On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.

A template-free, one-step and one-phase synthesis of single-layer MnO2 nanosheets has been developed via a redox reaction between KMnO4 and sodium dodecyl sulfate (SDS). The successful formation of single-layer MnO2 nanosheets has been confirmed by the characteristic absorption around 374 nm and the typical thickness of ~0.95 nm. The slow redox reaction controlled by the gradual hydrolysis of SDS is found to be the key factor for the successful formation of single-layer nanosheets. SDS not only serves as the precursor of dodecanol to reduce KMnO4 , but also aids the formation of single-layer MnO2 nanosheets as a structure-inducing agent. The resultant single-layer MnO2 nanosheets possess superior specific capacitance, which can be attributed to the extended surface and high porosity of MnO2 nanosheets on the electrode. The MnO2 nanosheets also show excellent durability, retaining 91% of the starting capacitance after 10 000 charge/discharge cycles. Moreover, the symmetric pseudocapacitor based on the synthesized single-layer MnO2 nanosheets exhibits a high specific capacitance, indicating great potential for real energy storage. Therefore, it has been demonstrated for the first time that a single readily available reagent, SDS, can play multiple roles in reducing KMnO4 to conveniently yield single-layer MnO2 nanosheets as a high-performance pseudocapacitive material.

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The development of efficient catalysts for the oxygen reduction reaction (ORR) is crucial for a number of emerging technologies, to counter energy and environment crises. Herein, we report an alkyne metathesis polymerization protocol to synthesize a conjugated microporous metalloporphyrin-based framework containing interconnected ORR catalytic centers. A simple composite of the framework and carbon black shows excellent ORR electrocatalytic activity and specificity through a four-electron reduction mechanism under both acidic and alkaline conditions. The pyrolysis of the catalyst, which is commonly involved in the preparation of ORR catalytic systems, is not necessary. Compared to monomeric metalloporphyrins, the framework shows enhanced ORR catalytic activity, presumably due to the porous and conjugated nature of the framework structure, which allows better exposure of the catalytically active sites, and efficient electron/mass transport. More importantly, the composite electrocatalyst exhibits superior durability and methanol tolerance over commercial Pt/C and metalloporphyrin monomers. Given the highly structural tunability of conjugated microporous polymers, it is conceivable that such a non-pyrolytic approach could enable the systematic exploration of the structure-activity relationship of organic framework-based ORR catalysts and eventually lead to the development of cost-effective replacements for Pt/C.

A series of triphenolsilane-coordinated molybdenum(VI) propylidyne catalysts has been developed, which are resistant to small alkyne polymerization and compatible with various functional groups (including phenol substrates). The catalysts remain active in solution for days at room temperature (months at À30 8C). The catalysts are also compatible with 5 molecular sieves (small alkyne scavengers), and have enabled the homodimerization of small alkyne substrates at 40-70 8C in a closed system, with dimer products being obtained in 76-96% yields. A shape-persistent aryleneethynylene macrocycle (11) was also prepared on a gram scale with 0.5 mol% catalyst loading, in almost quantitative yield.

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Resveratrol, a plant-derived polyphenolic compound with various health activities, is widely used in nutraceutical and food additives. Herein, combinatorial optimization of resveratrol biosynthetic pathway and intracellular environment of E. coli was carried out. By screening pathway genes from various species and exploring their expression pattern, we initially constructed resveratrol-producing strains. Further targeting at availability of malonyl-CoA through expressing ACC of Corynebacterium glutamicum and antisense inhibiting native fabD significantly increased resveratrol biosynthesis. Transport engineering for resveratrol secretion and molecular chaperones helping for folding heterologous enzymes were employed to improve the intracellular environments in remarkable degrees. By introducing PcTAL of Phanerochaete chrysosporium and tuning expression model of PcTAL, At4CL, and VvSTS, an engineered E. coli produced 57.77 mg/L of resveratrol from L-tyrosine. After integrating the above strategies, resveratrol titer reached to 238.71 mg/L from L-tyrosine. The combinatorial optimization in this study provides a promising strategy to produce valuable natural products in heterologous expression systems.

The innate immune response is important in paraquat-induced acute lung injury, but the exact pathways involved are not elucidated. The objectives of this study were to determine the specific role of the NLRP3 inflammasome in the process. Acute lung injury was induced by administering paraquat (PQ) intraperitoneally. NLRP3 inflammasome including NLRP3, ASC, and caspase-1 mRNA and protein expression in lung tissue and IL-1β and IL-18 levels in BALF were detected at 4, 8, 24, and 72 h after PQ administration in rats. Moreover, rats were pretreated with 10, 30, and 50 mg/kg NLRP3 inflammasome blocker glybenclamide, respectively, 1 h before PQ exposure. At 72 h after PQ administration, lung histopathology changes, NLRP3, ASC, and caspase-1 protein expression, as well as secretion of cytokines including IL-1β and IL-18 in BALF were investigated. The NLRP3 inflammasome including NLRP3, ASC, caspase-1 expression, and cytokines IL-1β and IL-18 levels in PQ poisoning rats were significantly higher than that in the control group. NLRP3 inflammasome blocker glybenclamide pretreatment attenuated lung edema, inhibited the NLRP3, ASC, and caspase-1 activation, and reduced IL-1β and IL-18 levels in BALF. In the in vitro experiments, IL-1β and IL-18 secreted from RAW264.7 mouse macrophages treated with paraquat were attenuated by glybenclamide. In conclusion, paraquat can induce IL-1β/IL-18 secretion via NLRP3-ASC-caspase-1 pathway, and the NLRP3 inflammasome is essential for paraquat-induced acute lung injury.