TERT promoter mutations and monoallelic activation of TERT in cancer.

Here we report that promoter mutations in telomerase (TERT), the most common noncoding mutations in cancer, give rise to monoallelic expression of TERT. Through deep RNA sequencing, we find that TERT activation in human cancer cell lines can occur in either mono- or biallelic manner. Without exception, hotspot TERT promoter mutations lead to the re-expression of only one allele, accounting for approximately half of the observed cases of monoallelic TERT expression. Furthermore, we show that monoallelic TERT expression is highly prevalent in certain tumor types and widespread across a broad spectrum of cancers. Taken together, these observations provide insights into the mechanisms of TERT activation and the ramifications of noncoding mutations in cancer.

Mn-doped GaN as photoelectrodes for the photoelectrolysis of water under visible light.

Hydrogen generation through direct photoelectrolysis of water was studied using photoelectrochemical (PEC) cells made of Mn-doped GaN photoelectrodes. In addition to its absorption of the ultraviolet spectrum, Mn-doped GaN photoelectrodes could absorb photons in the visible spectrum. The photocurrents measured from PEC cells made of Mn-doped GaN were at least one order higher than those measured from PEC cells made of undoped GaN-working electrodes. Under the visible light illumination and a bias voltage below 1.2 V, the Mn-doped GaN photoelectrodes could drive the water splitting reaction for hydrogen generation. However, hydrogen generation could not be achieved under the same condition wherein undoped GaN photoelectrodes were used. According to the results of the spectral responses and transmission spectra obtained from the experimental photoelectrodes, the enhanced photocurrent in the Mn-doped GaN photoelectrodes, compared with the undoped GaN photoelectrodes, was attributable to the Mn-related intermediate band within the band gap of GaN that resulted in further photon absorption.

Immersed finger-type indium tin oxide ohmic contacts on p-GaN photoelectrodes for photoelectrochemical hydrogen generation.

In this study, we demonstrated photoelectrochemical (PEC) hydrogen generation using p-GaN photoelectrodes associated with immersed finger-type indium tin oxide (IF-ITO) ohmic contacts. The IF-ITO/p-GaN photoelectrode scheme exhibits higher photocurrent and gas generation rate compared with p-GaN photoelectrodes without IF-ITO ohmic contacts. In addition, the critical external bias for detectable hydrogen generation can be effectively reduced by the use of IF-ITO ohmic contacts. This finding can be attributed to the greatly uniform distribution of the IF-ITO/p-GaN photoelectrode applied fields over the whole working area. As a result, the collection efficiency of photo-generated holes by electrode contacts is higher than that of p-GaN photoelectrodes without IF-ITO contacts. Microscopy revealed a tiny change on the p-GaN surfaces before and after hydrogen generation. In contrast, photoelectrodes composed of n-GaN have a short lifetime due to n-GaN corrosion during hydrogen generation. Findings of this study indicate that the ITO finger contacts on p-GaN layer is a potential candidate as photoelectrodes for PEC hydrogen generation.

Hydrogen gas generation using n-GaN photoelectrodes with immersed Indium Tin Oxide ohmic contacts.

An n-GaN photoelectrochemical (PEC) cell with immersed finger-type indium tin oxide (ITO) ohmic contacts was demonstrated in the present study to enhance the hydrogen generation rate. The finger-type ITO ohmic contacts were covered with SiO2 layers to prevent the PEC cell from generating leakage current. Using a 1M NaCl electrolyte and external biases, the typical photocurrent density and gas generation rate of the n-GaN working electrodes with ITO finger contacts were found to be higher than those with Cr/Au finger contacts. The enhancement in photocurrent density or gas generation rate can be attributed to the transparent ITO contacts which allowed the introduction of relatively more photons into the GaN layer. No significant corrosion was observed in the ITO layer after the PEC process compared with the Cr/Au finger contacts which were significantly peeled from the GaN layer. These results indicate that the use of n-GaN working electrodes with finger-type ITO ohmic contacts is a promising approach for PEC cells.

High-performance GaN metal-insulator-semiconductor ultraviolet photodetectors using gallium oxide as gate layer.

In this study, gallium nitride (GaN)-based metal-insulator-semiconductor (MIS) ultraviolet (UV) photodetectors (PDs) with a gallium oxide (GaO(x)) gate layer formed by alternating current bias-assisted photoelectrochemical oxidation of n-GaN are presented. By introducing the GaO(x) gate layer to the GaN MIS UV PDs, the leakage current is reduced and a much larger UV-to-visible rejection ratio (R(UV/vis)) of spectral responsivity is achieved. In addition, a bias-dependent spectral response results in marked increase of the R(UV/vis) with bias voltage up to ~10(5). The bias-dependent responsivity suggests the possible existence of internal gain in of the GaN MIS PDs.

Mechanism for a transcriptional activator that works at the isomerization step.

Transcriptional activators in prokaryotes have been shown to stimulate different steps in the initiation process including the initial binding of RNA polymerase (RNAP) to the promoter and a postbinding step known as the isomerization step. Evidence suggests that activators that affect initial binding can work by a cooperative binding mechanism by making energetically favorable contacts with RNAP, but the mechanism by which activators affect the isomerization step is unclear. A well-studied example of an activator that normally exerts its effect exclusively on the isomerization step is the bacteriophage lambda cI protein (lambdacI), which has been shown genetically to interact with the C-terminal region of the final sigma(70) subunit of RNAP. We show here that the interaction between lambdacI and final sigma can stimulate transcription even when the relevant portion of final sigma is transplanted to another subunit of RNAP. This activation depends on the ability of lambdacI to stabilize the binding of the transplanted final sigma moiety to an ectopic -35 element. Based on these and previous findings, we discuss a simple model that explains how an activator's ability to stabilize the binding of an RNAP subdomain to the DNA can account for its effect on either the initial binding of RNAP to a promoter or the isomerization step.

Amyloid beta-peptide possesses a transforming growth factor-beta activity.

Amyloid beta-peptide (Abeta) of 39-42 amino acid residues is a major constituent of Alzheimer's disease neurite plaques. Abeta aggregates (fibrils) are believed to be responsible for neuronal damage and dysfunction, as well as microglia and astrocyte activation in disease lesions by multiple mechanisms. Since Abeta aggregates possess the multiple valencies of an FAED motif (20th to 23rd amino acid residues), which resembles the putative transforming growth factor-beta (TGF-beta) active site motif, we hypothesize that Abeta monomers and Abeta aggregates may function as TGF-beta antagonists and partial agonists, analogous to previously described monovalent and multivalent TGF-beta peptide antagonists and agonists (Huang, S. S., Liu, Q., Johnson, F. E., Konish, Y., and Huang, J. S. (1997) J. Biol. Chem. 272, 27155-27159). Here, we report that the Abeta monomer, Abeta-(1-40) and its fragment, containing the motif inhibit radiolabeled TGF-beta binding to cell-surface TGF-beta receptors in mink lung epithelial cells (Mv1Lu cells). Abeta-(1-40)-bovine serum albumin conjugate (Abeta-(1-40)-BSA), a multivalent synthetic analogue of Abeta aggregates, exhibited cytotoxicity toward bovine cerebral endothelial cells and rat post-mitotic differentiated hippocampal neuronal cells (H19-7 cells) and inhibitory activities of radiolabeled TGF-beta binding to TGF-beta receptors and TGF-beta-induced plasminogen activator inhibitor-1 expression, that were approximately 100-670 times more potent than those of Abeta-(1-40) monomers. At less than micromolar concentrations, Abeta-(1-40)-BSA but not Abeta-(1-40) monomers inhibited proliferation of Mv1Lu cells. Since TGF-beta is an organizer of responses to neurodegeneration and is also found in neurite plaques, the TGF-beta antagonist and partial agonist activities of Abeta monomers and aggregates may play an important role in the pathogenesis of the disease.

Activated thyroglobulin possesses a transforming growth factor-beta activity.

Thyroglobulin (Tg), the thyroid hormone precursor, is a major protein component in the thyroid gland and may have other important functions. Here, we show that bovine Tg inhibited 125I-labeled transforming growth factor-beta1 (125I-TGF-beta1) binding to cell-surface TGF-beta receptors in mink lung epithelial cells with an IC50 of approximately 300 nM. After disuccinimidyl suberate (DSS) modification, reduction/alkylation, treatment with 8 M urea, 0. 1% SDS, or acidic pH (pH 4-5), Tg exhibited a approximately 5-10-fold increase of 125I-TGF-beta1 binding inhibitory activity with IC50 of approximately 30-60 nM. This inhibitory activity was an intrinsic property of the Tg and could not be segregated from Tg protein by 5% SDS-polyacrylamide gel electrophoresis or by immunoprecipitation using antiserum to Tg. Untreated Tg did not affect DNA synthesis but blocked the TGF-beta-induced inhibition of DNA synthesis in mink lung epithelial cells. After DSS activation, Tg possessed TGF-beta agonist activity and inhibited DNA synthesis of mink lung epithelial cells and rat thyroid cells. The activated Tg also exerted a small but significant TGF-beta agonist activity in transcriptional activation of plasminogen activator inhibitor-1. These results suggest that Tg possesses an authentic TGF-beta activity which can be induced by chemical modifications and treatments with denaturing agents and acidic pH.