Development of novel synthetic methodologies and their use in approaches for the preparation of lactacystin, lepadiformine and a Giardia lamblia fructose-1,6-bisphosphate aldolase inhibitor

The investigations carried out in my doctoral studies focus on (1) applications of pyridinium salt photochemical and tandem ene-yne-ene metathesis reactions to the synthesis of the natural products (+)-lactacystin and lepadiformine C, and (2) the preparation of a novel inhibitor for the class II Giardia lamblia fructose-1,6-bisphosphate aldolase. New developments in the area of pyridinium salt photochemistry were explored in the context of approaches to the natural product (+)-lactacystin. The results of this effort show that irradiation of a substituted 1,2-cyclopenta-fused pyridinium salt in aqueous solution followed by treatment with sodium bicarbonate leads to selective production of an unusual, structural and functional complex, and stereodefined tetracyclic carbamate. This substance contains structural features and a functionality array that would make it applicable as a late stage intermediate in a synthesis of the proteosome inhibitor, lactacystin. A novel strategy was developed for the synthesis of lepadiformine C, a structurally interesting, biologically active marine alkaloid derived from the marine organism Claveline moluccensis. that has a tricyclic structure. The approach, which begins with l-proline, relies on implementation of a ruthenium-alkylidene catalyzed, tandem ene-yne-ene metathesis process to construct the tricyclic structure. Class I and class II fructose-1,6-bisphosphate aldolases (FBPA), enzymes that exhibit no amino acid sequence homology and utilize different catalytic mechanisms, promote the retro-aldol conversion of fructose-1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and D-glyceraldehyde-3-phosphate as part of energy producing glycolysis pathways in bacteria, protists and humans. The mammalian class I FBPA employs a Schiff base mechanism, involving an active site lysine amine group, whereas the parasitic protozoan Giardia lamblia relies on a class II FBPA that utilizes an active site Zn+2 to stabilize the forming enolate of dihdroxyacetone phosphate. One subgoal of my studies was to develop a novel strategy for the design of inhibitors of the class II Giardia lamblia FBP (glFBPA). As part of an overall effort in this area, potential inhibitors that possess Zn+2 binding 3-hydroxy-2-pyridone moieties were designed and prepared. The inhibitory properties of these substances against glFBPA were determined. The results show that the structure-based inhibitor design is effective in identifying new 3-hydroxy-2-pyridone based glFBPA inhibitors that have modestly tight (low micromolar) binding affinities

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.

Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes

Study on Total Factor Carbon Emission Efficiency in the Yangtze River Economic Zone, China

With the continuous acceleration of the modernization process, the Eco-environmental problems of the Yangtze River Economic Zone in China have become increasingly prominent, which makes the study of carbon emission efficiency become a long-term concern. Based on the panel data of 11 provinces and cities of the Yangtze River Economic Zone in 2009～2016, this paper calculates the DEA-Malmquist index of the Total Factor Carbon Emission Efficiency containing undesirable output in various provinces and cities and three major regions. By studying the DEA-Malmquist index and its decomposition, the results show that the Total Factor Carbon Emission Efficiency of various regions in the Yangtze River Economic Zone presents a growth trend, and its main contribution comes from technological progress. In the future, the emission reduction rules of the Yangtze River Economic Zone will be transformed from the traditional top-down emission reduction model to the bottom-up “independent contribution” emission reduction model

Understanding the mechanism for building woven fabrics with wettability ranging from superhydrophobic to superamphiphobic via an aqueous process

We have recently developed a novel and simple approach based on aqueous solutions of block copolymer micelles for the construction of WFs with wettability ranging from the superhydrophobic to the superamphiphobic regime. That is, the copolymers were initially dispersed into water to yield a micelle solution with the insoluble fluorinated block serving as the micellar core and the water soluble block as the micellar corona. The polyethylene terephthalate (PET) or cotton WFs were then dipped into a copolymer micelle solution and then naturally dried at room temperature before they were cured at high temperature to yield WFs with various degrees of liquid repellency. Further investigation on the mechanism for the formation of either super hydrophobic or superamphiphobic WFs using this aqueous process would facilitate the commercial applications of these water-based coatings. In this contribution, polyethylene terephthalate (PET) films with different liquid repellencies based on copolymer aqueous micelle solutions were prepared via previously reported process, and AFM and XPS techniques were respectively employed to evaluate the morphology and chemical composition of the copolymer-coated PET films. The dependence of water and oil contact angles of PET films on the concentrations of the copolymer micelle solution were evaluated and further employed for the prediction different liquid repellencies of PET WFs. The mechanism for the formation of the superhydrophobic WFs or superamphiphobic WFs was also proposed

An oxygen-tolerant photo-induced metal-free reversible addition-fragmentation chain transfer polymerization

We report herein a visible light-induced metal-free living polymerization with high oxygen tolerance that can be performed in aqueous media. In contrast with ordinary living/controlled radical polymerizations, oxygen can be present throughout the entire reaction process. This reaction can be photo-induced and proceeds at room temperature. First, we have successfully synthesized a well-defined polymer in an ambient atmosphere by the photo-induced radical polymerization method, using acrylic acid as a monomer and fluorescein as a photocatalyst. However, the subsequent chain extension reaction did not occur, possibly due to oxidation of the chain transfer agent (CTA). Despite this, we found that the addition of vitamin C (ascorbic acid) imparted the process with oxygen tolerance. We conducted a systematic study to optimize the best concentrations of the key reagents including the monomer, CTA, fluorescein, and vitamin C. Through these optimizations we were able to synthesize in the presence of oxygen a series of well-defined poly(acrylic acid)s (PAAs) with dispersities () below 1.3 and molecular weights that closely matched the theoretical values. The kinetic study showed that the molecular weight of the produced PAA increased linearly with the conversion of the monomer, and chain extension reaction also yielded a block polymer with a higher molecular weight than that of the previous polymer. Therefore, we developed a novel photo-induced living polymerization method that can be conducted both in the absence of oxygen and in the presence of air. (c) 2018 Wiley Periodicals, Inc

Chromosome-level genome assembly and annotation of Zicaitai (Brassica rapa var. purpuraria)

Abstract Zicaitai is a seasonal vegetable known for its high anthocyanin content in both stalks and leaves, yet its reference genome has not been published to date. Here, we generated the first chromosome-level genome assembly of Zicaitai using a combination of PacBio long-reads, Illumina short-reads, and Hi-C sequencing techniques. The final genome length is 474.12 Mb with a scaffold N50 length of 43.82 Mb, a BUSCO score of 99.30% and the LAI score of 10.14. Repetitive elements accounted for 60.89% (288.72 Mb) of the genome, and Hi-C data enabled the allocation of 430.87 Mb of genome sequences to ten pseudochromosomes. A total of 42,051 protein-coding genes were successfully predicted using multiple methods, of which 99.74% were functionally annotated. Notably, comparing the genome of Zicaitai with seven other species in the Cruciferae family revealed strong conservation in terms of gene numbers and structures. Overall, the high-quality genome assembly provides a critical resource for studying the genetic basis of important agronomic traits in Zicaitai

Physiological mechanism beneath the inhibition of Cleome spinosa against the morphology and reproduction of Fusarium oxysporum

Fusarium oxysporum is a soil-borne plant pathogen that can cause various plant diseases including cucumber wilt. An experiment was conducted to explore the physiological mechanism underlying the inhibitory activity of Cleome spinosa against the morphology and reproduction of F. oxysporum. Different concentrations of C. spinosa extracts.−0 (Z0), 5 (Z5), 15 (Z15), 30 (Z30), 45 (Z45), and 60 (Z60) mg·mL−1 were applied to F. oxysporum. Cleome spinosa extract significantly reduced the colony diameter (89.7 %) and dry mass (78.9 %) of F. oxysporum under the Z45 treatment. Moreover, spore formation was also significantly inhibited by C. spinosa extract. The spore number and germination rate decreased by 73.5 % and 83.0 %, respectively, under the Z45 treatment. The number of mycelia in the unit field of view was significantly reduced, and the mycelia were wizened with rough surfaces and more bends under the Z45 treatment. Hence, C. spinosa extracts severely damaged the morphology of F. oxysporum mycelia. Additionally, F. oxysporum could not adjust to the osmotic changes caused by C. spinosa extract, leading to membrane injury and electrolyte leakage. Finally, they impaired the antioxidant system in F. oxysporum, resulting in cell membrane injury

DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism

Abstract Peripheral CD8+ T cell number is tightly controlled but the precise molecular mechanism regulating this process is still not fully understood. In this study, we found that epilepsy patients with loss of function mutation of DEPDC5 had reduced peripheral CD8+ T cells, and DEPDC5 expression positively correlated with tumor-infiltrating CD8+ T cells as well as overall cancer patient survival, indicating that DEPDC5 may control peripheral CD8+ T cell homeostasis. Significantly, mice with T cell-specific Depdc5 deletion also had reduced peripheral CD8+ T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8+ T cells produced high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis. Together, our study links DEPDC5-mediated mTORC1 signaling with CD8+ T cell protection from ferroptosis, thereby revealing a novel strategy for enhancing anti-tumor immunity via suppression of ferroptosis

Robust Superamphiphobic Coatings Based on Silica Particles Bearing Bifunctional Random Copolymers

Reported herein is the growth of bifunctional random copolymer chains from silica particles through a “grafting from” approach and the use of these copolymer-bearing particles to fabricate superamphiphobic coatings. The silica particles had a diameter of 90 ± 7 nm and were prepared through a modified Stöber process before atom transfer radical polymerization (ATRP) initiators were introduced onto their surfaces. Bifunctional copolymer chains bearing low-surface-free-energy fluorinated units and sol–gel-forming units were then grafted from these silica particles by surface-initiated ATRP. Perfluorooctyl ethyl acrylate (FOEA) and 3-(triisopropyloxy)­silylpropyl methacrylate (IPSMA) were respectively used as fluorinated and sol–gel-forming monomers in this reaction. Hydrolyzing the IPSMA units in the presence of an acid catalyst yielded silica particles that were adorned with silanol-bearing copolymer chains. Coatings were prepared by spraying these hydrolyzed silica particles onto glass and cotton substrates. A series of four different copolymer-functionalized silica particles samples bearing copolymers with similar FOEA molar fractions (<i>f</i>_F) of ∼80% but with different copolymer grafting mass ratios (<i>g</i>_m) that ranged between 12.3 wt % and 58.8 wt %, relative to silica, were prepared by varying the polymerization protocols. These copolymer-bearing silica particles with a <i>g</i>_m exceeding 34.1 wt % were used to coat glass and cotton substrates, yielding superamphiphobic surfaces. More importantly, these particulate-based coatings were robust and resistant to solvent extraction and NaOH etching thanks to the self-cross-linking of the copolymer chains and their covalent attachment to the substrates