Synthesis of Imidazo[1,2-a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process.

A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

The Effect of Dwarfing Interstocks on Vegetative Growth, Fruit Quality and Ionome Nutrition of 'Fuji' Apple Cultivar 'Tianhong 2'-A One-Year Study.

Dwarfing interstocks play an essential role in determining the performance of fruit trees. SH40, Jizhen 1, and Jizhen 2 are widely used dwarfing interstocks in Hebei Province, China. This study examined the influence of these three dwarfing interstocks on vegetative growth, fruit quality and yield, and leaf and fruit macro- (N, P, K, Ca, and Mg) and micro- (Fe, Zn, Cu, Mn, and B) element contents for 'Tianhong 2'. Five-year-old 'Fuji' apple cultivar, 'Tianhong 2', on 'Malus. Robusta' rootstock, was cultivated with SH40, Jizhen 1, or Jizhen2 dwarfing rootstock as an interstock bridge. Jizhen 1 and 2 had more branches and a higher proportion of short branches than SH40. Jizhen 2 had a higher yield, good fruit quality, and higher leaf macro- (N, P, K, and Ca) and micro-element (Fe, Zn, Cu, Mn, and B) contents; Jizhen 1 had the highest leaf Mg content in the growing period. The fruit N, P, K, Fe, Zn, Cu, Mn, and B contents were higher in Jizhen 2. SH40 had the highest fruit Ca content. There were significant correlations in nutrient elements between leaves and fruit in June and July. Comprehensive analysis showed that Tianhong 2 had moderate tree vigor, high yield, good fruit quality, and high mineral element content in leaves and fruits when Jizhen 2 was used as an interstock.

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.

Robotic Manipulation under Harsh Conditions Using Self-Healing Silk-Based Iontronics.

Progress toward intelligent human-robotic interactions requires monitoring sensors that are mechanically flexible, facile to implement, and able to harness recognition capability under harsh environments. Conventional sensing methods have been divided for human-side collection or robot-side feedback and are not designed with these criteria in mind. However, the iontronic polymer is an example of a general method that operates properly on both human skin (commonly known as skin electronics or iontronics) and the machine/robotic surface. Here, a unique iontronic composite (silk protein/glycerol/Ca(II) ion) and supportive molecular mechanism are developed to simultaneously achieve high conductivity (around 6 kΩ at 50 kHz), self-healing (within minutes), strong stretchability (around 1000%), high strain sensitivity and transparency, and universal adhesiveness across a broad working temperature range (-40-120 °C). Those merits facilitate the development of iontronic sensing and the implementation of damage-resilient robotic manipulation. Combined with a machine learning algorithm and specified data collection methods, the system is able to classify 1024 types of human and robot hand gestures under challenging scenarios and to offer excellent object recognition with an accuracy of 99.7%.

Elucidation of ligninolysis mechanism of a newly isolated white-rot basidiomycete Trametes hirsuta X-13.

BACKGROUND: Lignin is a complex aromatic heteropolymer comprising 15-30% dry weight of the lignocellulose. The complex structural characteristic of lignin renders it difficult for value-added utilization. Exploring efficient lignin-degrading microorganisms and investigating their lignin-degradation mechanisms would be beneficial for promoting lignin valorization. In this study, a newly isolated white-rot basidiomycete, Trametes hirsuta X-13, with capacity to utilize alkaline lignin as the sole substrate was investigated. RESULTS: The analysis of the fermentation properties of T. hirsuta X-13 using alkaline lignin as the sole substrate, including the mycelial growth, activities of ligninolytic enzymes and the rates of lignin degradation and decolorization confirmed its great ligninolysis capacity. The maximum lignin degradation rate reached 39.8% after 11 days of T. hirsuta X-13 treatment, which was higher than that of reported fungi under the same condition. Fourier transform infrared spectrometry (FTIR), gas chromatography-mass spectrometry (GC-MS) scanning electron micrographs (SEM), two-dimensional heteronuclear single quantum coherence NMR analysis (2D-HSQC NMR) collaborated with pyrolysis gas chromatography-mass spectrometry (py-GC/MS) analyses proved that lignin structure was severely deconstructed along with amounts of monomer aromatics generated. Furthermore, according to those chemical analysis, in addition to canonical Cα-Cß breakage, the cleavage of lignin interunit linkages of ß-ß might also occur by T. hirsuta X-13. CONCLUSIONS: This study characterized a newly isolated white-rot basidiomycete T. hirsuta X-13 with impressive alkaline lignin degradation ability and provided mechanistic insight into its ligninolysis mechanism, which will be valuable for the development of lignin valorization strategies.

Selective delignification of poplar wood with a newly isolated white-rot basidiomycete Peniophora incarnata T-7 by submerged fermentation to enhance saccharification.

BACKGROUND: Pretreatment is a critical step required for efficient conversion of woody biomass into biofuels and platform chemicals. Fungal pretreatment is regarded as one of the most promising technology for woody biomass conversion but remains challenging for industrial application. The exploration of potential fungus strain with high efficient delignification and less processing time for woody biomass pretreatment will be valuable for development of biorefinery industry. Here, a newly isolated white-rot basidiomycete Peniophora incarnate T-7 was employed for poplar wood pretreatment. RESULTS: The chemical component analysis showed that cellulose, hemicellulose and lignin from poplar wood declined by 16%, 48% and 70%, respectively, after 7 days submerged fermentation by P. incarnate T-7. Enzymatic saccharification analysis revealed that the maximum yields of glucose and xylose from 7 days of P. incarnate T-7 treated poplar wood reached 33.4% and 27.6%, respectively, both of which were enhanced by sevenfold relative to the untreated group. Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD) and pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) characterization confirmed that lignocellulosic structure of poplar wood was largely broken by P. incarnate T-7, including delignification and de-crystalline of cellulose. Meanwhile, lignin component of poplar wood was selectively degraded by P. incarnate T-7, and G-type unit of lignin was preferentially attacked by the strain. Furthermore, quantitative proteomic analysis revealed that a considerable amount of lignocellulolytic enzymes were detected in the secretory proteins of P. incarnate T-7, especially with high abundance of lignin-degrading enzymes and hemicellulases. Combination of quantitative proteomic with transcriptomic analysis results showed that most of those lignocellulolytic enzymes were highly upregulated on poplar wood substrate compared to glucose substrate. CONCLUSIONS: This study showed that P. incarnate T-7 could selectively delignify poplar wood by submerged fermentation with short time of 7 days, which greatly improved its enzymatic saccharification efficiency. Our results suggested that P. incarnate T-7 might be a promising candidate for industrial woody biomass pretreatment.

Clonogenically Culturing and Expanding CD34+ Liver Cancer Stem Cells in Vitro.

A large number of cancer stem cells (CSCs) have been isolated and identified; however, none has been cultured in an unlimited manner in vitro without losing tumorigenicity and multipotency. In this study, we successfully clonogenically cultured a newly identified CD34+ liver CSC (LCSC) on feeder cells up to 22 passages (to date) without losing CSC property. Cloned CD34+ LCSC formed a round packed morphology and it could also be cryopreserved and recultured. Stem cell markers, CD34, CD117, and SOX2; normal liver stem cell markers, alpha fetoprotein, CK19, CK18, and OV6; putative CSC markers, CD44, CD133, EpCAM, and CD90; as well as CD31 were expressed in cloned CD34+ LCSC. SOX2 was the major factor in maintaining this LCSC before colonization, and interestingly, OCT4, SOX2, NAONG, Klf4, c-Myc, and Lin28 were upregulated in association with symmetric self-renewal for colony growth of CD34+ LCSC on feeder cells. Gene expression patterns of in vitro differentiation were consistent with our in vivo finding; furthermore, the tumorigenicity of cloned CD34+ LCSC was not different from uncloned CD34+ LCSC sorted from parental PLC. These results show that our cloned CD34+ LCSC maintained CSC property, including self-renewal, bipotency, and tumorigenicity after long-term culture, demonstrating that this LCSC can be cultured in an unlimited manner in vitro. Thus, establishing pure population of CSCs isolated from the patients will provide an opportunity to explore the mechanisms of tumorigenesis and cancer development, and to identify unique biomarkers presenting potential indicators of drug efficacy against CSCs for establishment of a novel strategy for cancer therapy.

Identification of cancer stem cell subpopulations of CD34(+) PLC/PRF/5 that result in three types of human liver carcinomas.

CD34(+) stem cells play an important role during liver development and regeneration. Thus, we hypothesized that some human liver carcinomas (HLCs) might be derived from transformed CD34(+) stem cells. Here, we determined that a population of CD34(+) cells isolated from PLC/PRF/5 hepatoma cells (PLC) appears to function as liver cancer stem cells (LCSCs) by forming HLCs in immunodeficient mice with as few as 100 cells. Moreover, the CD34(+) PLC subpopulation cells had an advantage over CD34(-) PLCs at initiating tumors. Three types of HLCs were generated from CD34(+) PLC: hepatocellular carcinomas (HCCs); cholangiocarcinomas (CC); and combined hepatocellular cholangiocarcinomas (CHCs). Tumors formed in mice transplanted with 12 subpopulations and 6 progeny subpopulations of CD34(+) PLC cells. Interestingly, progenies with certain surface antigens (CD133, CD44, CD90, or EPCAM) predominantly yielded HCCs. CD34(+) PLCs that also expressed OV6 and their progeny OV6(+) cells primarily produced CHC and CC. This represents the first experiment to demonstrate that the OV6(+) antigen is associated with human CHC and CC. CD34(+) PLCs that also expressed CD31 and their progeny CD31(+) cells formed CHCs. Gene expression patterns and tumor cell populations from all xenografts exhibited diverse patterns, indicating that tumor-initiating cells (TICs) with distinct antigenic profiles contribute to cancer cell heterogeneity. Therefore, we identified CD34(+) PLC cells functioning as LCSCs generating three types of HLCs. Eighteen subpopulations from one origin had the capacity independently to initiate tumors, thus functioning as TICs. This finding has broad implications for better understanding of the multistep model of tumor initiation and progression. Our finding also indicates that CD34(+) PLCs that also express OV6 or CD31 result in types of HLCs. This is the first report that PLC/PRF/5 subpopulations expressing CD34 in combination with particular antigens defines categories of HLCs, implicating a diversity of origins for HLC.

[Study about outcomes of non-pharmacological conservative treatment for lumbar spinal stenosis].

OBJECTIVE: To describe the short-term outcomes of a non-pharmacological conservative approach to patients with LSS. METHODS: This is a prospective consecutive case series with short-term follow-up of 21 consecutive patients who were diagnosed with LSS. Patients recruited from the outpatients of orthopaedic department and rehabilitation department in the Peking University People's Hospital from March 2010 to March 2011. Patients had baseline interviews with follow-up questionnaires in the end of the first and the third month. MAIN OUTCOME MEASURES: pain intensity was measured using the Numerical Rating Scale (NRS) and disability was measured using the Roland Morris Disability Questionnaire (RMDQ), as well as the 36-item Short Form Health Surrey (SF-36) and efficacy assessment for evaluation. RESULTS: All of 21 eligible consenting patients initially enrolling completed the follow-up. Pain at worst, functional status, quality of life improved significantly in the end of the first month. These were considered to be clinically meaningful in the end of the third month. No patients went on to require surgery. No major complications of treatment were noted. CONCLUSIONS: A non-pharmacological conservative treatment may be useful and safe in bringing about clinically meaningful improvement in pain and disability in patients with LSS. Before surgical management, a non-surgical approach should be taken into account at first.

[Dynamic assessment of grassland degradation in Naqu of northern Tibet].

Based on the past years vegetation cover, annual maximal grass yield and June-September mean modified soil-adjusted vegetation index (MSAVI) that were inversely deduced from the 10-day composite data of NOAA/AVHRR channels 1 and 2 and NDVI in 1982-2000, this paper analyzed the recent 20 years dynamics of grassland desertification in Naqu of northern Tibet. The results showed that in recent 20 years, the area of degraded grassland in Naqu was averagely 43.1% of the total land area. It was decreased in the former ten years while increased in the latter ten years, but overall, had a decreasing trend. The degraded area was larger in west part of Naqu than in its other regions. Among the eight climatic factors including temperature, precipitation, potential evapotranspiration, vapor pressure, wind velocity, sunshine hour, ratio of precipitation to evapotranspiration, and ratio of temperature to precipitation, the most remarkable factor affecting the dynamic of grassland degradation was the potential evapotranspiration.