Summary The induction of pluripotency or trans-differentiation of one cell type to another can be accomplished with cell lineage-specific transcription factors. Here we report that repression of a single RNA binding protein PTB, which occurs during normal brain development via the action of miR-124, is sufficient to induce trans-differentiation of fibroblasts into functional neurons. Besides its traditional role in regulated splicing, we show that PTB has a previously undocumented function in the regulation of microRNA functions, suppressing or enhancing microRNA targeting by competitive binding on target mRNA or altering local RNA secondary structure. A key event during neuronal induction is the relief of PTB-mediated blockage of microRNA action on multiple components of the REST complex, thereby de-repressing a large array of neuronal genes, including miR-124 and multiple neuronal-specific transcription factors, in non-neuronal cells. This converts a negative feedback loop to a positive one to elicit cellular reprogramming to the neuronal lineage.

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The first transition-metal-catalyzed activation of silyl C(sp(3))-H bond was realized and synthetically applied. A variety of organic skeletons substituted with SiMe(3) groups could undergo the Pd-catalyzed intramolecular coupling reaction, resulting in an unprecedented synthetic method for yielding six-membered silacycles. It was found that the adjacent Si atom played an essential role for the activation of the C(sp(3))-H bond of the SiMe(3) group; no activation reaction of the C(sp(3))-H bond of the CMe(3) group took place under the same reaction conditions.

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

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Three identical membrane bioreactors (MBRs) were operated over 2 years at different sludge retention time (SRT) of 10 d, 40 d and no sludge withdrawal (NS), to elucidate and quantify the effect of SRT on the sludge characteristics and membrane fouling. The hydraulic retention times of these MBRs were controlled at 12 h. With increasing SRT, the sludge concentrations in the MBRs increased, whereas the ratio of volatile suspended solid to the total solid decreased, and the size of sludge granule diminished in the meantime. A higher sludge concentration at long SRT could maintain a better organic removal efficiency, and a longer SRT was propitious to the growth of nitrifiers. The performance of these MBRs for the removal of COD and NH 4 + -N did not change much with different SRTs. However, the bioactivity decreased as SRT increase. The measurement of specific oxygen uptake rates (SOUR) and fluorescence in situ hybridization (FISH) with rRNA-targeted oligonucleotide probes testified that SOUR and the proportion of the bacteria-specific probe EUB338 in all DAPI-stainable bacteria decreased with increasing SRT. The concentrations of total organic carbon, protein, polysaccharides and soluble extracellular polymeric substance (EPS) in the mixed liquor supernatant also decreased with increasing SRT. The membrane fouling rate was higher at shorter SRT, and the highest fouling rate appeared at a SRT of 10 d. Both the sludge cake layer and gel layer had contribution to the fouling resistance, but the relative contribution of the gel layer decreased as SRT increase.