Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.

Effi cient transparent organic light-emitting diodes (OLEDs) with improved stability based on conductive, transparent poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) electrodes are reported. Based on optical simulations, the device structures are carefully optimized by tuning the thickness of doped transport layers and electrodes. As a result, the performance of PEDOT:PSS-based OLEDs reaches that of indium tin oxide (ITO)-based reference devices. The effi ciency and the long-term stability of PEDOT:PSS-based OLEDs are signifi cantly improved. The structure engineering demonstrated in this study greatly enhances the overall performances of ITO-free transparent OLEDs in terms of effi ciency, lifetime, and transmittance. These results indicate that PEDOT:PSS-based OLEDs have a promising future for practical applications in low-cost and fl exible device manufacturing.

The performance of both organic light-emitting diodes (OLEDs) and organic solar cells (OSC) depends on efficient coupling between optical far field modes and the emitting/absorbing region of the device. Current approaches towards OLEDs with efficient light-extraction often are limited to single-color emission or require expensive, non-standard substrates or top-down structuring, which reduces compatibility with large-area light sources. Here, we report on integrating solution-processed nano-particle based light-scattering films close to the active region of organic semiconductor devices. In OLEDs, these films efficiently extract light that would otherwise remain trapped in the device. Without additional external outcoupling structures, translucent white OLEDs containing these scattering films achieve luminous efficacies of 46 lm W−1 and external quantum efficiencies of 33% (both at 1000 cd m−2). These are by far the highest numbers ever reported for translucent white OLEDs and the best values in the open literature for any white device on a conventional substrate. By applying additional light-extraction structures, 62 lm W−1 and 46% EQE are reached. Besides universally enhancing light-extraction in various OLED configurations, including flexible, translucent, single-color, and white OLEDs, the nano-particle scattering film boosts the short-circuit current density in translucent organic solar cells by up to 70%.

A new POSS (polyhedral oligomeric silsesquioxane)-substituted polyfluorene was synthesized from the nickel-catalyzed Yamamoto coupling reaction. The synthesized polymers could be well characterized by 1 H NMR, FT-IR, and elemental analysis. PL spectra of PFPOSSs on the quartz film showed reduced aggregation/excimer formation because the bulky POSS group prohibited interchain interactions. This effective dilution effect and the high thermal stability of the POSS unit also improved the color stability of PFPOSSs blue emission even after thermal annealing at 150 °C. The fluorescence quantum yields (Φ FL) of PFPOSSs in both solution and solid state were higher than those of poly(dialkylfluorene)s. Moreover, the ITO/PEDOT-PSS/polymer/Ca/Al LED device using this polymer as emitting layer showed a very stable blue light emission. LED devices of PFPOSSs showed a low turn-on voltage of 3.7-4.4 V, high brightness of 350-1010 cd/m 2 , and external efficiencies of 0.11-0.36%.

The clinical applicability of direct cell fate conversion depends on obtaining tissue from patients that is easy to harvest, store, and manipulate for reprogramming. Here, we generate induced neural progenitor cells (iNPCs) from neonatal and adult peripheral blood using single-factor OCT4 reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, OCT4 reprogramming of blood was facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood-derived (BD) iNPCs differentiate in vivo and respond to guided differentiation in vitro, producing glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes, including dopaminergic (CNS related) and nociceptive neurons (peripheral nervous system [PNS]). Furthermore, nociceptive neurons phenocopy chemotherapy-induced neurotoxicity in a system suitable for high-throughput drug screening. Our findings provide an easily accessible approach for generating human NPCs that harbor extensive developmental potential, enabling the study of clinically relevant neural diseases directly from patient cohorts.

The p53 tumor suppressor protein is a key regulator of cellular functions including responses to numerous stress signals, and triggers apoptosis in many cell types, including neurons. The major mechanisms known to regulate p53 stabilization and activation include phosphorylation and ubiquitin ligase-mediated proteasomal degradation. Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, is most active in the central nervous system and plays a variety of roles in neuronal degeneration. Here, we demonstrate for the first time that Cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that Cdk5 phosphorylates p53 on Ser15, Ser33 and Ser46 in vitro, and that increased Cdk5 activity in the nucleus mediates these phosphorylation events in response to genotoxic and oxidative stresses. Cdk5 mediates disruption of the interaction between p53 and Hdm2 (also known as Mdm2), and prevents Hdm2-induced p53 ubiquitylation and downregulation. Cdk5 additionally enhances phosphorylation-dependent binding of the p300 coactivator, inducing acetylation of p53. Cdk5-stabilized p53 protein is transcriptionally active, resulting in the induction of pro-apoptotic genes and subsequent mitochondria-mediated apoptosis in response to genotoxic or oxidative stress. Collectively, these novel findings help define the mechanisms underlying neuronal apoptosis occurring as a result of Cdk5-mediated p53 stabilization and transcriptional activation.

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a dual-specificity phosphatase that is involved in the regulation of cell survival, differentiation and apoptosis through inactivating MAPKs by dephosphorylation. Here, we provide evidence for a role of MKP-1 in the glutamate-induced cell death of HT22 hippocampal cells and primary mouse cortical neurons. We suggest that, during glutamate-induced oxidative stress, protein kinase C (PKC) δ becomes activated and induces sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) through a mechanism that involves degradation of MKP-1. Glutamate-induced activation of ERK1/2 was blocked by inhibition of PKCδ, confirming that ERK1/2 is regulated by PKCδ. Prolonged exposure to glutamate caused reduction in the protein level of MKP-1, which correlated with the sustained activation of ERK1/2. Furthermore, knockdown of endogenous MKP-1 by small interfering (si)RNA resulted in pronounced enhancement of ERK1/2 phosphorylation accompanied by increased cytotoxicity under glutamate exposure. In glutamate-treated cells, MKP-1 was polyubiquitylated and proteasome inhibitors markedly blocked the degradation of MKP-1. Moreover, inhibition of glutamate-induced PKCδ activation suppressed the downregulation and ubiquitylation of MKP-1. Taken together, these results demonstrate that activation of PKCδ triggers degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby contributing to persistent activation of ERK1/2 under glutamate-induced oxidative toxicity.

Rice tungro disease (RTD) is a serious constraint to rice production in South and Southeast Asia. RTD is caused by Rice tungro spherical virus (RTSV) and Rice tungro bacilliform virus. Rice cv. Utri Merah is resistant to RTSV. To identify the gene or genes involved in RTSV resistance, the association of genotypic and phenotypic variations for RTSV resistance was examined in backcross populations derived from Utri Merah and rice germplasm with known RTSV resistance. Genetic analysis revealed that resistance to RTSV in Utri Merah was controlled by a single recessive gene (tsv1) mapped within an approximately 200-kb region between 22.05 and 22.25 Mb of chromosome 7. A gene for putative translation initiation factor 4G (eIF4G(tsv1)) was found in the tsv1 region. Comparison of eIF4G(tsv1) gene sequences among susceptible and resistant plants suggested the association of RTSV resistance with one of the single nucleotide polymorphism (SNP) sites found in exon 9 of the gene. Examination of the SNP site in the eIF4G(tsv1) gene among various rice plants resistant and susceptible to RTSV corroborated the association of SNP or deletions in codons for Val(1060-1061) of the predicted eIF4G(tsv1) with RTSV resistance in rice.