Cooperative Rh/Achiral Phosphoric Acid-Enabled [3+3] Cycloannulation of Carbonyl Ylides with Quinone Monoimines: Synthesis of Benzofused Dioxabicyclo[3.2.1]octane Scaffolds.

A cooperative Rh/achiral phosphoric acid-enabled [3+3] cycloaddition of in situ-generated carbonyl ylides with quinone monoimines has been developed. With the ability to build up the molecular complexity rapidly and efficiently, this method furnishes highly functionalized oxa-bridged benzofused dioxabicyclo[3.2.1]octane scaffolds bearing two quaternary centers in good to excellent yields under mild conditions. Moreover, the utility of the current method was demonstrated by gram-scale synthesis and elaboration of the products into various functionalized oxa-bridged heterocycles.

Neurofilament light is a novel biomarker for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a complicated maternally inherited disorder lacking of sensitive and specific biomarkers. The objective of this study was to investigate the serum neurofilament light chain (NfL) as a novel biomarker of neurological dysfunction in MELAS. Patients with different status of MELAS were enrolled in this study. The Mini-Mental State Examination (MMSE) was given to the participants to evaluate cognition status. Multiple functional MRI was performed on the participants. Blood samples were collected and the serum NfL concentrations were determined by the single-molecule array technology (Simoa). This study enrolled 23 patients with MELAS, 15 people in the acute attack phase of MELAS and 10 people in the remission phase, including 2 patients in both acute attack and remission phase. Sixteen healthy controls (HCs) were also enrolled. Serum NfL level increased significantly in patients with MELAS. Serum NfL level in the acute attack group (146.73 [120.91-411.31] pg/ml, median [IQR]) was higher than in the remission group (40.31 [19.54-151.05] pg/ml, median [IQR]) and HCs group (7.70 [6.13-9.78] pg/ml, median [IQR]) (p < 0.05). The level of NfL in the remission phase group was higher than in HCs group (p < 0.05). A negative correlation was found between the serum NfL level and MMSE (p = 0.006, r = -0.650). The NfL concentration correlated positively with stroke-like lesion volume in the brain (r = 0.740, p < 0.001). Serum NfL may serve as a novel biomarker for the neurological dysfunction in MELAS patients.

Diagnostic performance of convolutional neural network-based Tanner-Whitehouse 3 bone age assessment system.

BACKGROUND: Bone age can reflect the true growth and development status of a child; thus, it plays a critical role in evaluating growth and endocrine disorders. This study established and validated an optimized Tanner-Whitehouse 3 artificial intelligence (TW3-AI) bone age assessment (BAA) system based on a convolutional neural network (CNN). METHODS: A data set of 9,059 clinical radiographs of the left hand was obtained from the picture archives and communication systems (PACS) between January 2012 and December 2016. Among these, 8,005/9,059 (88%) samples were treated as the training set for model implementation, 804/9,059 (9%) samples as the validation set for parameters optimization, and the remaining 250/9,059 (3%) samples were used to verify the accuracy and reliability of the model compared to that of 4 experienced endocrinologists and 2 experienced radiologists. The overall variation of TW3-metacarpophalangeal, radius, ulna and short bones (RUS) and TW3-Carpal bone score, as well as each bone (13 RUS + 7 Carpal) between reviewers and the AI, were compared by Bland-Altman (BA) chart and Kappa test, respectively. Furthermore, the time consumption between the model and reviewers was also compared. RESULTS: The performance of TW3-AI model was highly consistent with the reviewers' overall estimation, and the root mean square (RMS) was 0.50 years. The accuracy of the BAA of the TW3-AI model was better than the estimate of the reviewers. Further analysis revealed that human interpretations of the male capitate, hamate, the first distal and fifth middle phalanx and female capitate, the trapezoid, and the third and fifth middle phalanx, were most inconsistent. The average image processing time was 1.5±0.2 s in the TW3-AI model, which was significantly shorter than manual interpretation. CONCLUSIONS: The diagnostic performance of CNN-based TW3 BAA was accurate and timesaving, and possesses better stability compared to diagnostics made by experienced experts.

Xylaridines C and D, Unusual Thiopyranodipyridine Alkaloids from the Fungus Xylaria longipes.

Structurally unique thiopyranodipyridine alkaloids xylaridines C (1) and D (2) were isolated from the fungus Xylaria longipes. Their structures were established by comprehensive spectroscopic analysis combined with single-crystal X-ray diffraction and electron-capture detection (ECD) calculations. Compound 1 possesses two piperidine moieties fused with a centered thiopyran ring, while compound 2 is a dimer of 1. Compound 1 was resoluted into optical pure enatiomers (+)-1 and (-)-1 by chiral HPLC. Moreover, compound 2 was resoluted into an optically pure compound (+)-2 and a mixture of (-)-2 and meso-2. Plausible biosynthetic pathways of compounds 1 and 2 are proposed.

Cytotoxic 19,20-epoxycytochalasans from endophytic fungus Xylaria cf. curta.

Nine new 19,20-epoxycytochalasans (1-9) were isolated from the rice fermentation extracts of endophytic fungus Xylaria cf. curta, along with four known compounds 19,20-epoxycytochalasin C (10), 18-desoxy-19,20-epoxycytochalasin C (11), 19,20-epoxycytochalasin D (12) and 5,6-dihydro-7-oxo-19,20-epoxycytochalasin C (13). Their structures and absolute configurations were determined by 1D and 2D NMR, HRESIMS, X-ray diffraction and ECD calculation. The cytotoxicity of obtained compounds (1-13) was evaluated against human cancer cell lines HL-60, A549, SMMC-7721, MCF-7, and SW480. Remarkably, compound 10 showed significant specific cytotoxicity against HL-60 cell lines with IC50 value of 1.11 µM.

(±)-Xylaridines A and B, Highly Conjugated Alkaloids from the Fungus Xylaria longipes.

Two highly conjugated alkaloids xylaridines A (1) and B (2) were obtained as racemates from the fungus Xylaria longipes. They were resoluted into optically pure enantiomers, respectively. Their structures were determined by extensive spectroscopic analyses, X-ray diffraction, and equivalent circulating density (ECD) calculations. Compound 1 possesses a 5/6/6/5/5 fused ring system with unique 2-azaspiro[4.4]nonane substructure. The hypothesis of biosynthesis pathways for 1 and 2 was proposed.

Cytochalasans from the Endophytic Fungus Xylaria cf. curta with Resistance Reversal Activity against Fluconazole-Resistant Candida albicans.

Curtachalasins C-E (1-3), which have an unprecedent bridged 6/6/6/6 ring system, were identified from the endophytic fungus Xylaria cf. curta. Residual dipolar coupling analyses associating with density functional theory calculations were utilized to determine the relative configuration of noncrystallizable compound 2. The absolute configurations of 1-3 were determined by X-ray diffraction and electronic circular dichroism calculations. Remarkably, curtachalasin C (1) showed significant resistance reversal activity against fluconazole-resistant Candida albicans.

Tricholopardins A and B, Anti-inflammatory Terpenoids from the Fruiting Bodies of Tricholoma pardinum.

Two new Tricholoma terpenoids, tricholopardins A and B, were isolated from the fruiting bodies of the basidiomycetes Tricholoma pardinum. Their structures were elucidated by spectroscopic methods, as well as electronic circular dichroism and optical rotatory dispersion calculations. Tricholopardin A potently inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with an IC50 of 0.08 µM. Its anti-inflammatory effects on three inflammatory mediators were also evaluated. A plausible biosynthetic pathway for these products is discussed.

Ophiorrhines A and B, Two Immunosuppressive Monoterpenoid Indole Alkaloids from Ophiorrhiza japonica.

Two monoterpenoid indole alkaloids, ophiorrhines A (1) and B (2), were obtained from plant Ophiorrhiza japonica BI. Their structures were elucidated by extensive spectroscopic methods and single crystal X-ray diffraction. Compounds 1 and 2 possess a novel spirocyclic ring system. Its biosynthesis pathway is proposed. Compound 2 exhibits potent inhibitory activity against concanavalin A (Con A) induced T cell proliferation and lipopolysaccharide (LPS) induced B lymphocyte cell proliferation with IC50 values 13.3 and 7.5 µM, respectively. Compound 1 exhibits significant inhibition specifically against the LPS-induced proliferation of B lymphocyte cells with IC50 value 18.6 µM.

Trichothecrotocins A-C, Antiphytopathogenic Agents from Potato Endophytic Fungus Trichothecium crotocinigenum.

Two trichothecene sesquiterpenoids, trichothecrotocins A (1) and B (2), and a merosesquiterpenoid racemate, (±)-trichothecrotocin C (3), were obtained from potato endophytic fungus Trichothecium crotocinigenum by bioguided isolation. Their structures were elucidated by extensive spectroscopic methods, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Compounds 1 and 2 are trichothecenes possessing new ring systems. Compound 3 possesses a novel 6/6-5/5/5 fused ring system. Compounds 1-3 showed antiphytopathogenic activities with MIC values of 8-128 µg/mL.

Accessing benzooxadiazepines via formal [4 + 3] cycloadditions of aza-o-quinone methides with nitrones.

An unprecedented and efficient [4 + 3] cycloaddition of N-(ortho-chloromethyl)aryl amides with nitrones has been developed. This approach provides easy access to a series of seven-membered benzooxadiazepine derivatives in good to excellent yields (up to 99% yield) under mild reaction conditions.

Identification of interacting proteins of the TaFVE protein involved in spike development in bread wheat.

WD-40 repeat-containing protein MSI4 (FVE)/MSI4 plays important roles in determining flowering time in Arabidopsis. However, its function is unexplored in wheat. In the present study, coimmunoprecipitation and nanoscale liquid chromatography coupled to MS/MS were used to identify FVE in wheat (TaFVE)-interacting or associated proteins. Altogether 89 differentially expressed proteins showed the same downregulated expression trends as TaFVE in wheat line 5660M. Among them, 62 proteins were further predicted to be involved in the interaction network of TaFVE and 11 proteins have been shown to be potential TaFVE interactors based on curated databases and experimentally determined in other species by the STRING. Both yeast two-hybrid assay and bimolecular fluorescence complementation assay showed that histone deacetylase 6 and histone deacetylase 15 directly interacted with TaFVE. Multiple chromatin-remodelling proteins and polycomb group proteins were also identified and predicted to interact with TaFVE. These results showed that TaFVE directly interacted with multiple proteins to form multiple complexes to regulate spike developmental process, e.g. histone deacetylate, chromatin-remodelling and polycomb repressive complex 2 complexes. In addition, multiple flower development regulation factors (e.g. flowering locus K homology domain, flowering time control protein FPA, FY, flowering time control protein FCA, APETALA 1) involved in floral transition were also identified in the present study. Taken together, these results further elucidate the regulatory functions of TaFVE and help reveal the genetic mechanisms underlying wheat spike differentiation.

Stimuli-responsive and hemocompatible pseudozwitterionic interfaces.

We report a novel biomacromolecular formula for the design of hemocompatible gel interfaces of N-isopropylacrylamide (NIPAAm) and mixed-charge pairs of [2-(methacryloyloxy)ethyl]trimethylammonium (TMA) and 3-sulfopropyl methacrylate (SA) with overall electrical neutrality. The study stresses on how well-defined compositions of nonionic NIPAAm and pseudozwitterionic TMA/SA in the poly(NIPAAm-co-TMA/SA) hydrogels along with environmental conditions (temperature, ionic strength, and solution pH) affect swelling and adhesion of biofoulants on their surfaces. When challenged with plasma proteins, bacteria, recalcified platelets, or whole blood, stimuli-responsive hydrogels better resisted their adhesion as the content of mixed charges in the copolymer increased, to reach nonbiofouling for the gels made of 100% TMA/SA. The low hemolytic activity (0.5%) associated with a long plasma clotting time (10 min) suggests excellent hemocompatibility excellent hemocompatibility. Finally, hydrogels containing both NIPAAm and TMA/SA tend to exhibit preferential adhesion of leukocytes.

Research of shRNAmir inhibitory effects towards focal adhesion kinase expression in the treatment of gastric cancer.

Gastric cancer is the fourth most common type of malignant tumor, with a poor prognosis. Focal adhesion kinase (FAK) mediates the crosslink of intracellular signaling networks, playing a key role in cell migration and invasion. The aim of the present study was to investigate the effects of FAK interference on the proliferation ability, invasion and metastasis of gastric cancer cells. The FAK-RNAi lentiviral vector was infected into SGC7901 gastric cancer cells in order to observe the in vivo situations of tumor growth and metastasis before and after the FAK interference. The growth of SGC7901 gastric cancer cells in the interference group was significantly inhibited compared with that of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK expression significantly decreased (P<0.05). The in vitro invasion and metastasis experiments showed that the cell invasion and metastasis abilities of the interference group significantly decreased when compared with those of the negative control (P<0.05) and blank control groups (P<0.05). In the nude mouse subcutaneous tumor transplantation model, the mean ± standard deviation tumor weight of the interference group (1.474±0.9840 g) was lower than that of the negative control (3.134±0.3299 g) and blank control (2.68±0.12 g) groups (P<0.05). In the nude mice, the liver and peritoneal metastasis rates of the interference group were significantly lower than those of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK mRNA of the interference group significantly reduced (P<0.05). In conclusion, FAK interference could effectively suppress the proliferation, invasion and metastasis of transfected SGC7901 gastric cancer cells, and could inhibit the growth and distant metastasis of gastric cancer in nude mice.

Distinct expression pattern of miRNAs in Marek's disease virus infected-chicken splenic tumors and non-tumorous spleen tissues.

MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. Emerging evidence suggests that differential miRNA expression is associated with viral infection and tumorigenesis. Recently discovered microRNAs in the Marek's disease virus (MDV) genome have been suggested to have regulatory roles during MDV oncogenesis. To gain more insight into the molecular mechanisms of the tumorigenesis of MDV, we used microarrays to screen host and viral miRNAs that were sensitive to infection by MDV. Microarray analysis showed significant differential expression of 79 miRNAs, which was confirmed by qRT-PCR analysis. These data suggest that differentially expressed miRNAs may have major roles in MDV-induced tumorigenesis. In addition, we found two clades of chicken miRNAs had increased expression in splenic tumors and non-tumorous spleen tissues from GA-infected chickens. Thus, the expression of these miRNAs can be considered signatures for MDV infection and tumorigenesis.

A proteomic study of spike development inhibition in bread wheat.

Spike development in wheat is a complicated development process and determines the wheat propagation and survival. We report herein a proteomic study on the bread wheat mutant strain 5660M underlying spike development inhibition. A total of 121 differentially expressed proteins, which were involved in cold stress response, protein folding and assembly, cell-cycle regulation, scavenging of ROS, and the autonomous pathway were identified using MS/MS and database searching. We found that cold responsive proteins were highly expressed in the mutant in contrast to those expressed in the wild-type line. Particularly, the autonomous pathway protein FVE, which modulates flowering, was dramatically downregulated and closely related to the spike development inhibition phenotype of 5660M. A quantitative RT-PCR study demonstrated that the transcription of the FVE and other six genes in the autonomous pathway and downstream flowering regulators were all markedly downregulated. The results indicate that spike development of 5660M cannot complete the floral transition. FVE might play an important role in the spikes development of the wheat. Our results provide the theory basis for studying floral development and transition in the reproductive growth period, and further analysis of wheat yield formation.

Synthesis of a series of novel chiral Lewis base catalysts and their application in promoting asymmetric hydrosilylation of ß-enamino esters.

A series of novel chiral Lewis base catalysts were synthesized from L-serine and applied in the hydrosilylation of ß-enamino esters, in which the optimal one promoted the reactions to afford a wide variety of ß-amino esters in good yields with good enantioselectivities. It is noteworthy that several cyclic substrates were hydrosilylated under the optimal conditions to give the cyclic ß-amino esters with high yields, good diastereoselectivities as well as good ee values.

[Synthesis of 1,3-dihydro-1,3-dioxo-2H-isoindole derivatives].

OBJECTIVE: To synthesize a series of derivatives of Thalidomide. METHODS: The N-Phthaloyl-L-glutamic anhydride was ammonolyzed with amino acid benzyl esters, followed by hydrogenization. The reaction between the hydogenized products and ammonia gas produced ammonium salt, 1,3-dihydro-1,3-dioxo-2H-isoindole derivatives. RESULTS: Four new derivatives of Thalidomide were obtained and confirmed by spectral detection. CONCLUSION: The derivatives of Thalidomide can be efficiently synthesized under mild conditions.