Near-Ideal Copper Oxide Heterostructure Design for Photoelectrochemical Water Splitting.

In recent years, photoelectrochemical (PEC) hydrogen generation through water splitting has gained significant attention as a carbon-free solar-to-energy conversion strategy. Among various materials, copper oxides, specifically cupric oxide (CuO) and cuprous oxide (Cu2O), have been extensively investigated for their suitable band positions and prominent performance, particularly in heterostructures. However, previously reported heterostructures, such as CuO layers on Cu2O, are not ideal configurations in terms of photoelectrical properties. In this study, we introduce the fabrication approach for an ideal heterostructure consisting of Cu2O nanowires on a CuO/Cu2O mixed-phase film, fabricated by a straightforward electrochemical/thermal method. The Cu2O nanowire with Cr layer (CNwC) shows potential for solar energy harvesting due to its suitable band positions and narrow bandgap, enabling enhanced photoabsorption across the entire visible spectrum. A thin chromium (Cr) layer underlying the nanostructure contributes to the formation of the ideal copper oxide heterostructure, acting as an adhesive and protective layer. The Cr layer is oxidized during the fabrication process of the CNwC and supports the hydrogen evolution reaction for water splitting. Moreover, the anodization time critically influences the phase composition, size, and density of the nanowires. Under optimal conditions, collective and slanted Cu2O nanowires can absorb incident light, maximizing both photon absorption and photon-to-energy conversion efficiency.

CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer.

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286-300 (p286) of GAD65. These mice have GAD65-specific CD4(+) T cells, as shown by staining with an I-A(g7)(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4(+) T cells, or p286-tetramer(+)CD4(+) Tcells, from GAD65 286-300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.

The Toxoplasma gondii dense granule protein GRA7 is phosphorylated upon invasion and forms an unexpected association with the rhoptry proteins ROP2 and ROP4.

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals throughout the world and is an opportunistic pathogen of humans. As it invades a host cell, Toxoplasma forms a novel organelle, the parasitophorous vacuole, in which it resides during its intracellular development. The parasite modifies the parasitophorous vacuole and its host cell with numerous proteins delivered from rhoptries and dense granules, which are secretory organelles unique to the phylum Apicomplexa. For the majority of these proteins, little is known other than their localization. Here we show that the dense granule protein GRA7 is phosphorylated but only in the presence of host cells. Within 10 min of invasion, GRA7 is present in strand-like structures in the host cytosol that contain rhoptry proteins. GRA7 strands also contain GRA1 and GRA3. Independently of its phosphorylation state, GRA7 associates with the rhoptry proteins ROP2 and ROP4 in infected host cells. This is the first report of interactions between proteins secreted from rhoptries and dense granules.

The BSR4 protein is up-regulated in Toxoplasma gondii bradyzoites, however the dominant surface antigen recognised by the P36 monoclonal antibody is SRS9.

The protozoan parasite, Toxoplasma gondii, interconverts between fast-growing tachyzoites and slow-growing bradyzoites within intermediate hosts. The surface of T. gondii is covered by the SAG1-related sequence (SRS) superfamily of glycosyl phosphatidyl inositol-anchored proteins, many of which are stage-specific. Previous transient transfection of BSR4, a member of the SRS superfamily, showed reactivity with the bradyzoite-specific P36 mAb by immunofluorescene assay. BSR4 mRNA levels were equally abundant in tachyzoites and bradyzoites, suggesting post-transcriptional regulation of the protein. In this study, we show that BSR4 protein is present in both tachyzoites and bradyzoites, but up-regulated in bradyzoites. However, stable expression of BSR4 in two BSR4-negative T. gondii strains shows minimal reactivity to the P36 mAb by Western immunoblotting, even though the BSR4 protein is abundant. We discovered that the SRS9 protein, a bradyzoite-specific member of the SRS superfamily and encoded immediately downstream of BSR4, was also ablated in the BSR4-negative strains, suggesting that SRS9 is the surface antigen recognised by the P36 mAb. Stable expression of SRS9 in the BSR4 mutant strains shows robust reactivity to the P36 mAb. Immunoprecipitation experiments confirm that the P36 mAb interacts with the SRS9 protein. These data indicate that while the BSR4 protein is up-regulated in bradyzoites, the dominant antigen that the P36 mAb recognises is SRS9.

Phase II study of ifosfamide, etoposide, and oxaliplatin (IFETOx) chemotherapy for relapsed or refractory non-Hodgkin's lymphoma.

As part of an effort to develop a more effective and safe treatment for relapsed or refractory non-Hodgkin's lymphoma (NHL), we conducted a phase II study of the oxaliplatin, etoposide, and ifosfamide (IFETOx) regimen. Patients with relapsed or refractory NHL and a performance status of 0-2 were eligible. The IFETOx consisted of etoposide at 100 mg/m(2) on days 1-3, oxaliplatin at 130 mg/m(2) on day 2, and ifosfamide 5,000 mg/m(2) on day 2, every 21 days. The primary endpoint was the overall response rate (ORR) for IFETOx regimen. A total of 23 eligible patients were enrolled. The median age was 58 years (range 19-76 years), and the male-to-female ratio was 15:8. The disease status was as follows: 15 patients had relapsed and 8 patients were refractory to treatment. The ORR for IFETOx chemotherapy was 65.2 %. In the 15 patients who responded to the protocol treatment, five underwent hematopoietic stem cell transplantation. The 2-year probability of progression-free survival and overall survival rates were 51.4 and 56.1 %, respectively. Grade 3/4 neutropenia was observed in 73.9 % of the patients. No significant renal impairment was observed. In conclusion, IFETOx chemotherapy shows a tolerable toxicity profile and efficacy as a salvage treatment regimen for relapsed or refractory NHL.

Addition of rituximab to reduced-dose CHOP chemotherapy is feasible for elderly patients with diffuse large B-cell lymphoma.

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of reduced-dose (RD) RCHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy for elderly patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This study comprised 85 patients, aged ≥ 60 years, who were diagnosed with DLBCL; patients were enrolled at a single center between June 2004 and December 2009. Patients received either 6 or 8 cycles of RD-RCHOP, spaced 3 weeks apart, at the physician's discretion. The RD-RCHOP regimen consisted of 375 mg/m(2) rituximab, 600 mg/m(2) cyclophosphamide, 30 mg/m(2) doxorubicin, and 1-mg vincristine on day 1 of each cycle, and 40-mg prednisone on days 1-5. The patients received granulocyte colony-stimulating factor if they experienced grade 4 neutropenia or febrile neutropenia during any cycle. RESULTS: The average relative dose intensity was 97.3% for doxorubicin and 97.4% for cyclophosphamide. The complete remission (CR) and overall response rate were 67.1 and 89.5%, respectively. The 3-year event-free survival and overall survival rates were 71.9% ± 5.1% and 83.3% ± 5.1%. By using multivariate analyses, we determined that C-reactive protein levels greater than 1.31 mg/dl and the absence of CR were poor prognostic factors. Grade 3 or 4 neutropenia occurred in 35.3% of patients, and febrile neutropenia occurred in only 3 (3.5%) patients. CONCLUSIONS: RD-RCHOP chemotherapy is well tolerated and effective in elderly patients with DLBCL.

Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling.

Toxoplasma gondii is an obligate intracellular parasite that persists for the life of a mammalian host. The parasite's ability to block the potent IFN-gamma response may be one of the key mechanisms that allow Toxoplasma to persist. Using a genome-wide microarray analysis, we show here a complete dysregulation of IFN-gamma-inducible gene expression in human fibroblasts infected with Toxoplasma. Notably, 46 of the 127 IFN-gamma-responsive genes were induced and 19 were suppressed in infected cells before they were exposed to IFN-gamma, indicating that other stimuli produced during infection may also regulate these genes. Following IFN-gamma treatment, none of the 127 IFN-gamma-responsive genes could be significantly induced in infected cells. Immunofluorescence assays showed at single-cell levels that infected cells, regardless of which Toxoplasma strain was used, could not be activated by IFN-gamma to up-regulate the expression of IFN regulatory factor 1, a transcription factor that is under the direct control of STAT1, whereas uninfected cells in the same culture expressed IFN regulatory factor 1 normally in response to IFN-gamma. STAT1 trafficked to the nucleus normally and indistinguishably in all uninfected and infected cells treated with IFN-gamma, indicating that the inhibitory effects of Toxoplasma infection likely occur via blocking STAT1 transcriptional activity in the nucleus. In contrast, a closely related apicomplexan, Neospora caninum, was unable to inhibit IFN-gamma-induced gene expression. A differential ability to interfere with the IFN-gamma response may, in part, account for the differences in the pathogenesis seen among Toxoplasma and Neospora parasite strains.

Bradyzoite-specific surface antigen SRS9 plays a role in maintaining Toxoplasma gondii persistence in the brain and in host control of parasite replication in the intestine.

Toxoplasma gondii is a ubiquitous parasite that persists for the life of a healthy mammalian host. A latent, chronic infection can reactivate upon immunosuppression and cause life-threatening diseases, such as encephalitis. A key to the pathogenesis is the parasite's interconversion between the tachyzoite (in acute infection) and bradyzoite (in chronic infection) stages. This developmental switch is marked by differential expression of numerous, closely related surface proteins belonging to the SRS (SAG1-related sequence) superfamily. To probe the functions of bradyzoite-specific SRSs, we created a bioluminescent strain lacking the expression of SRS9, one of the most abundant SRSs of the bradyzoite stage. Imaging of mice intraperitoneally infected with tachyzoites revealed that during an acute infection, wild-type and Deltasrs9 strains replicated at similar rates, disseminated systemically following similar kinetics, and initially yielded similar brain cyst numbers. However, during a chronic infection, Deltasrs9 cyst loads substantially decreased compared to those of the wild type, suggesting that SRS9 plays a role in maintaining parasite persistence in the brain. In oral infection with bradyzoite cysts, the Deltasrs9 strain showed oral infectivity and dissemination patterns indistinguishable from those of the wild type. When chronically infected mice were treated with the immunosuppressant dexamethasone, however, the Deltasrs9 strain reactivated in the intestinal tissue after only 8 to 9 days, versus 2 weeks for the wild-type strain. Thus, SRS9 appears to play an important role in both persistence in the brain and reactivation in the intestine. Possible mechanisms for this are discussed.

Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors.

The protozoan parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, instead producing an attraction to the pheromone; this may increase the likelihood of a cat predating a rat. This is thought to reflect adaptive, behavioral manipulation by Toxoplasma in that the parasite, although capable of infecting rats, reproduces sexually only in the gut of the cat. The "behavioral manipulation" hypothesis postulates that a parasite will specifically manipulate host behaviors essential for enhancing its own transmission. However, the neural circuits implicated in innate fear, anxiety, and learned fear all overlap considerably, raising the possibility that Toxoplasma may disrupt all of these nonspecifically. We investigated these conflicting predictions. In mice and rats, latent Toxoplasma infection converted the aversion to feline odors into attraction. Such loss of fear is remarkably specific, because infection did not diminish learned fear, anxiety-like behavior, olfaction, or nonaversive learning. These effects are associated with a tendency for parasite cysts to be more abundant in amygdalar structures than those found in other regions of the brain. By closely examining other types of behavioral patterns that were predicted to be altered we show that the behavioral effect of chronic Toxoplasma infection is highly specific. Overall, this study provides a strong argument in support of the behavioral manipulation hypothesis. Proximate mechanisms of such behavioral manipulations remain unknown, although a subtle tropism on part of the parasite remains a potent possibility.

Stage-specific expression of surface antigens by Toxoplasma gondii as a mechanism to facilitate parasite persistence.

Toxoplasma persists in the face of a functional immune system. This success critically depends on the ability of parasites to activate a strong adaptive immune response during acute infection with tachyzoites that eliminates most of the parasites and to undergo stage conversion to bradyzoites that encyst and persist predominantly in the brain. A dramatic change in antigenic composition occurs during stage conversion, such that tachyzoites and bradyzoites express closely related but antigenically distinct sets of surface Ags belonging to the surface Ag 1 (SAG1)-related sequence (SRS) family. To test the contribution of this antigenic switch to parasite persistence, we engineered parasites to constitutively express the normally bradyzoite-specific SRS9 (SRS9(c)) mutants and tachyzoite-specific SAG1 (SAG1(c)) mutants. SRS9(c) but not wild-type parasites elicited a SRS9-specific immune response marked by IFN-gamma production, suggesting that stage-specificity of SRS Ags determines their immunogenicity in infection. The induction of a SRS9-specific immune response correlated with a continual decrease in the number of SRS9(c) cysts persisting in the brain. In contrast, SAG1(c) mutants produced reduced brain cyst loads early in chronic infection, but these substantially increased over time accompanying a hyperproduction of IFN-gamma, TNF-alpha, and IL-10, and severe encephalitis. We conclude that stage-specific expression of SRS Ags is among the key mechanisms by which optimal parasite persistency is established and maintained.

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells.

Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-gamma and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.