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Introduction: CAR T cell immunotherapy represents a major breakthrough in treatment of hematological tumors. Its manufacture is based on the ex vivo manipulation of human lymphocytes, which are later reinfused to the patient. New methodologies for the generation of CAR T cells are needed, with a focus on reducing the ex vivo manipulation period as well as preventing adverse effects. Here, we produced CAR T cells using DNA-loaded Lipid Nanoparticles (LNPs), assessing the expression anti-CD19 CAR as well as activation of effector cells and specific killing of tumor cells. Methods: To assess the transfection efficiency of LNPs, Jurkat cells were transfected with an LNP encapsulating a pDNA for a second-generation CAR targeting CD19 (LNP-CAR). Activation of transfected Jurkat cells was evaluated by coplating CAR expressing cells with Raji cells for 24 hours at a 1:1 ratio or at different ratios and measuring the expression levels of CD69 in CAR+ cells. Primary human T-cells isolated from healthy donors were transfected with the optimized LNP and coplated with Raji cells to evaluate specific killing by flow cytometry. Results: A peak of CAR+ cells was observed 3 days after transfection, which diminished overtime, indicating the transient expression of CAR in these cells. A screening of LNP-CAR using Jurkat as a model identified an optimized formulation for the transfection of T-cells (LNP-9-CAR). We observed, by evaluating the expression of CD69 in CAR+ cells, that the activation of Jurkat cells transfected with LNP-9-CAR was dependent on the effector-to-target ratio. Primary T lymphocytes transfected with our optimized LNP-9-CAR were effective in killing CD19+ Raji cells also in a ratio-dependent manner. Conclusion: We developed an LNP platform for the delivery of pDNA to produce anti-CD19 CAR T cells ex vivo. This transfection method showed low toxicity to transfected cells even when compared to standard methods. Primary CAR T cells produced using LNP-9-CAR were activated and induced specific killing of CD19+ tumor cells. As a non-viral delivery method, LNPs open an alternative to produce CAR T-cells in less time than viral vectors, thus reducing the associated costs and improving the effectiveness of the adoptive cells. This method can also be applied using other CAR constructs, opening possibilities for the personalized treatment of different tumors, as well as to treat autoimmune diseases and other B-cell related illnesses.

Colorectal carcinoma (CRC) is a common cause of mortality 1 , but a comprehensive description of its genomic landscape is lacking 2-9 . Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli pks+ colibactin in rectal cancers 10 and the importance of the SBS93 signature 11-13 , which suggests that diet or smoking is a risk factor. Immune-escape driver mutations 14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care., (© 2024. The Author(s).)

The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis., (© 2023. The Author(s).)

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

ConspectusDuring the last few decades, the design of catalytic systems for CO 2 reduction has been extensively researched and generally involves (1) traditional approaches using molecular organic/organometallic materials and heterogeneous inorganic semiconductors and (2) combinatory approaches wherein these materials are combined as needed. Recently, we have devised a number of new TiO 2 -mediated multicomponent hybrid systems that synergistically integrate the intrinsic merits of various materials, namely, molecular photosensitizers/catalysts and n -type TiO 2 semiconductors, and lower the energetic and kinetic barriers between components. We have termed such multicomponent hybrid systems assembled from the hybridization of various organic/inorganic/organometallic units in a single platform inorganometallic photocatalysts . The multicomponent inorganometallic (MIOM) hybrid system onto which the photosensitizer and catalyst are coadsorbed efficiently eliminates the need for bulk-phase diffusion of the components and avoids the accumulation of radical intermediates that invokes a degradation pathway, in contrast to the homogeneous system, in which the free reactive species are concentrated in a confined reaction space. In particular, in energetic terms, we discovered that in nonaqueous media, the conduction band (CB) levels of reduced TiO 2 (TiO 2 (e - )) are positioned at a higher level (in the range -1.5 to -1.9 V vs SCE). This energetic benefit of reduced TiO 2 allows smooth electron transfer (ET) from injected electrons (TiO 2 (e - )) to the coadsorbed CO 2 reduction catalyst, which requires relatively high reducing power (at least more than -1.1 V vs SCE). On the other hand, the existence of various shallow surface trapping sites and surface bands, which are 0.3-1.0 eV below the CB of TiO 2 , efficiently facilitates electron injection from any photosensitizer (including dyes having low excited energy levels) to TiO 2 without energetic limitation. This is contrasted with most photocatalytic systems, wherein successive absorption of single high-energy photons is required to produce excited states with enough energy to fulfill photocatalytic reaction, which may allow unwanted side reactions during photocatalysis. In this Account, we present our recent research efforts toward advancing these MIOM hybrid systems for photochemical CO 2 reduction and discuss their working mechanisms in detail. Basic ET processes within the MIOM system, including intervalence ET in organic/organometallic redox systems, metal-to-ligand charge transfer of organometallic complexes, and interfacial/outer-sphere charge transfer between components, were investigated by conducting serial photophysical and electrochemical analyses. Because such ET events occur primarily at the interface between the components, the efficiency of interfacial ET between the molecular components (organic/organometallic photosensitizers and molecular reduction catalysts) and the bulk inorganic solid (mainly n -type TiO 2 semiconductors) has a significant influence on the overall photochemical reaction kinetics and mechanism. In some TiO 2 -mediated MIOM hybrids, the chemical attachment of organic or organometallic photosensitizing units onto TiO 2 semiconductors efficiently eliminates the step of diffusion/collision-controlled ET between components and prevents the accumulation of reactive species (oxidatively quenched cations or reductively quenched anions) in the reaction solution, ensuring steady photosensitization over an extended reaction period. The site isolation of a single-site organometallic catalyst employing TiO 2 immobilization promotes the monomeric catalytic pathway during the CO 2 reduction process, resulting in enhanced product selectivity and catalytic performance, including lifetime extension. In addition, as an alternative inorganic solid scaffold, the introduction of a host porphyrin matrix (interlinked in a metal-organic framework (MOF) material) led to efficient and durable photocatalytic CO 2 conversion by the new MOF-Re(I) hybrid as a result of efficient light harvesting/exciton migration in the porphyrinic MOF and rapid quenching of the photogenerated electrons by the doped Re(I) catalytic sites. Overall, the case studies presented herein provide valuable insights for the rational design of advanced multicomponent hybrid systems for artificial photosynthesis involving CO 2 reduction.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote "off-the-shelf" precision immunotherapies, alleviating limitations of personalized treatments.

Ovarian cancer (OC) represents the most common and lethal gynecologic malignancy, due to its increased incidence and mortality rate. It is usually diagnosed in advanced stages and, even though surgery and platinum-based treatments are initially efficient, recurrences emerge in over 70% of cases. Although there are multiple options of chemotherapy drugs from which to choose, little is known regarding the best strategy for prolonged survival. Thus, this study aimed to assess the effect that most frequently used chemotherapeutic regimens have upon time-to-treatment-failure (TTF) from the first line and beyond, considering clinical and biological factors which influence the treatment outcome of platinum-resistant recurrent OC. We retrospectively analyzed data from 78 patients diagnosed with platinum-resistant OC, who underwent chemotherapy-based treatment with or without anti-angiogenic therapy at OncoHelp Oncology Center, Romania (January 2016-February 2021). Our study identified positive predictive factors for TTF related to histology (serous carcinoma subtype), anthropometry (age over 60 for patients treated with topotecan with or without bevacizumab), renal function (creatinine levels between 0.65 and 1 mg/dL for patients treated with regimens containing bevacizumab and pegylated liposomal doxorubicin) and treatment choice (bevacizumab in combination with pegylated liposomal doxorubicin or topotecan used from the first line and beyond).

The glycolytic modulator TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) is overexpressed in several types of cancer and has a role in metabolic rewiring during tumor development. However, little is known about the role of this enzyme in proliferative tissues under physiological conditions. In the current work, we analysed the role of TIGAR in primary human lymphocytes stimulated with the mitotic agent Concanavalin A (ConA). We found that TIGAR expression was induced in stimulated lymphocytes through the PI3K/AKT pathway, since Akti-1/2 and LY294002 inhibitors prevented the upregulation of TIGAR in response to ConA. In addition, suppression of TIGAR expression by siRNA decreased the levels of the proliferative marker PCNA and increased cellular ROS levels. In this model, TIGAR was found to support the activity of glucose 6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentose phosphate pathway (PPP), since the inhibition of TIGAR reduced G6PDH activity and increased autophagy. In conclusion, we demonstrate here that TIGAR is upregulated in stimulated human lymphocytes through the PI3K/AKT signaling pathway, which contributes to the redirection of the carbon flux to the PPP.

A porphyrinic metal-organic framework ( PMOF ) known as PCN-222(Zn) was chemically doped with a molecular Re(I) catalyst-bearing carboxylate anchoring group to form a new type of metal-organic framework (MOF)-Re(I) hybrid photocatalyst. The porphyrinic MOF-sensitized hybrid ( PMOF/Re ) was prepared with an archetypical CO 2 reduction catalyst, (L)Re I (CO) 3 Cl (Re(I); L = 4,4'-dicarboxylic-2,2'-bipyridine), in the presence of 3 vol % water produced CO with no leveling-off tendency for 59 h to give a turnover number of ≥1893 [1070 ± 80 μmol h -1 (g MOF) -1 ]. The high catalytic activity arises mainly from efficient exciton migration and funneling from photoexcited porphyrin linkers to the peripheral Re(I) catalytic sites, which is in accordance with the observed fast exciton (energy) migration (≈1 ps) in highly ordered porphyrin photoreceptors and the effective funneling into Re(I) catalytic centers in the Re(I)-doped PMOF sample. Enhanced catalytic performance is convincingly supported by serial photophysical measurements including decisive Stern-Volmer interpretation.

Oligothiophene derivatives, which are known as p-type materials, have been synthesized, and their ultrathin layer-by-layer films have been constructed on an electrode using a simple and convenient dipping method. The stepwise deposition behavior of quaterthiophene and sexithiophene derivatives on the electrode via hydrogen bonding was monitored by electronic spectra measurement, and the constructed films were evaluated by X-ray photoelectron spectroscopy, grazing-incidence small-angle X-ray scattering, and cyclic voltammetry. It has been clarified that the constructed layer-by-layer films were electroactive and photoelectroactive.

Herein, we report the synthesis, and photochemical and -physical properties, as well as the catalytic performance, of a series of heteroleptic Ir III photosensitizers (IrPSs), [Ir(C^N) 2 (N^N Aryl )] + , possessing ancillary ligands that are varied with aryl-substituents on bipyridyl unit [C^N=(2-pyridyl)benzo[b]thiophen-3-yl (btp); N^N Aryl =4,4'-Y 2 -bpy (Y=-Ph or -PhSi(Ph) 3 ]. We found that the π-extension of bipyridyl ligand by aryl-substitution put bipyridyl ligand in use as an electron relay unit that performed charge accumulation before delivering to the catalytic center, greatly improving the overall CO 2 -to-CO conversion activities. In a typical run, the aryl-substituted IrPS ( tBu IrP-Ph Si )-sensitized homogeneous systems (IrPS+Re I catalyst) gave a turnover number of 1340 (Φ CO =24.2 %) at the early stage of photolysis (<5 h). This study demonstrates that the π-character modulation on the ancillary bipyridyl ligand is critical for forthcoming catalytic performance., (© 2020 Wiley-VCH GmbH.)

A fundamental goal in cancer research is to understand the mechanisms of cell transformation. This is key to developing more efficient cancer detection methods and therapeutic approaches. One milestone towards this objective is the identification of all the genes with mutations capable of driving tumours. Since the 1970s, the list of cancer genes has been growing steadily. Because cancer driver genes are under positive selection in tumorigenesis, their observed patterns of somatic mutations across tumours in a cohort deviate from those expected from neutral mutagenesis. These deviations, which constitute signals of positive selection, may be detected by carefully designed bioinformatics methods, which have become the state of the art in the identification of driver genes. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In this Review, we present the Integrative OncoGenomics (IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational cancer drivers. Its application to somatic mutations of more than 28,000 tumours of 66 cancer types reveals 568 cancer genes and points towards their mechanisms of tumorigenesis. The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion 1,2 . Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

A series of heteroleptic iridium(III) complexes functionalized with two phosphonic acid (-PO 3 H 2 ) groups ( dfppy IrP, ppy IrP, btp IrP, and piq IrP) were prepared and anchored onto rhenium(I) catalyst (ReP)-loaded TiO 2 particles (TiO 2 /ReP) to build up a new IrP-sensitized TiO 2 photocatalyst system (IrP/TiO 2 /ReP). The photosensitizing behavior of the IrP series was examined within the IrP/TiO 2 /ReP platform for the photocatalytic conversion of CO 2 into CO. The four IrP-based ternary hybrids showed increased conversion activity and durability than that of the corresponding homo- (IrP+ReP) and heterogeneous (IrP+TiO 2 /ReP) mixed systems. Among the four IrP/TiO 2 /ReP photocatalysts, the low-energy-light (>500 nm) activated piq IrP immobilized ternary system ( piq IrP/TiO 2 /ReP) exhibited the most durable conversion activity, giving a turnover number of ≥730 for 170 h. A similar kinetic feature observed through time-resolved photoluminescence measurements of both btp IrP/TiO 2 and TiO 2 -free btp IrP films suggests that the net electron flow in the ternary hybrid proceeds dominantly through a reductive quenching mechanism, unlike the oxidative quenching route of typical dye/TiO 2 -based photolysis., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Red light-sensitized squaraine ( SQ ) dyes were developed and incorporated into dye-sensitized catalysts (DSCs) with the formula of SQ /TiO 2 /Cat, and their efficacies were evaluated in terms of performance on either water or carbon dioxide reduction. Pt nanoparticles or fac -[Re(4,4'-bis-(diethoxyphosphorylmethyl)-2,2'-bipyridine)(CO) 3 Cl] were used as each catalytic center within the DSC frame of SQ /TiO 2 /Pt (Type I) or SQ /TiO 2 /Re(I) (Type II). In order to convey the potential utility of SQ in low energy sensitization, the following catalytic reductions were carried out under selective lower energy irradiation (>500 nm). Type I and II showed different catalytic performances, primarily due to the choice of solvent for each catalytic condition: hydrogenation was carried out in H 2 O, but CO 2 reduction in dimethylformamide (DMF), and SQ was more stable in aqueous acid conditions for hydrogen generation than CO 2 reduction in DMF. A suspension of Type I in 3 mL water containing 0.1 M ascorbic acid (pH = 2.66) resulted in efficient photocatalytic hydrogen evolution, producing 37 μmol of H 2 for 4 h. However, in photocatalysis of Type II ( SQ /TiO 2 /Re(I)) in 3 mL DMF containing 0.1 M 1,3-dimethyl-2-phenyl-1,3-dihydrobenzimidazole, the TiO 2 -bound SQ dyes were not capable of working as a low energy sensitizer because SQ was susceptible to dye decomposition in nucleophilic DMF conditions, resulting in DSC deactivation for the CO 2 reduction. Even with the limitation of solvent, the DSC conditions for the utility of SQ have been established: the anchoring group effect of SQ with either phosphonic acid or carboxylic acid onto the TiO 2 surface; energy alignment of SQ with the flat band potentials ( E fb ) of TiO 2 semiconductors and the reduction power of electron donors; and the wavelength range of the light source used, particularly when >500 nm., Competing Interests: The authors declare no competing financial interest.

Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose 2,6-bisphosphate (Fru-2,6-P 2 ) and the enzyme responsible for its synthesis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). PFKFB3 gene, which encodes for the most abundant PFK-2 isoenzyme in proliferating tissues, has been found overexpressed during cell activation in several models, including immune cells. However, there is limited knowledge on the pathways underlying PFKFB3 regulation in human T-lymphocytes, and the role of this gene in human immune response. The aim of this work is to elucidate the molecular mechanisms of PFKFB3 induction during human T-lymphocyte activation by mitotic agents. The results obtained showed PFKFB3 induction during human T-lymphocyte activation by mitogens such as phytohemagglutinin (PHA). PFKFB3 increase occurred concomitantly with GLUT-1, HK-II, and PCNA upregulation, showing that mitotic agents induce a metabolic reprograming process that is required for T-cell proliferation. PI3K-Akt pathway inhibitors, Akti-1/2 and LY294002, reduced PFKFB3 gene induction by PHA, as well as Fru-2,6-P 2 and lactate production. Moreover, both inhibitors blocked activation and proliferation in response to PHA, showing the importance of PI3K/Akt signaling pathway in the antigen response of T-lymphocytes. These results provide a link between metabolism and T-cell antigen receptor signaling in human lymphocyte biology that can help to better understand the importance of modulating both pathways to target complex diseases involving the activation of the immune system.

A series of cationic Ir(III) complexes ([Ir(btp) 2 (bpy-X 2 )] + (Ir-X + : btp = (2-pyridyl)benzo[b]thiophen-3-yl; bpy-X 2 = 4,4'-X 2 -2,2'-bipyridine (X = OMe, t Bu, Me, H, and CN)) were applied as visible-light photosensitizer to the CO 2 reduction to CO using a hybrid catalyst (TiO 2 /ReP) prepared by anchoring of Re(4,4'-Y 2 -bpy)(CO) 3 Cl (ReP; Y = CH 2 PO(OH) 2 ) on TiO 2 particles. Irradiation of a solution containing Ir-X + , TiO 2 /ReP particles, and an electron donor (1,3-dimethyl-2-phenyl-1,3-dihydrobenzimidazole) in N,N-dimethylformamide at greater than 400 nm resulted in the reduction of CO 2 to CO with efficiencies in the order X = OMe > t Bu ≈ Me > H; Ir-CN + has no photosensitization effect. A notable observation is that Ir- t Bu + and Ir-Me + are less efficient than Ir-OMe + at an early stage of the reaction but reveal persistent photosensitization behavior for a much longer period of time unlike the latter. Comparable experiments showed that (1) the Ir-X + sensitizers are commonly superior compared to Ru(bpy) 3 2+ , a widely used transition-metal photosensitizer, and (2) the system comprising Ir-OMe + and TiO 2 /ReP is much more efficient than a homogeneous-solution system using Ir-OMe + and Re(4,4'-Y' 2 -bpy)(CO) 3 Cl (Y' = CH 2 PO(OEt) 2 ). Implications of the present observations involving reaction mechanisms associated with the different behavior of the photosensitizers are discussed in detail.

Efficient hybrid photocatalysts for carbon dioxide reduction were developed from dye-sensitized TiO 2 nanoparticles and their catalytic performance was optimized by ternary organic/inorganic components. Thus, the hybrid system consists of (E)-2-cyano-3-(5'-(5''-(p-(diphenylamino)phenyl)thiophen-2''-yl)thiophen-2'-yl)-acrylic acid as a sensitizer and fac-[Re(4,4'-bis(diethoxyphosphorylmethyl)-2,2'-bipyridine)(CO) 3 Cl] as a reduction catalyst (ReP), both of which have been fixed onto TiO 2 semiconductors (s-TiO 2 , h-TiO 2 , d-TiO 2 ). Mott-Schottky analysis on flat-band potential (E fb ) of TiO 2 mesoporous films has verified that E fb can be finely modulated by volume variation of water (0 to 20 vol%). The increase of added water resulted in substantial positive shifts of E fb from -1.93 V at 0 vol% H 2 O, to -1.74 V (3 vol% H 2 O), to -1.56 V (10 vol% H 2 O), and to -1.47 V (20 vol% H 2 O). As a result, with addition of 3-10 vol% water in the photocatalytic reaction, conversion efficiency of CO 2 to CO increased significantly reaching a TON value of ∼350 for 30 h. Catalytic activity enhancement is mainly attributed to (1) the optimum alignment of E fb by 3-10 vol% water with respect to the of the dye and E red of ReP for smooth electron transfer from photo-excited dye to RePvia the TiO 2 semiconductor and (2) the water-induced acceleration of chemical processes on the fixed ReP. In addition, the energy level was further tuned by variation of the dye and ReP amounts. We also found that the intrinsic properties of TiO 2 sources (morphology, size, agglomeration) exert a great influence on the overall photocatalytic activity of this hybrid system. Implications of the present observations and reaction mechanisms are discussed in detail.

We investigated the electrochemical and excited-state properties of 2,3-bis(2-pyridyl)pyrazine (dpp)-bridged bimetallic complexes, (L) 2 Ir-dpp-PtCl [1, L = 2-(4',6'-difluorophenyl)pyridinato-N,C 2 (dfppy); 2, L = 2-phenylpyridinato-N,C 2 (ppy)] and [(L) 2 Ir] 2 (dpp) [3, L = dfppy; 4, L = ppy] compared to monometallic complexes, (L) 2 Ir-dpp (5, L = dfppy; 6, L = ppy) and dpp-PtCl (dpp-Pt II Cl 2 ; 7). The single-crystal X-ray crystallographic structures of 1, 3, 5, and 6 showed that 1 and 3 have approximately coplanar structures of the dpp unit, while the noncoordinated pyridine ring of dpp in 5 and 6 is largely twisted with respect to the pyrazine ring. We found that the properties of the bimetallic complex significantly depended on the electronic and geometrical modulations of each fragment: (1) electronic structure of the main L (C^N) ligand in an iridium chromophore (L = dfppy or ppy) and (2) planarity of the bridging ligand (dpp). Their electrochemical and photophysical properties revealed that efficient electron-transfer processes predominated in the bimetallic systems regardless of the second metal participation. The low efficiencies of photoluminescence of dpp-bridged Ir-Pt and Ir-Ir bimetallic complexes (1-4) could be explained by assuming the involvement of crossing to platinum- and iridium-based d-d states from the emissive state. Such stereochemical and electronic situations around dpp allowed thermally activated crossing to platinum- and iridium-based d-d states from the emissive triplet metal-to-ligand charge-transfer ( 3 MLCT) state, followed by cleavage of the dpp-Pt and (L) 2 Ir-dpp bonds. The transient absorption study further confirmed that the planarity of the dpp bridging ligand, which was defined as the magnitude of tilt between the pyridine ring and pyrazine, had a direct correlation with the degree of nonradiative decay from the emissive iridium-based 3 MLCT to the Ir d-d or Pt d-d state, leading to photoinduced dissociation of bimetallic complexes. From the dissociation pattern of metal complexes analyzed after photoirradiation, we found that their dissociation pathways were directly related to the quenching direction (either Ir d-d or Pt d-d) with a significant dependency on the relative 3 MLCT levels of the (L) 2 Ir-dpp component.

Visible-light irradiation of a ternary hybrid catalyst prepared by grafting a dye, an H 2 evolving Co III catalyst and a CO-producing Re I catalyst on TiO 2 have been found to produce both H 2 and CO (syngas) in CO 2 -saturated N,N-dimethyl formamide (DMF)/water solution containing a 0.1 m sacrificial electron donor. The H 2 /CO ratios are effectively controlled by changing either the water content of the solvent or the molar ratio of the Re I and Co III catalysts ranging from 1:2 to 15:1. The controlled syngas formation is discussed in terms of competitive electron flow from TiO 2 to each of the CO 2 -reduction and hydrogen-evolving sites depending on the efficiencies of the two catalytic reaction cycles under given reaction conditions., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Improvement of the stability of blue phosphorescent dopant material is one of the key factors for real application of organic light-emitting diodes (OLEDs). In this study, we found that the intramolecular hydrogen bonding in an ancillary ligand from a heteroleptic Ir(III) complex can play an important role in the stability of blue phosphorescence. To rationalize the role of intramolecular hydrogen bonding, a series of Ir(III) complexes is designed and prepared: Ir(dfppy)2(pic-OH) (1a), Ir(dfppy)2(pic-OMe) (1b), Ir(ppy)2(pic-OH) (2a), and Ir(ppy)2(pic-OMe) (2b). The emission lifetime of Ir(dfppy)2(pic-OH) (1a) (τem = 3.19 μs) in dichloromethane solution was found to be significantly longer than that of Ir(dfppy)2(pic-OMe) (1b) (τem = 0.94 μs), because of a substantial difference in the nonradiative decay rate (knr = 0.28 × 10(5) s(-1) for (1a) vs 2.99 × 10(5) s(-1) for (1b)). These results were attributed to the intramolecular OH···O═C hydrogen bond of the 3-hydroxy-picolinato ligand. Finally, device lifetime was significantly improved when 1a was used as the dopant compared to FIrpic, a well-known blue dopant. Device III (1a as dopant) achieved an operational lifetime of 34.3 h for an initial luminance of 400 nits compared to that of device IV (FIrpic as dopant), a value of 20.1 h, indicating that the intramolecular hydrogen bond in ancillary ligand is playing an important role in device stability.

Herein we report a detailed investigation of a highly robust hybrid system (sensitizer/TiO2/catalyst) for the visible-light reduction of CO2 to CO; the system comprises 5'-(4-[bis(4-methoxymethylphenyl)amino]phenyl-2,2'-dithiophen-5-yl)cyanoacrylic acid as the sensitizer and (4,4'-bis(methylphosphonic acid)-2,2'-bipyridine)Re(I)(CO)3Cl as the catalyst, both of which have been anchored on three different types of TiO2 particles (s-TiO2, h-TiO2, d-TiO2). It was found that remarkable enhancements in the CO2 conversion activity of the hybrid photocatalytic system can be achieved by addition of water or such other additives as Li(+), Na(+), and TEOA. The photocatalytic CO2 reduction efficiency was enhanced by approximately 300% upon addition of 3% (v/v) H2O, giving a turnover number of ≥570 for 30 h. A series of Mott-Schottky (MS) analyses on nanoparticle TiO2 films demonstrated that the flat-band potential (V(fb)) of TiO2 in dry DMF is substantially negative but positively shifts to considerable degrees in the presence of water or Li(+), indicating that the enhancement effects of the additives on the catalytic activity should mainly arise from optimal alignment of the TiO2 V(fb) with respect to the excited-state oxidation potential of the sensitizer and the reduction potential of the catalyst in our ternary system. The present results confirm that the TiO2 semiconductor in our heterogeneous hybrid system is an essential component that can effectively work as an electron reservoir and as an electron transporting mediator to play essential roles in the persistent photocatalysis activity of the hybrid system in the selective reduction of CO2 to CO.

Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development., (©2015 American Association for Cancer Research.)

Hybrid systems prepared by fixing a Re(i) complex and a dye on three types of TiO2 nanoparticles in two different ways commonly revealed persistent photocatalysis of the CO2 reduction to CO with no levelling-off tendency under visible-light irradiation in DMF, giving a turnover number of ≥435.

Visible-light-driven H(2) evolution based on Dye/TiO(2)/Pt hybrid photocatalysts was investigated for a series of (E)-3-(5'-{4-[bis(4-R(1)-phenyl)amino]phenyl}-4,4'-(R(2))(2)-2,2'-bithiophen-5-yl)-2-cyanoacrylic acid dyes. Efficiencies of hydrogen evolution from aqueous suspensions in the presence of ethylenediaminetetraacetic acid as electron donor under illumination at λ>420 nm were found to considerably depend on the hydrophilic character of R(1), varying in the order MOD (R(1)=CH(3)OCH(2), R(2)=H)≈MO4D (R(1)=R(2)=CH(3)OCH(2))>HD (R(1)=R(2)=H)>PD (R(1)=C(3)H(7), R(2)=H). In the case of MOD/TiO(2)/Pt, the apparent quantum yield for photocatalyzed H(2) generation at 436 nm was 0.27±0.03. Transient absorption measurements for MOD- or PD-grafted transparent films of TiO(2) nanoparticles dipped into water at pH 3 commonly revealed ultrafast formation (<100 fs) of the dye radical cation (Dye(·+) ) followed by multicomponent decays, which involve minor fast decays (<5 ps) almost independent of R(1) and major slower decays with significant differences between the two samples: 1) the early decay of the major components for MOD is about 2.5 times slower than that for PD and 2) a redshift of the spectrum occurred for MOD with a time constant of 17 ps, but not for PD. The substituent effects on H(2) generation as well as on transient behavior have been discussed in terms substituent-dependent charge recombination (CR) of Dye(·+) with electrons in bulk, inner-trap, and/or interstitial-trap states, arising from different solvent reorganization., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Effects of intermolecular interactions on the occupied electronic structure of amorphous solid of a carbazole-based material were investigated under an assumption that the organic solid consists of randomly oriented assemblies of dimers. The electronic energy states were calculated on the ensemble of large number of random dimers, of which geometries are relaxed using semiempirical van der Waals density functional theory. Intermolecular interactions result in splitting of energy level, and further disorders occur by aggregation of randomly orientated molecules. As a result, frontier occupied energy states can be represented by a superposition of Gaussian distributions, including (i) a main distribution with full width at half maximum of 80-110 meV, depending on the methods of relaxation and (ii) shoulders separated from the center of the main distribution with a value as large as 150 meV. A possible origin for the appearance of these shoulders was ascribed to the presence of molecular assemblies consisting of more tightly bound dimers compared with the others.

A bright combination: a new type of donor-acceptor dyad, carbazolylaryl-substituted ortho-carboranes, which are conveniently prepared from the corresponding acetylenes and decaborane pathways, showed unique excited-state behavior associated with electron transfer unlike the meta- and para-counterparts., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We prepared a series of new heteroleptic ruthenium(II) complexes, Ru(NCS)(2)LL' (3a-3e), where L is 4,4'-di(hydroxycarbonyl)-2,2'-bipyridine and L' is 4,4'-di(p-X-phenyl)-2,2'-pyridine (X = CN (a), F (b), H (c), OMe (d), and NMe(2) (e)), in an attempt to explore the structure-activity relationships in their photophysical and electrochemical behavior and in their performance in dye-sensitized solar cells (DSSCs). When substituent X is changed from electron-donating NMe(2) to electron-withdrawing CN, the absorption and emission maxima reveal systematic bathochromic shifts. The redox potentials of these dyes are also significantly influenced by X. The electronic properties of the dyes were theoretically analyzed using density functional theory calculations; the results show good correlations with the experimental results. The solar-cell performance of DSSCs based on dye-grafted nanocrystalline TiO(2) using 3a-3e and standard N3 (bis[(4,4'-carboxy-2,2'-bipyridine)(thiocyanato)]ruthenium(II)) were compared, revealing substantial dependences on the dye structures, particularly on the remote substituent X. The 3d-based device showed the best performance: η = 8.30%, J(SC) = 16.0 mA·cm(-2), V(OC) = 717 mV, and ff = 0.72. These values are better than N3-based device.

A series of dyes were synthesized to examine the roles of the hydrophilic characteristics of R in sensitized hydrogen generation by dye-grafted Pt/TiO(2) under visible light irradiation. The hydrogen-generation efficiencies and optimum amounts of the dyes grafted to Pt/TiO(2) were affected substantially by the hydrophilic and steric effects of R; moderately hydrophilic DEO1 and DEO2 showed higher sensitization activity at a lower loading than hydrophobic D-H.

The direct coupling reactions of 1,8-naphthalimide compounds efficiently occurred at 130 or 170 degrees C without the intervention of the leuco form dyes in the presence of base complex reagent, t-BuOK/1,5-diazabicyclo[4.3.0]non-5-ene (DBN), to give the corresponding perylene dyes in good yields with > 95% purities. A possible mechanistic speculation for these oxidative coupling reactions is briefly discussed.

The oxidation reactions of hydroquinones, 2-naphthols, or 2,6-di-tert-butylphenol efficiently occurred by catalysis with alumina-supported copper(II) sulfate to give the corresponding benzoquinones, 1,1'-bi-2-naphthols, and 4,4'-diphenoquinone, respectively, in good yields. The synthetic potentiality of the catalytic reactions was demonstrated by easy isolation of the final products using only filtration and solvent evaporation as well as by application to large-scale syntheses of the benzoquinones and binaphthols. The catalysis with alumina-supported copper(II) sulfate was also applied to the oxidative intramolecular coupling of 5,5'-diacenaphthene to the corresponding perylene compound.

We have investigated the photosensitized monomerization of the cis,syn-cyclobutane dimer of 1,3-dimethylthymine using riboflavin tetraacetate and a 5-deazaflavin derivative as photosensitizer. Although little monomerization of the dimer is induced by photoexcitation of the flavins in the absence of any additives, the flavins can function as an efficient photosensitizer in the presence of magnesium perchlorate. Mechanistic studies involving spectroscopic, quantum-yield and flash-photolysis measurements demonstrated that the photosensitized monomerization exclusively proceeds through electron transfer from the dimer to the triplet flavins complexed with Mg2+. The effects of magnesium perchlorate are compared with those on the chloranil-photosensitized monomerization and also with the effects of HClO4 on the flavin-photosensitized reaction.

The photosensitized monomerization of the cyclobutane dimers of 1,3-dimethylthymine by p-chloranil was investigated by means of steady-state irradiation and laser-flash photolysis. Quantum yields for the monomerization are 0.34 for the cis,syn dimer, 0.39 for the trans,syn dimer, and much less than 10(-2) for the cis,anti isomer. Formation of the chloranil anion radical associated with quenching of triplet chloranil by the dimers demonstrates that electron transfer from dimers to triplet chloranil occurs to initiate the monomerization. Kinetic analysis suggested that the syn-dimer cation radicals undergo the ring cleavage at greater than or equal to 10(9) s-1 before escaping from the solvent cage, while the reactivity of the anti-dimer cation radical is very low. The different reactivities of the syn and anti dimer cation radicals are discussed in terms of through-bond coupling between the n orbitals of N(1) and N(1') involving the cyclobutane-ring sigma orbitals. In the cases of the syn-dimers, the sensitizer-dimer ion-radical pairs undergo the rapid geminate recombination that works as a major energy dissipating channel responsible for the lower-than-unity quantum yields. It has been found that the presence of Mg(ClO4)2 at 0.1 M enhances approximately 1.5 times either the monomerization of the syn dimers or the formation of the chloranil anion radical. A laser-flash photolysis study shows that Mg2+ forms a complex with either the triplet or the anion radical of chloranil. The net salt effects are attributed to the retardation of the rapid geminate recombination by the participation of Mg2+ in the sensitizer-dimer ion-radical pairs.