosynthesis genes (StSy/RS) by overexpression of VqMYB14. The promoter of VqMYB14 (pVqMYB14) was shown to be induced as part of both basal immunity (also called pathogen-associated molecular pattern (PAMP)-triggered immunity, PTI) and effector-triggered immunity (ETI), triggered by the elicitors flg22 and harpin, respectively. This was demonstrated by expression of pVqMYB14 in Nicotiana benthamiana and Vitis. We identified sequence differences, notably an 11 bp segment in pVqMYB14 that is important for the PTI/ETI, and particularly for the harpin-induced ETI response. In addition, we showed that activation of the MYB14 promoter correlates with differences in the expression of MYB14 and stilbene pattern induced by flg22 and harpin. An experimental model of upstream signaling in V. quinquangularis-PY is presented, where early defense responses triggered by flg22 and harpin partially overlap, but where the timing and levels differ. This translates into a qualitative difference with respect to patterns of stilbene accumulation.

The transcription factor MYB15 is essential for basal immunity (PTI) in Chinese wild grape.

MAIN CONCLUSION: MYB15 promoter of Vitis quinquangularis has potential as a target for disease resistance breeding, and its involvement in PTI is associated with a range of defense mechanisms. China is a center of origin for Vitis and is home to diverse wild Vitis genotypes, some of which show superior pathogen resistance, although the underlying molecular basis for this has not yet been elucidated. In the current study, we identified a transcription factor, MYB15, from the Chinese wild grape, Vitis quinquangularis, whose promoter region (pVqMYB15) was shown to be induced by basal immunity (also called PAMP-triggered immunity, PTI) triggered by flg22, following heterologous expression in Nicotiana benthamiana and homologous expression in grapevine. By analyzing the promoter structure and activity, we identified a unique 283 bp sequence that plays a key role in the activation of basal immunity. In addition, we showed that activation of the MYB15 promoter correlates with differences in the expression of MYB15 and RESVERATROL SYNTHASE (RS) induced by the flg22 elicitor. We further tested whether the MYB15 induction triggered by flg22 was consistent with MYB15 and RS expression following inoculation with Plasmopara viticola in grape (V. quinquangularis and Vitis vinifera) leaves. Mapping upstream signals, we found that calcium influx, an RboH-dependent oxidative burst, an MAPK cascade, and jasmonate and salicylic acid co-contributed to flg22-triggered pVqMYB15 activation. Our data suggest that the MYB15 promoter has potential as a target for disease resistance breeding, and its involvement in PTI is associated with a range of defense mechanisms.