Failure Modes of Platinized pn+-GaInP Photocathodes for Solar-Driven H2 Evolution.

The long-term stability for the hydrogen-evolution reaction (HER) of homojunction pn+-Ga0.52In0.48P photocathodes (band gap = 1.8 eV) with an electrodeposited Pt catalyst (pn+-GaInP/Pt) has been systematically evaluated in both acidic and alkaline electrolytes. Electrode dissolution during chronoamperometry was correlated with changes over time in the current density-potential (J-E) behavior to reveal the underlying failure mechanism. Pristine pn+-GaInP/Pt photocathodes yielded an open-circuit photopotential (Eoc) as positive as >1.0 V vs the potential of the reversible hydrogen electrode (RHE) and a light-limited current density (Jph) of >12 mA cm-2 (1-sun illumination). However, Eoc and Jph gradually degraded at either pH 0 or pH 14. The performance degradation was attributed to three different failure modes: (1) gradual thinning of the n+-emitter layer due to GaInP dissolution in acid; (2) active corrosion of the underlying GaAs substrate at positive potentials causing delamination of the upper GaInP epilayers; and (3) direct GaAs/electrolyte contact compromising the operational stability of the device. This work reveals the importance of both substrate stability and structural integrity of integrated photoelectrodes toward stable solar fuel generation.

Botch is a γ-glutamyl cyclotransferase that deglycinates and antagonizes Notch.

Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.

Botch promotes neurogenesis by antagonizing Notch.

Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development.

Pyrrolidine dithiocarbamate and diethyldithiocarbamate are active against growing and nongrowing persister Mycobacterium tuberculosis.

Diethyldithiocarbamate (DETC) and pyrrolidine dithiocarbamate (PDTC) were highly active against tubercle bacilli, with MICs of 8 microg/ml and 0.13 microg/ml, respectively. DETC and PDTC were active against old cultures, enhanced pyrazinamide or pyrazinamide/rifampin activity, and had serum inhibitory titers of 1:2 and 1:4, respectively, in mice given 100 mg/kg orally.

Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model.

There is an urgent need for the development of new drugs that are active against drug-resistant Mycobacterium tuberculosis strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity in vitro. This study evaluated ketoconazole (KTC) for activity against M. tuberculosis. The MIC of KTC for different M. tuberculosis strains ranged from 8 to 16 microg ml(-1) under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli in vitro when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg(-1) led to an inhibitory serum concentration 2 h after administration. The in vivo activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.

Aspirin antagonism in isoniazid treatment of tuberculosis in mice.

Salicylate has previously been shown to reduce the susceptibility of Mycobacterium tuberculosis to several drugs in vitro. In this study, aspirin, a salicylate anti-inflammatory, antagonized isoniazid treatment of murine pulmonary tuberculosis, whereas the nonsalicylate ibuprofen did not. These results may have implications on concurrent administration of anti-inflammatory and antituberculosis drugs.

Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis.

OBJECTIVES: Aspirin (acetylsalicylic acid) or ibuprofen [2-(4-isobutyl-phenyl)-propionic acid] was administered to mice undergoing treatment of tuberculosis infection with pyrazinamide to determine if these non-steroidal anti-inflammatory drugs (NSAIDs) enhance pyrazinamide activity in vivo. METHODS: BALB/c mice were infected with Mycobacterium tuberculosis H37Rv through aerosol exposure. Mice were treated orally with aspirin, ibuprofen or pyrazinamide, alone and in combination. The impact of daily administration of these drugs for 1 month was determined by enumerating viable bacteria in the lung and spleen. RESULTS: Aspirin or ibuprofen alone at 20 mg/kg per day had little effect on tuberculosis infection after 1 month of treatment, while pyrazinamide at 150 mg/kg per day led to a reduction of about 1.5 log(10) cfu in the lung and 2 log(10) cfu in the spleen compared with the control. Simultaneous administration of either aspirin or ibuprofen with pyrazinamide resulted in a further decrease of about 0.4 log(10) cfu in the lung and more than 1 log(10) cfu in the spleen compared with mice receiving pyrazinamide alone. All spleens in the pyrazinamide-only treatment group were positive for infection. Of mice treated with both aspirin and pyrazinamide, two of five spleens were negative for colony formation, with a lower limit of detection of 0.90 log(10) cfu per organ. Three of five mice given ibuprofen and pyrazinamide had culture-negative spleens. CONCLUSIONS: Aspirin and ibuprofen enhance the effect of pyrazinamide during the initial phase of tuberculosis treatment in the mouse model. Further investigation is necessary to determine the impact of NSAIDs on long-term treatment with pyrazinamide and other antituberculosis drugs in the mouse model of tuberculosis infection and the clinical implications of these findings on tuberculosis treatment in humans.