A pharynx-to-brain axis controls pharyngeal inflammation-induced anxiety.

Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTSNE). These NTSNE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynx→NJP→NTSNE→vBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response.

Adaptive Selection of Cis-regulatory Elements in the Han Chinese.

Cis-regulatory elements have an important role in human adaptation to the living environment. However, the lag in population genomic cohort studies and epigenomic studies, hinders the research in the adaptive analysis of cis-regulatory elements in human populations. In this study, we collected 4,013 unrelated individuals and performed a comprehensive analysis of adaptive selection of genome-wide cis-regulatory elements in the Han Chinese. In total, 12.34% of genomic regions are under the influence of adaptive selection, where 1.00% of enhancers and 2.06% of promoters are under positive selection, and 0.06% of enhancers and 0.02% of promoters are under balancing selection. Gene ontology enrichment analysis of these cis-regulatory elements under adaptive selection reveals that many positive selections in the Han Chinese occur in pathways involved in cell-cell adhesion processes, and many balancing selections are related to immune processes. Two classes of adaptive cis-regulatory elements related to cell adhesion were in-depth analyzed, one is the adaptive enhancers derived from neanderthal introgression, leads to lower hyaluronidase level in skin, and brings better performance on UV-radiation resistance to the Han Chinese. Another one is the cis-regulatory elements regulating wound healing, and the results suggest the positive selection inhibits coagulation and promotes angiogenesis and wound healing in the Han Chinese. Finally, we found that many pathogenic alleles, such as risky alleles of type 2 diabetes or schizophrenia, remain in the population due to the hitchhiking effect of positive selections. Our findings will help deepen our understanding of the adaptive evolution of genome regulation in the Han Chinese.

G4LDB 2.2: a database for discovering and studying G-quadruplex and i-Motif ligands.

Noncanonical nucleic acid structures, such as G-quadruplex (G4) and i-Motif (iM), have attracted increasing research interests because of their unique structural and binding properties, as well as their important biological activities. To date, thousands of small molecules that bind to varying G4/iM structures have been designed, synthesized and tested for diverse chemical and biological uses. Because of the huge potential and increasing research interests on G4-targeting ligands, we launched the first G4 ligand database G4LDB in 2013. Here, we report a new version, termed G4LDB 2.2 (http://www.g4ldb.com), with upgrades in both content and function. Currently, G4LDB2.2 contains >3200 G4/iM ligands, ∼28 500 activity entries and 79 G4-ligand docking models. In addition to G4 ligand library, we have also added a brand new iM ligand library to G4LDB 2.2, providing a comprehensive view of quadruplex nucleic acids. To further enhance user experience, we have also redesigned the user interface and optimized the database structure and retrieval mechanism. With these improvements, we anticipate that G4LDB 2.2 will serve as a comprehensive resource and useful research toolkit for researchers across wide scientific communities and accelerate discovering and validating better binders and drug candidates.

Tandem mass spectrometry (MS/MS) molecular networking guided profiling of small molecules from Aquilaria sinensis (Lour.) Gilg leaves and their bioactivity evaluation.

INTRODUCTION: Agarwood, a fragrant resinous wood mainly formed by Aquilaria spp., is used worldwide as a natural fragrance and traditional medicine. A large amount of Aquilaria sinensis (Lour.) Gilg leaves are underutilised during the process of the agarwood industry, and the development of A. sinensis leaves as tea has recently attracted more and more attention. However, the small molecule profile of A. sinensis leaves and their bioactivities has been rarely reported. OBJECTIVE: To conduct a rapid untargeted liquid chromatography-mass spectrometry (LC-MS) analysis of A. sinensis leaves with a molecular networking (MN) strategy and evaluate its antioxidant and antidiabetic value. METHOD: A MN-assisted tandem mass spectrometry (MS/MS) analysis strategy was used to investigate the small molecule profile of A. sinensis leaves. Additionally, the integration of antioxidant and α-glucosidase inhibitory assays with MN analysis was executed to expeditiously characterise the bioactive compounds for potential prospective application. RESULTS: Five main chemical groups including phenol C-glycosides, organic acids, 2-(2-phenylethyl) chromones, benzophenone O-glycosides and flavonoids were rapidly revealed from the A. sinensis leaves. Eighty-one compounds were provisionally identified by comparing their MS/MS fragments with canonical pathways. The featured xanthone C-glycosides and benzophenone C-glycosides were recognised as the primary components of A. sinensis leaves. Several dimers and a trimer of mangiferin were reported firstly in A. sinensis leaves. Furthermore, 17 and 14 potential bioactive molecules were rapidly annotated from antioxidant and α-glucosidase inhibitory fraction, respectively. CONCLUSION: Our findings will help expand the utilisation of A. sinensis leaves and thus promote the high-quality development of agarwood industry.

A DNA Nano Firework for Imaging and Inhibitor Screening of Flap Endonuclease 1 in Living Cells.

In situ observation of changes in the activity of marker proteins in living cells is crucial for both biomarker-based disease diagnosis and drug screening. Flap endonuclease 1 (FEN1) has been recognized as a broad-spectrum cancer biomarker and therapeutic target. However, simple and reliable methods for in situ studying the FEN1 activity changes in living cells are limited. Here, we introduce a nano firework as a fluorescent sensor to sense and report FEN1 activity changes in living cells through FEN1 recognizing the substrates on the surface of the nano firework to release and restore the fluorescence of the prequenched fluorophores. We verified the high selectivity, anti-interference ability, stability, and quantitative performance of the nano firework in tubes and living cells, respectively. A series of controlled experiments have demonstrated that the nano firework could accurately report changes in FEN1 activity in different cells, enabling "sensors in, results out" in the manner of simple addition to the cell culture medium. Using an in silico molecular docking study and experiments, we also explored the ability of the nano firework for rapid screening of FEN1 inhibitors and found two new candidate compounds myricetrin and neoisoliquritin, which could be used as FEN1 inhibitors for further research. These performances of the nano firework suggest that it can be used in high-throughput screening applications, providing a promising tool for biomarker-based new drug discovery.

Intermolecular Triazene Alkene Cycloaddition via Lewis Base Catalysis: Access to Diverse Trifluoromethylated Pyrazolines.

A novel approach to chemoselective synthesis of biologically important CF3 -subsituted pyrazolines was developed via a Lewis base catalyzed intermolecular triazene cycloaddition reaction of an array of terminal/internal alkenes with CF3 CHN2 . This strategy features a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene, high yields (up to 95 %), wide substrate scope and excellent functional group tolerance (54 examples). Importantly, we preformed scaffold diversification of a panel of known pharmaceuticals, natural products, and bioactive heterocycles to generate the corresponding pyrazoline derivatives with potential broad bioactivities for further development.

Shielding Effects of Aromatic (Indole) Ring for Structural Analysis.

This review provides a critical analysis of shielding effects induced by an aromatic (indole) ring of small molecules mainly including three members of naturally occurring secondary metabolites asterric acid analogs, diketopiperazines (DKPs) possessing an aromatic or an indole ring, and rubrolides. Empirical rules about the shielding effects induced by an aromatic (indole) ring are classified, based on which some 1H NMR chemical shift values in the A-ring and structures of asterric acid analogs are revised, and the relative configurations of some DKPs possessing an indole ring are also assigned or revised. The empirical rules could provide an efficient and convenient method for NMR data analysis and configuration determination for the three members of small molecules mentioned above.

Pd-Catalyzed direct C-H arylation of pyrrolo[1,2-a]quinoxalines.

An efficient Pd-catalyzed direct C-H arylation of pyrrolo[1,2-a]quinoxalines with aryl iodides is described, providing a selective route toward a series of 1-arylated and 1,3-diarylated pyrrolo[1,2-a]quinoxalines in good yields. This method features a broad substrate scope, good functional group tolerance and gram-scale synthesis. Furthermore, the C3-thiocyanation of the arylated product is also achieved. We believe that these novel aryl-substituted pyrrolo [1,2-a]quinoxalines will have a variety of applications in organic synthesis and medicinal chemistry.

Outcomes of adolescent and young patients with hepatocellular carcinoma after curative liver resection: a retrospective study.

BACKGROUND: The risk of HCC is documented to be age-related. The outcomes of young HCC patients on postoperative prognosis are not well understood. The study aims to compare the characteristic differences between adolescent and young (AYA) and non-AYA HCC patients. METHODS: We performed a retrospective analysis of the clinical and pathological findings and the survival of 243 HCC patients who underwent operations between 2007 and 2018. RESULTS: The AYA group had a higher AFP level and a higher prevalence of family history of HCC or other cancers than the non-AYA group (P < 0.01 and P < 0.05). AYA patients had more unfavorable pathological characteristics including bigger lesion size, microvascular invasion, portal vein invasion, and hepatic capsule invasion. They also had a more unfavorable Edmondson grade and less tumor capsule formation (P < 0.01). Age was an independent predictor of survival in HCC patients. AYA patients had poorer disease-free and overall survival than non-AYA patients did (P < 0.01). Patients under 30 years old had an even poorer disease-free survival than those aged 30-40 (P = 0.047). CONCLUSIONS: AYA patients exhibited a higher recurrence rate and disease-related death rate with more unfavorable pathological characteristics. Enhanced follow-up for young HCC patients should be applied.

Morphological and physiological correlates of among- individual variation in basal metabolic rate in two passerine birds.

Basal metabolic rate (BMR) has been shown to be a highly phenotypic flexibility trait within species. A significant proportion of an individual's energy budget is accounted for by BMR, hence among-individual variation in this trait may affect other energetic processes, as well as fitness. In this study, we measured BMR, organ mass, mitochondrial respiration capacities and cytochrome c oxidase (COX) activities in muscle and liver and circulating levels of plasma triiodothyronine (T3) in Chinese bulbuls (Pycnonotus sinensis) and Eurasian tree sparrows (Passer montanus). Our results showed that heart and kidney mass was positively correlated with BMR in Chinese bulbuls, whereas liver and kidney mass was positively correlated with BMR in Eurasian tree sparrows. Regarding metabolic biochemical markers of tissues, state 4 respiration and COX activity in the muscles of the Chinese bulbuls was correlated with BMR, while state 4 respiration in the muscle and liver was correlated with BMR in Eurasian tree sparrows. T3 was significantly and positively correlated with BMR in Chinese bulbuls and Eurasian tree sparrows. Consistent with the above results, our findings suggest that T3 levels play an important role in modulating BMR in Chinese bulbuls and Eurasian tree sparrows. Moreover, individual variation in BMR can be explained partly by morphological and physiological mechanisms.

Box-copper catalyzed cascade asymmetric amidation for chiral exo-methylene aminoindoline derivatives.

Enantioselective copper-catalyzed cascade inter- and intramolecular amidation was achieved between ethynyl benzoxazinanones and α-halohydroxamates in the presence of an indapybox ligand. The one-pot cascade transformation was triggered by the attack of hydroxamates to dipolar copper-allenylidene intermediates, followed by a nucleophilic annulation reaction. Thus, a series of exo-methylene 3-aminoindoline derivatives were obtained in good yields with high enantioselectivities under mild reaction conditions.

Shenfuqiangxin Capsule inhibits apoptosis through mitogen-activated protein kinase signal pathway in rats with cardio-renal syndrome induced by infrarenal aortic-clamping.

OBJECTIVE: To investigate the effect of Shenfuqiangxin capsule and the underlying mechanism on cardio-renal syndrome (CRS) in rats induced by infrarenal aortic-clamping after renal ischaemia. METHODS: Male Wistar rats underwent infrarenal aortic-clamping after renal ischaemia or sham operation. The surviving CRS rats were divided randomly into three groups: CRS group (CRS + 10 mL·kg(-1)· d(-1) pure water by gavage), SFQX group (CRS + 13.2 g crude drug·kg－ 1·d－ 1 Shenfuqiangxin by gavage), and handleregionpeptide(HRP)group(CRS+10mg/kg HRP by vein). Sham operation rats were given 10 mL·kg－1·d－1 pure water. Treatments were given 8 weeks after surgery, which lasted for 4 weeks. The rats were detected for heart structure and function by transthoracic echocardiography. PPR mRNA was detected by Reverse Transcription Polymerase Chain Reaction (RT-PCR). To determine whether the mitogen-activated protein kinase (MAPK) signal pathway is included in the heart and kidney protective function of Shenfuqiangxin capsule, MAPK related proteins such as posophorylated C-Jun amino terminal kinase (p-JNK), posophorylated extracellular signal-regulated kinase ½ (p-ERK1/2), posophorylated p38 (p-p38) were examined by Western Blot. Apoptosis in heart and kidney tissues were detected by dUTP Nick End Labeling staining. RESULTS: Shenfuqiangxin capsule alleviated myocardial apoptosis and inhibited PRR mRNA expression and p-JNK, p-ERK1/2, p-p38 proteins expression in CRS rats. CONCLUSION: All the results suggest that Shenfuqiangxin capsule improves the injured heart and kidney function maybe through inhibition of MAPK response pathway.

The facile synthesis and optical waveguide properties of single-crystal 1,2,3,4,5-pentaphenyl-1,3-cyclopentadiene microrods.

Single-crystalline 1,2,3,4,5-pentaphenyl-1,3-cyclopentadiene (PPCP) microrods were prepared by a facile solution process. The PPCP microrods with smooth surfaces could absorb excitation light and propagate the photoluminescence (PL) emission. They showed excellent properties in the low optical loss of a single rod and feasible transfer between neighboring rods. Moreover, PPCP displayed typical aggregation-induced emission enhancement (AIEE) characteristics in the solution state.

Metal Ions Mediated Morphology and Phase Transformation of Chalcogenide Semiconductor: From CuClSe2 Microribbon to CuSe Nanosheet.

Foreign ions are of significant importance in controlling and modulating the morphology of semiconductor nanocrystals during the colloidal synthesis process. Herein, we demonstrate the potential of foreign metal ions to simultaneously control the morphology and crystal phase of chalcogenide semiconductors. The results indicate that the introduction of Al(3+) ions can induce the structural transformation from monoclinic CuClSe2 microribbons (MRs) to klockmannite CuSe nanosheets (NSs) and the growth of large-sized CuSe NSs. The as-prepared micrometer-sized CuSe NSs exhibit a high-conducting behavior, long-term durability, and environment stability. The novel properties enable CuSe NSs to open up a bright prospect for printable electrical interconnects and flexible electronic devices.

In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.

RATIONALE: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca(2+) channels in the cell membrane/T-tubules and ryanodine receptors in the sarcoplasmic reticulum becomes defective, partially because of the decreased expression of a T-tubule-sarcoplasmic reticulum anchoring protein, junctophilin-2. MicroRNA (miR)-24, a junctophilin-2 suppressing miR, is upregulated in hypertrophied and failing cardiomyocytes. OBJECTIVE: To test whether miR-24 suppression can protect the structural and functional integrity of L-type Ca(2+) channel-ryanodine receptor signaling in hypertrophied cardiomyocytes. METHODS AND RESULTS: In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction, but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in L-type Ca(2+) channel-ryanodine receptor signaling fidelity/efficiency and whole-cell Ca(2+) transients. Further studies showed that antagomir treatment stabilized junctophilin-2 expression and protected the ultrastructure of T-tubule-sarcoplasmic reticulum junctions from disruption. CONCLUSIONS: MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.

Preparation and Optical Waveguiding Property of Single-Crystal Organic NPB Microsheets.

2D microstructures of N,N'-diphenyl-N,N'-bis(1-naphthyl)-1,1'-biphenyl-4,4'-di-amine (NPB) have been prepared by a facile solution method and fully characterized. The as-prepared NPB microsheets have well-defined shapes and very smooth surfaces, and are ideal building blocks for 2D optical waveguides. The results indicate that the optic losses within NPB microsheets are closely related to the direction of propagation, and the shape of microsheets can change the direction of waveguiding light. Such 2D optical waveguides may have potential applications in future miniaturized light-based circuits serve as interconnectors different from 1 D optical waveguides.

Mir-24 regulates junctophilin-2 expression in cardiomyocytes.

RATIONALE: Failing cardiomyocytes exhibit decreased efficiency of excitation-contraction (E-C) coupling. The downregulation of junctophilin-2 (JP2), a protein anchoring the sarcoplasmic reticulum to T-tubules, has been identified as a major mechanism underlying the defective E-C coupling. However, the regulatory mechanism of JP2 remains unknown. OBJECTIVE: To determine whether microRNAs regulate JP2 expression. METHODS AND RESULTS: Bioinformatic analysis predicted 2 potential binding sites of miR-24 in the 3'-untranslated regions of JP2 mRNA. Luciferase assays confirmed that miR-24 suppressed JP2 expression by binding to either of these sites. In the aortic stenosis model, miR-24 was upregulated in failing cardiomyocytes. Adenovirus-directed overexpression of miR-24 in cardiomyocytes decreased JP2 expression and reduced Ca(2+) transient amplitude and E-C coupling gain. CONCLUSIONS: MiR-24-mediated suppression of JP2 expression provides a novel molecular mechanism for E-C coupling regulation in heart cells and suggests a new target against heart failure.

Preparation of cocrystal nanofibres of cobalt octaethylporphyrin and tetracyanoquinodimethane with good photoresponse.

Cocrystal nanofibres of cobalt octaethylporphyrin and tetracyanoquinodimethane were prepared by a facile solution method and fully characterized by SEM, AFM, XRD, Raman, EDX, and UV-vis-NIR. The as-prepared cocrystal nanofibres had smooth surfaces and uniform dimension. When incorporated into prototype devices, they exhibited good photoresponse at ambient conditions. Additionally, the phototransistor characteristics with a maximum I(on)/I(off) ratio of -460 was demonstrated. The facile synthesis and good photoresponse may boost the potential applications of cocrystal-based nanostructures in future miniaturized devices.

FTIR determination of the degree of molar substitution for hydroxypropyl chitosan.

We developed and validated a novel Fourier transform infrared (FTIR) method to determine the degree of molar substitution (MS) for hydroxypropyl chitosan (HPCS) using nuclear magnetic resonance (1H NMR) as a reference, and investigated the factors influencing the MS assay. Through extensive screening of integration methods for candidate bands in the FTIR spectrum of HPCS using 20 HPCS samples with degrees of acetylation (DA) ranging from 0.003 to 0.139, we found that when using band area at 2970 cm-1 as a probe integral, the MS values obtained via the 1H NMR method exhibited linear correlations (R2 > 0.98) with at least 16 integral ratios derived from their FTIR spectra. The optimal reference bands with high reliability are located at 3440 cm-1 and 1415 cm-1, with R2 exceeding 0.99 and a MS range of 0.17-1.92. The band at 2875 cm-1 is less affected by the trace moisture present in HPCS samples than the others. The results of the method validation demonstrated a mean recovery of 98.9 ± 2.8 % and an RSD below 10 %, suggesting a simple, robust, and highly accurate and precise method. This method could be extendable for the determination of the MS of insoluble HPCS derivatives and other hydroxypropylated polysaccharides.

Graded diagnosis of Helicobacter pylori infection using hyperspectral images of gastric juice.

Helicobacter pylori is a potential underlying cause of many diseases. Although the Carbon 13 breath test is considered the gold standard for detection, it is high cost and low public accessibility in certain areas limit its widespread use. In this study, we sought to use machine learning and deep learning algorithm models to classify and diagnose H. pylori infection status. We used hyperspectral imaging system to gather gastric juice images and then retrieved spectral feature information between 400 and 1000 nm. Two different data processing methods were employed, resulting in the establishment of one-dimensional (1D) and two-dimensional (2D) datasets. In the binary classification task, the random forest model achieved a prediction accuracy of 83.27% when learning features from 1D data, with a specificity of 84.56% and a sensitivity of 92.31%. In the ternary classification task, the ResNet model learned from 2D data and achieved a classification accuracy of 91.48%.