Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.

METTL14 promotes IL-6-induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27.

Interleukin-6 (IL-6) is a cytokine generated by healthy constituents of the skin, but is also up-regulated by a wide range of skin lesions and inflammatory conditions to trigger cytopathy of skin cells. TRIM27 was identified to contribute to the functional effects of IL-6 on skin cells. However, the underlying mechanism was not clear. Lentivirus infection was used for gene overexpression or silencing. RT-PCR and Western blot were used to respectively assess mRNA and protein levels. Cell viability was assessed by CCK-8 assay. Extracellular flux analysis was used to assess the levels of oxygen consumption rate and extracellular acidification rate. Mouse back skin was treated with imiquimod to produce psoriasis-like inflammation in vivo. Histological assessment and immunohistochemistry staining were respectively applied to analyse lesioned mouse and human skin samples. IL-6-induced increased viability, glycolysis and inflammation in keratinocytes was inhibited both by a chemical methylation inhibitor and by METTL14 knockdown. Further investigation found that METTL14 induces m6A methylation of TRIM27, which is recognized by a m6A reader, IGF2BP2. Elevation of TRIM27 level and activation of IL-6/STAT3 signalling pathway were found in an in vivo psoriasis-like inflammation model, whereas inhibition m6A methylation strongly alleviated the inflammation. Finally, METTL14, TRIM27, STAT3, p-STAT3 and IL-6 expressions were all found to be increased in clinical skin samples of psoriatic patients. Our results unravelled METTL14/TRIM27/IGF2BP2 signalling axis in keratinocyte cytopathy, which plays a critical role in facilitating the activation of IL-6/STAT3 signalling pathway. Our findings should provide inspirations for the design of new therapeutics for skin inflammatory diseases including psoriasis.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

Identification of a novel m6A-related lncRNAs signature and immunotherapeutic drug sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related with poor prognosis and immunotherapeutic effect in PDAC. The aim of this study is to construct and validate a m6A-related lncRNAs signature and assess immunotherapeutic drug sensitivity in PDAC. METHODS: RNA-seq data for 178 cases of PDAC patients and 167 cases of normal pancreatic tissue were obtained from TCGA and GTEx databases, respectively. A set of 21 m6A-related genes were downloaded based on the previous report. Co-expression network was conducted to identify m6A-related lncRNAs in PDAC. Cox analyses and least absolute shrinkage and selection operator (Lasso) regression model were used to construct a risk prognosis model. The relationship between signature genes and immune function was explored by single-sample GSEA (ssGSEA). The tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB) were utilized to evaluate the response to immunotherapy. Furthermore, the expression levels of 4 m6A-related lncRNAs on PDAC cell lines were measured by the quantitative real-time PCR (qPCR). The drug sensitivity between the high- and low-risk groups was validated using PDAC cell lines by Cell-Counting Kit 8 (CCK8). RESULTS: The risk prognosis model was successfully constructed based on 4 m6A-related lncRNAs, and PDAC patients were divided into the high- and low-risk groups. The overall survival (OS) of the high-risk groups was more unfavorable compared with the low-risk groups. Receiver operating characteristic (ROC) curves demonstrated that the risk prognosis model reasonably predicted the 2-, 3- and 5-year OS of PDAC patients. qPCR analysis confirmed the decreased expression levels of 4 m6A-related lncRNAs in PDAC cells compared to the normal pancreatic cells. Furthermore, CCK8 assay revealed that Phenformin exhibited higher sensitivity in the high-risk groups, while Pyrimethamine exhibited higher sensitivity in the low-risk groups. CONCLUSION: The prognosis of patients with PDAC were well predicted in the risk prognosis model based on m6A-related lncRNAs, and selected immunotherapy drugs have potential values for the treatment of pancreatic cancer.

Versatile GO/ANFs Aerogel for Highly Efficient Solar-Powered Water Purification in Wide Environments.

Solar-driven interfacial evaporation is a very promising choice for producing clean water. Despite the considerable investigation of pure NaCl brine purification, solar-driven complex water purification, such as real-world seawater desalination as well as domestic and industrial wastewater treatment, has rarely been investigated, mainly due to its compositions being much more complicated than NaCl brine. Herein, we developed a graphene oxide/aramid nanofiber (GO/ANFs) aerogel by a freeze-drying process. The GO/ANFs aerogel combined opened porous microchannels, superhydrophilicity, anti-oil-fouling capacity, enhanced broad-spectrum light absorption (more than 92%), and good solar/heat management. These integrated properties enabled the GO/ANFs aerogel to be an advanced solar interfacial evaporator for efficient freshwater production with the characteristics of localized heat conversion, quick water transport, and salt crystallization inhibition, and the rate of steam production rate was as high as 2.25 kg m-2 h-1 upon exposure to 1 solar irradiation. Importantly, the high-water-vapor generation rate was maintained even under complicated conditions, including real-world seawater, dye water, emulsions, and corrosive liquid environments. Considering its promising adaptability to a wide range of environments, this work hopes to inspire the development of brine desalination, wastewater purification, clean water production, and solar energy utilization.

Mechanical Robust GO/PVA Hydrogel for Strong and Recyclable Adhesion in Air, Underwater, and Underoil Environments.

Adhesive hydrogels are considered to be promising interfacial adhesive materials for various applications; however, their adhesive strength is significantly reduced when immersed in liquid environments (water and oil) due to obstruction of the liquid layer or swelling in liquid, and they could not always be reused when the failure of the adhesive performance occurred. Herein, a graphite oxide/poly(vinyl alcohol) (GO/PVA) hydrogel with strong adhesion in air and under liquid environments was developed by rationally regulating the interactions of water and dimethyl sulfoxide (DMSO) in the binary liquid system. The strong interaction between water and DMSO allowed the water layer of the GO/PVA hydrogel on the hydrogel surface to act as a shield to repel oil in air, under water, and even when immersed in oil, and it also endowed the obtained hydrogel with antiswelling property when immersed in water and oil. Importantly, the GO/PVA hydrogel could serve as an advanced adhesive to firmly bond different substrates in air, under water, and under oil, and interestingly, its dry and wet adhesive performance was repeatable and recyclable. This work is expected to be an important addition to the field of adhesive soft materials.

Characterisation of a casein-/whey protein concentrate-Antarctic krill oil emulsion system and improvement of its storage stability.

AIMS: To develop Antarctic krill oil emulsions with casein and whey protein concentrate (WPC) and study their physicochemical properties and storage stability. METHODS: Emulsions were prepared by homogenisation and ultrasonication. The properties of the emulsions were investigated via ultraviolet ray spectroscopy, dynamic light scattering, confocal laser scanning microscope, sodium dodecyl sulphate-polyacrylamide gel electrophoresis, Fourier transform infra-red spectrometer, and fluorescence spectrum. Shelf life was predicted by the Arrhenius model. RESULTS: Casein- and WPC-krill oil emulsions were well formed; the mean particle diameters were less than 128.19 ± 0.64 nm and 158 ± 1.56 nm, the polymer dispersity indices were less than 0.26 ± 0.01 and 0.27 ± 0.01, and the zeta potential were around -46.88 ± 5.02 mV and -33.51 ± 2.68 mV, respectively. Shelf life was predicted to be 32.67 ± 1.55 days and 29.62 ± 0.65 days (40 °C), 27.69 ± 1.15 days and 23.58 ± 0.14 days (50 °C), 24.02 ± 0.15 days and 20.1 ± 0.08 days (60 °C). CONCLUSION: The prepared krill oil emulsions have great potential to become a new krill oil supplement.

Simple and Rapid Way to a Multifunctionally Conductive Hydrogel for Wearable Strain Sensors.

Conductive hydrogels have gained increasing attention in the field of wearable smart devices. However, it remains a big challenge to develop a multifunctionally conductive hydrogel in a rapid and facile way. Herein, a conductive tannic acid-iron/poly (acrylic acid) hydrogel was synthesized within 30 s at ambient temperature by the tannic acid-iron (TA@Fe3+)-mediated dynamic catalytic system. The TA@Fe3+ dynamic redox autocatalytic pair could efficiently activate the ammonium persulfate to initiate the free-radical polymerization, allowing the gelation to occur easily and rapidly. The resulting hydrogel exhibited enhanced stretchability (3560%), conductivity (33.58 S/m), and strain sensitivity (gauge factor = 2.11). When damaged, it could be self-healed through the dynamic and reversible coordination bonds between the Fe3+ and COO- groups in the hydrogel network. Interestingly, the resulting hydrogel could act as a strain sensor to monitor various human motions including the huge movement of deformations (knuckle, wrist) and subtle motions (smiling, breathing) in real time due to its enhanced self-adhesion, good conductivity, and improved strain sensitivity. Also, the obtained hydrogel exhibited efficient electromagnetic interference (EMI) shielding performance with an EMI shielding effectiveness value of 24.5 dB in the X-band (8.2-12.4 GHz). Additionally, it displayed antibacterial properties, with the help of the activity of TA.

Design of an interface heating device based on polydivinylbenzene/SiO2/Bi2WO6 and its visible light response performance for water purification.

Environmental pollution and the shortage of drinking water are the challenges that mankind is facing. Solar interface evaporation technology has been demonstrated as an important method for producing clean water, but its application to sewage still faces problems, mainly manifested in solubility and oily pollutants. Therefore, an evaporator device contains a superhydrophobic Bi2WO6 felt floating layer, a filter paper hydrophilic layer, and a copper foam/CuO photothermal layer, of which the water contact angle of the superhydrophobic felt can reach 159°. The floating layer not only has the ability to adsorb n-hexane but the Rh B degradation can also be realized under indoor/outdoor light conditions. The carrier life of Bi2WO6 is 28.8 ns. A copper foam/CuO photothermal layer prepared through a low-temperature treatment is combined with the floating and hydrophilic layer to obtain an evaporation rate of 1.53 kg m-2 h-1.

Heterostructured α-Fe2 O3 @ZnO@ZIF-8 Core-Shell Nanowires for a Highly Selective MEMS-Based ppb-Level H2 S Gas Sensor System.

Highly selective and sensitive H2 S sensors are in high demand in various fields closely related to human life. However, metal oxide semiconductors (MOSs) suffer from poor selectivity and single MOS@metal organic framework (MOF) core-shell nanocomposites are greatly limited due to the intrinsic low sensitivity of MOF shells. To simultaneously improve both selectivity and sensitivity, heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell nanowires (NWs) are meticulously synthesized with the assistance of atomic layer deposition. The ZIF-8 shell with regular pores and special surface functional groups is attractive for excellent selectivity and the heterostructured α-Fe2 O3 @ZnO core with an additional electron depletion layer is promising with enhanced sensitivity compared to a single MOS core. As a result, the heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell NWs achieve remarkable H2 S sensing performance with a high response (Rair /Rgas  = 32.2 to 10 ppm H2 S), superior selectivity, fast response/recovery speed (18.0/31.8 s), excellent long-term stability (at least over 3 months), and relatively low limit of detection (down to 200 ppb) at low operating temperature of 200 °C, far beyond α-Fe2 O3 @ZIF-8 or α-Fe2 O3 @ZnO core-shell NWs. Furthermore, a micro-electromechanical system-based H2 S gas sensor system with low power consumption is developed, holding great application potential in smart cities.

Synthesis of 4-Tetrazolyl-Substituted 3,4-Dihydroquinazoline Derivatives with Anticancer Activity via a One-Pot Sequential Ugi-Azide/Palladium-Catalyzed Azide-Isocyanide Cross-Coupling/Cyclization Reaction.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.

Iodine-catalyzed oxidative annulation: facile synthesis of pyrazolooxepinopyrazolones via methyl azaarene sp3 C-H functionalization.

An iodine-catalyzed methyl azaarene sp3 C-H functionalization has been developed for the synthesis of a seven-membered O-heterocyclic architecture containing three different heterocyclic aromatic hydrocarbons. This method can be applied to a wide range of substituted methyl azaarenes and diverse 2,4-dihydro-3H-pyrazol-3-ones, and brings about the efficient preparation of 2,9-dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(7H)-ones in high yields with the merits of low catalyst loading, good functional group tolerance and metal-free conditions.

Risk factors for the mortality of hemodialysis patients with COVID-19: A multicenter study from the overall hemodialysis population in Wuhan.

INTRODUCTION: Maintenance hemodialysis (MHD) patients are highly threatened in the novel coronavirus disease 2019 (COVID-19) pandemic, but evidence of risk factors for mortality in this population is still lacking. METHODS: We followed outcomes of the overall MHD population of Wuhan, including 7154 MHD patients from 65 hemodialysis centers, from January 1 to May 4, 2020. Among them, 130 were diagnosed with COVID-19. The demographic and clinical data of them were collected and compared between survivors and nonsurvivors. RESULTS: Compared to the corresponding period of last year, the all-cause mortality rate of the Wuhan MHD population significantly rose in February, and dropped down in March 2020. Of the 130 COVID-19 cases, 51 (39.2%) were deceased. Advanced age, decreased oxygen saturation, low diastolic blood pressure (DBP) on admission, and complications including acute cardiac injury (HR 5.03 [95% CI 2.21-11.14], p < 0.001), cerebrovascular event (HR 2.80 [95% CI 1.14-6.86], p = 0.025) and acute respiratory distress syndrome (HR 3.50 [95% CI 1.63-7.51], p = 0.001) were identified as independent risk factors for the death of COVID-19. The median virus shedding period of survivors was 25 days, longer than the general population. CONCLUSIONS: Maintenance hemodialysis patients are a highly vulnerable population at increased risk of mortality and prolonged virus shedding period in the ongoing COVID-19 pandemic. Advanced age, decreased oxygen saturation, low DBP on admission, and complications like acute cardiac injury are parameters independently associated with poor prognosis.

Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2.

Acute lung injury (ALI) is a sudden onset systemic inflammatory response. ALI causes severe morbidity and death and currently no effective pharmacological therapies exist. Natural products represent an excellent resource for discovering new drugs. Screening anti-inflammatory compounds from the natural product bank may offer viable candidates for molecular-based therapies for ALI. In this study, 165 natural compounds were screened for anti-inflammatory activity in lipopolysaccharide (LPS)-challenged macrophages. Among the screened compounds, flavokawain B (FKB) significantly reduced LPS-induced pro-inflammatory IL-6 secretion in macrophages. FKB also reduced the formation of LPS/TLR4/MD2 complex by competitively binding to MD2, suppressing downstream MAPK and NF-κB signaling activation. Finally, FKB treatment of mice reduced LPS-induced lung injury, systemic and local inflammatory cytokine production, and macrophage infiltration in lungs. These protective activities manifested as increased survival in the ALI model, and reduced mortality upon bacterial infection. In summary, we demonstrate that the natural product FKB protects against LPS-induced lung injury and sepsis by interacting with MD2 and inhibiting inflammatory responses. FKB may potentially serve as a therapeutic option for the treatment of ALI.

Using pre-operative radiomics to predict microvascular invasion of hepatocellular carcinoma based on Gd-EOB-DTPA enhanced MRI.

OBJECTIVES: We aimed to investigate the value of performing gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) radiomics for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) based on multiple sequences. METHODS: We randomly allocated 165 patients with HCC who underwent partial hepatectomy to training and validation sets. Stepwise regression and the least absolute shrinkage and selection operator algorithm were used to select significant variables. A clinicoradiological model, radiomics model, and combined model were constructed using multivariate logistic regression. The performance of the models was evaluated, and a nomogram risk-prediction model was built based on the combined model. A concordance index and calibration curve were used to evaluate the discrimination and calibration of the nomogram model. RESULTS: The tumour margin, peritumoural hypointensity, and seven radiomics features were selected to build the combined model. The combined model outperformed the radiomics model and the clinicoradiological model and had the highest sensitivity (90.89%) in the validation set. The areas under the receiver operating characteristic curve were 0.826, 0.755, and 0.708 for the combined, radiomics, and clinicoradiological models, respectively. The nomogram model based on the combined model exhibited good discrimination (concordance index = 0.79) and calibration. CONCLUSIONS: The combined model based on radiomics features of Gd-EOB-DTPA enhanced MRI, tumour margin, and peritumoural hypointensity was valuable for predicting HCC microvascular invasion. The nomogram based on the combined model can intuitively show the probabilities of MVI.

Association Between Acoustic Features and Neuropsychological Test Performance in the Framingham Heart Study: Observational Study.

BACKGROUND: Human voice has increasingly been recognized as an effective indicator for the detection of cognitive disorders. However, the association of acoustic features with specific cognitive functions and mild cognitive impairment (MCI) has yet to be evaluated in a large community-based population. OBJECTIVE: This study aimed to investigate the association between acoustic features and neuropsychological (NP) tests across multiple cognitive domains and evaluate the added predictive power of acoustic composite scores for the classification of MCI. METHODS: This study included participants without dementia from the Framingham Heart Study, a large community-based cohort with longitudinal surveillance for incident dementia. For each participant, 65 low-level acoustic descriptors were derived from voice recordings of NP test administration. The associations between individual acoustic descriptors and 18 NP tests were assessed with linear mixed-effect models adjusted for age, sex, and education. Acoustic composite scores were then built by combining acoustic features significantly associated with NP tests. The added prediction power of acoustic composite scores for prevalent and incident MCI was also evaluated. RESULTS: The study included 7874 voice recordings from 4950 participants (age: mean 62, SD 14 years; 4336/7874, 55.07% women), of whom 453 were diagnosed with MCI. In all, 8 NP tests were associated with more than 15 acoustic features after adjusting for multiple testing. Additionally, 4 of the acoustic composite scores were significantly associated with prevalent MCI and 7 were associated with incident MCI. The acoustic composite scores can increase the area under the curve of the baseline model for MCI prediction from 0.712 to 0.755. CONCLUSIONS: Multiple acoustic features are significantly associated with NP test performance and MCI, which can potentially be used as digital biomarkers for early cognitive impairment monitoring.

The determination of monosaccharide in different years Qingzhuan Dark Tea polysaccharide by liquid chromatography-mass spectrometry.

AIM: To establish a fast, sensitive and accurate high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for determining the monosaccharide content of Qingzhuan Dark Tea polysaccharides in different years (2 years, 5 years and 11 years). METHODS: The optimised chromatographic conditions were achieved on a C18 column (5.0 µm, 250 mm × 4.6 mm inner diameter). The mobile phase flow rate was 0.9 mL/min and the column temperature was set to 27°C. The aqueous phase A (5 mM aqueous ammonium acetate) and organic phase B (acetonitrile) were used to elute the target analyses isocratically (0-60 min: 18% B). The mass spectrometer detector was equipped with an electron spray ionisation (ESI)source, and multiple reaction monitoring (MRM) mode was used for the determination of 1-phenyl-3-methyl-5-pyrazolone (PMP) derived monosaccharides. RESULTS: We carried out a comprehensive methodological validation of PMP derived monosaccharides, including linearity, precision, stability and repeatability. Nine monosaccharides (rhamnose, mannose, ribose, glucose, galacturonic acid, xylose, galactose, fucose and arabinose) of Qingzhuan Dark Tea polysaccharides were identified, in which ribose and fucose were reported for the first time. The results showed the contents of these nine monosaccharides differed significantly among different years. CONCLUSIONS: The validated method is reliable, accurate, repeatable and can be applied to quality assessment of these monosaccharides.

Synthesis of Diversified Pyrazolo[3,4-b]pyridine Frameworks from 5-Aminopyrazoles and Alkynyl Aldehydes via Switchable C≡C Bond Activation Approaches.

A cascade 6-endo-dig cyclization reaction was developed for the switchable synthesis of halogen and non-halogen-functionalized pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and alkynyl aldehydes via C≡C bond activation with silver, iodine, or NBS. In addition to its wide substrate scope, the reaction showed good functional group tolerance as well as excellent regional selectivity. This new protocol manipulated three natural products, and the arylation, alkynylation, alkenylation, and selenization of iodine-functionalized products. These reactions demonstrated the potential applications of this new method.

Transcriptome analysis reveals the early resistance of zebrafish larvae to oxidative stress.

Oxidative stress is one of most common environmental stresses encountered by fish, especially during their fragile larval stage. More and more studies are aimed at understanding the antioxidant defense mechanism of fish larvae. Herein we characterized the early resistance of zebrafish larvae to oxidative stress and investigated the underlying transcriptional regulations using RNA-seq. We found that pre-exposure of zebrafish larvae to 2 mM H2O2 for 1 or 3 h significantly improved their survival under higher doses of H2O2 (3 mM), suggesting the antioxidant defenses of zebrafish larvae were rapidly built under pre-exposure of H2O2. Comparative transcriptome analysis showed that 310 (185 up and 125 down) and 512 (331 up and 181 down) differentially expressed genes were generated after 1 and 3 h of pre-exposure, respectively. KEGG enrichment analysis revealed that protein processing in endoplasmic reticulum is a highly enriched pathway; multiple genes (e.g., hsp70.1, hsp70.2, and hsp90aa1.2) encoding heat shock proteins in this pathway were sharply upregulated presumably to correct protein misfolding and maintaining the cellular normal functions during oxidative stress. More importantly, the Keap1/Nrf2 system-mediated detoxification enzyme system was significantly activated, which regulates the upregulation of target genes (e.g., gstp1, gsr, and prdx1) to scavenger reactive oxygen species, thereby defending against apoptosis. In addition, the MAPK, as a transmitter of stress signals, was activated, which may play an important role in activating antioxidant system in the early stages of oxidative stress. Altogether, these findings demonstrate that zebrafish larvae rapidly establish resistance to oxidative stress, and this involves changes in protein processing, stress signal transmission, and the activation of detoxification pathways.

[Combination characteristics of frankincense and myrrh and progress and prospect of their combination efficacy and mechanism].

Herbal pair is formed based on the experience summary of doctors' deep understanding and perception of the medicinal nature in long-term clinical practice. It gradually becomes the exquisite structural unit for preparing traditional Chinese medicine(TCM) prescriptions, and often plays a core bridge role in the prescription combination. Frankincense and myrrh are raw resin materials of incense abroad, which are subsequently included as Chinese medicinal herbs and endowed with rich medicinal connotation. With the functions of relaxing Zang-fu organs, activating blood and relieving pain, they have definite clinical efficacy. From the perspective of herbal description and clinical application, this study systematically analyzed the combination of frankincense and myrrh as well as their combination proportion, efficacy characterization, diseases and syndromes, effective components and action mechanism. On this basis, the focus of in-depth research of frankincense-myrrh and the application prospects were proposed, in order to further reveal the potential meditation law of this herbal pair, thus contributing to clinical practice and drug innovation of traditional Chinese medicine, and providing reference for understanding of TCM medicinal nature and research of herbal pairs.