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Assembly of pluripotent stem cells to initiate self-organized tissue formation on engineered scaffolds is an important process in stem cell engineering. Pluripotent stem cells are known to exist in diverse pluripotency states, with heterogeneous subpopulations exhibiting differential gene expression levels, but how such diverse pluripotency states orchestrate tissue formation is still an unrevealed question. In this study, using microstructured adhesion-limiting substrates, we aimed to clarify the contribution to self-organized layer formation by mouse embryonic stem cells in different pluripotency states: ground and naïve state. We found that while ground state cells as well as sorted REX1-high expression cells formed discontinuous cell layers with limited lateral spread, naïve state cells could successfully self-organize to form a continuous layer by progressive mesh closure within 3 days. Using sequential immunofluorescence microscopy to examine the mesh closure process, we found that KRT8+ cells were particularly localized around unfilled holes, occasionally bridging the holes in a manner suggestive of their role in the closure process. These results highlight that compared with ground state cells, naïve state cells possess a higher capability to contribute to self-organized layer formation by mesh closure. Thus, this study provides insights with implications for the application of stem cells in scaffold-based tissue engineering.

The 13th Symposium on Polar Science/Ordinary sessions [OM] Polar meteorology and glaciology, Wed. 16 Nov.

The 13th Symposium on Polar Science/Ordinary sessions [OM] Polar meteorology and glaciology, Wed. 16 Nov.

Though TCRs have been subject to limited engineering in the context of therapeutic design and optimization, they are used largely as found in nature. On the other hand, CARs are artificial, composed of different segments of proteins that function in the immune system. This characteristic raises the possibility of altered response to immune regulatory stimuli. Here we describe a large-scale, systematic comparison of CARs and TCRs across 5 different pMHC targets, with a total of 19 constructs examined in vitro. These functional measurements include CAR- and TCR-mediated activation, proliferation, and cytotoxicity in both acute and chronic settings. Surprisingly, we find no consistent difference between CARs and TCRs as receptor classes with respect to their relative sensitivity to major regulators of T cell activation: PD-L1, CD80/86 and IL-2. Though TCRs often emerge from human blood directly as potent, selective receptors, CARs must be heavily optimized to attain these properties for pMHC targets. Nonetheless, when iteratively improved and compared head to head in functional tests, CARs appear remarkably similar to TCRs with respect to immune modulation.

Tumor immunotherapy is rapidly evolving as one of the major pillars of cancer treatment. Cell-based immunotherapies, which utilize patient's own immune cells to eliminate cancer cells, have shown great promise in treating a range of malignancies, especially those of hematopoietic origins. However, their performance on a broader spectrum of solid tumor types still fall short of expectations in the clinical stage despite promising preclinical assessments. In this review, we briefly introduce cell-based immunotherapies and the inhibitory mechanisms in tumor microenvironments that may have contributed to this discrepancy. Specifically, a major obstacle to the clinical translation of cell-based immunotherapies is in the lack of preclinical models that can accurately assess the efficacies and mechanisms of these therapies in a (patho-)physiologically relevant manner. Lately, tissue engineering and organ-on-a-chip tools and microphysiological models have allowed for more faithful recapitulation of the tumor microenvironments, by incorporating crucial tumor tissue features such as cellular phenotypes, tissue architecture, extracellular matrix, physical parameters, and their dynamic interactions. This review summarizes the existing engineered tumor models with a focus on tumor immunology and cell-based immunotherapy. We also discuss some key considerations for the future development of engineered tumor models for immunotherapeutics. STATEMENT OF SIGNIFICANCE: Cell-based immunotherapies have shown great promise in treating hematological malignancies and some epithelial tumors. However, their performance on a broader spectrum of solid tumor types still fall short of expectations. Major obstacles include the inhibitory mechanisms in tumor microenvironments (TME) and the lack of preclinical models that can accurately assess the efficacies and mechanisms of cellular therapies in a (patho-)physiologically relevant manner. In this review, we introduce recent progress in tissue engineering and microphysiological models for more faithful recapitulation of TME for cell-based immunotherapies, and some key considerations for the future development of engineered tumor models. This overview will provide a better understanding on the role of engineered models in accelerating immunotherapeutic discoveries and clinical translations.

The Sahel region, located between the tropical rainforests of Africa and the Sahara Desert, has rainfall that varies widely from year to year, associated with extremely deep convection. This deep convection, strongly heated by water vapor condensation, suggests the possibility of exerting a remote influence on mid- and high-latitude climate similar to the well-known influences of tropical oceanic convection on global climate. Here we investigate the possibility that deep convection over the Sahel initiates a semi-circumglobal teleconnection extending to eastern Eurasia. Statistical analysis and numerical experiments support the possible existence of this teleconnection at an interannual time scale. We propose that the anomalous heat source due to deep convection over the Sahel in the late monsoon season influences meandering of the mid-latitude jet stream over Europe through the combination of a Matsuno-Gill response and advection of absolute vorticity. This subtropical jet meander may in turn drive an eastward propagation of a Rossby wave across Eurasia as far as East Asia. Because deep convection over other subtropical land areas may exert a similar remote influence upon extratropical extreme weather, further studies of the influence of overland convection may provide us with an expanded comprehension of teleconnections.

TheCEACAM5gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)–based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02–expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.

Granules prepared by a continuous twin screw granulator (TSG) were analyzed by X-ray micro-computed tomography (X-ray μCT) and the relationships between porosity of granules and granule properties were investigated. A model formulation containing ibuprofen, lactose monohydrate, microcrystalline cellulose, and hydroxypropyl cellulose was used. The porosity of granules was measured by X-ray μCT and mercury porosimetry. The data sets obtained by both methods showed linear correlation despite different values, which were attributed to the resolution of X-ray μCT and a low-signal-to-noise ratio of the original cross-sectional images. The porosity of granules measured by X-ray μCT decreased from 11-14 to 6-7% as liquid-to-solid ratio (L/S) increased, while the standard deviation (S.D.) of the porosity of individual granules decreased from 4-5 to 2%. L/S affected the porosity of granules. By contrast, the effect of screw speed was not significant. Pressure transmission, G, which indicates the liquid dispersion in wet kneaded masses, increased as the porosity of granules and the S.D. decreased. The cross-sectional images showed that granules were densified as L/S increased. Based on these results, the effect of L/S on the porosity of granules can be explained by liquid dispersion and densification of the wet granules. The porosity of granules measured by X-ray μCT showed good linear correlation with friability and drug dissolution rate (R2 = 0.9107 and 0.8834, respectively). This study revealed that the drug dissolution rate was regulated by a disintegration step in which the porosity of granules plays an important role.

In North America and Asia, extreme cold weather characterized the winter of 2017–18. At the same time, the Pacific, the Bering Sea, and the Atlantic Arctic regions experienced anomalously low sea ice extent in the early winter. The jet stream dividing cold Arctic air from warm air deviated from normal zonal patterns northward into the ice-free areas north of the Bering Strait. Large southward jet stream pathways formed over Asia and America, allowing cold air to spread into Asia and the southern areas of North America. We hypothesise that the late autumn Bering Strait sea-ice anomaly and Pacific atmospheric rivers were partially responsible for the cold winter. We used data analyses and numerical experiments to test this hypothesis. We propose a positive feedback mechanism between the sea ice anomaly and atmospheric river activity, with anomalous south winds toward the sea ice anomaly potentially leading to more warm water injected by the wind-driven current through the Bering Strait. Our findings suggest that Poleward propagation of the atmospheric rivers made upper air warm, leading to their upgliding, which further heated the overlying air, causing poleward jet meanders. As a part of this response the jet stream meandered southward over Asia and North America, resulting in cold intrusions. We speculate that the positive feedback mechanism observed during the 2017–18 winter could recur in future years when the sea-ice reduction in the Pacific Arctic interacts with enhanced atmospheric river activity.

The 11th Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

The 11th Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

The 11th Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

The 11th Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

T lymphocytes are the central coordinator and executor of many immune functions. The activation and function of T lymphocytes are mediated through the engagement of cell surface receptors and regulated by a myriad of intracellular signaling network. Bioengineering tools, including imaging modalities and fluorescent probes, have been developed and employed to elucidate the cellular events throughout the functional lifespan of T cells. A better understanding of these events can broaden our knowledge in the immune systems biology, as well as accelerate the development of effective diagnostics and immunotherapies. Here we review the commonly used and recently developed techniques and probes for monitoring T lymphocyte intracellular events, following the order of intracellular events in T cells from activation, signaling, metabolism to apoptosis. The techniques introduced here can be broadly applied to other immune cells and cell systems. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Immune System Diseases > Biomedical Engineering Infectious Diseases > Biomedical Engineering.

Signaling between the C C chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized. In vitro, KLAK-MCP-1 micelles were observed to bind and induce cytotoxicity to cancer cells through interaction with CCR2. In vivo, KLAK-MCP-1 micelles inhibited tumor growth (34 ± 11%) in a subcutaneous B16F10 murine melanoma model despite minimal tumor accumulation upon intravenous injection. Tumors treated with KLAK-MCP1 demonstrated reduced intratumor CCR2 expression and altered infiltration of TAMs and CTLs as evidenced by immunohistochemical and flow cytometric analysis. These studies highlight the potential application of CCR2-targeted nanotherapeutic micelles in cancer treatment.

The Chukchi Sea, on the Pacific side of the Arctic Ocean, recorded its largest ice-free area in the winter of 2017-18, a period when the Arctic Oscillation (AO) was persistently in its negative phase. In association with the negative AO, East Asia suffered its coldest winter since 1985 while the Arctic region was anomalously warm. Recent studies argued that the decline in Chukchi Sea ice forced the jet stream to meander southward over Asia and America, allowing cold air to spread there (e.g., Tachibana 2020). However, cold Asian winters are typically explained by La Niña and reduced Arctic ice in the Atlantic sector. As Chukchi Sea ice coverage has severely declined in recent years, the importance of its role with respect to these traditional factors should be investigated on a multiannual time scale in light of anticipated global warming. Here we present a statistical analysis showing that 2017-18 was the only winter since 1985 in which declining ice in the Chukchi Sea played a leading role and that previously its contribution was much smaller than those of Barents Sea ice and La Niña. A simple numerical experiment involving an anomalous heat source over the Pacific sector of the Arctic successfully simulated a cold Asia and warm Arctic. Thus, an anomalous negative AO along with the cold Asian winter of 2017-18 may be partially explained by the decline in Chukchi Sea ice. In the context of global warming, long-term forecasts of Chukchi Sea ice may improve predictions of Asian climate., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

BackgroundMesothelin (MSLN) and carcinoembryonic antigen (CEA) are classic tumor-associated antigens that are expressed in many solid tumors including the majority of lung, colorectal and pancreatic cancers. However, both MSLN and CEA are also expressed in vital normal organs. This normal expression creates risk of serious inflammation for CEA- or MSLN-directed therapeutics. To date all active CEA- or MSLN-targeted investigational therapeutics have been toxic when administered systemically.MethodsWe have developed a safety mechanism to protect normal tissues without abrogating sensitivity of cytotoxic T cells directed at MLSN(+) or CEA(+) tumors in a subset of patients with defined loss of heterozygosity (LOH) in their tumors (figure 1). This dual-receptor (Tmod< sup >TM) system exploits common LOH at the HLA locus in cancer cells, allowing T cells to recognize the difference between tumor and normal tissue.1 2 T cells engineered with specific Tmod constructs contain: (i) a MSLN- or CEA-activated CAR; and, (ii) an inhibitory receptor gated by HLA-A*02. HLA-A*02 binding blocks T cell cytotoxicity, even in the presence of MSLN or CEA. The Tmod system is designed to treat heterozygous HLA class I patients, selected for HLA LOH. When HLA-A*02 is absent from tumors selected for LOH, the CARs are predicted to mediate potent killing of the A*02(-) malignant cells.ResultsThe Tmod system robustly protects surrogate normal cells even in mixed-cell populations in vitro while mediating robust cytotoxicity of tumor cells in xenograft models (see example in figure 2). The MSLN CAR can also be paired with other blockers, supporting scalability of the approach to patients beyond HLA-A*02 heterozygotes.Abstract 122 Figure 1Illustration of the Tmod T cell engaging with tumor cells with somatic loss of HLA-A*02 and with normal cells.Abstract 122 Figure 2Bioluminescence measurements show the average difference between the size of the MSLN(+)A*02(+) ‘normal’ graft compared to the MSLN(+)A*02(-) tumor graft on the two flanks of mice after T cell infusion. Both tumor and normal grafts are destroyed by CAR-Ts (CAR-3 and M5 benchmark) while the MSLN Tmod cells kill the tumor but not the normal graft.ConclusionsThe Tmod mechanism may provide an alternative route to leverage solid-tumor antigens such as MSLN and CEA in safer, more effective ways than previously possible.ReferencesHamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol 2020;128:298–310.Hwang MS, Mog BJ, Douglass J, et al. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A 2021;118(12):e2022410118.

Hypoxia plays a central role in cancer progression and resistance to therapy. We have engineered a microdevice platform to recapitulate the intratumor oxygen gradients that drive the heterogeneous hypoxic landscapes in solid tumors. Our design features a “tumor section”-like culture by incorporating a cell layer between two diffusion barriers, where an oxygen gradient is established by cellular metabolism and physical constraints. We confirmed the oxygen gradient by numerical simulation and imaging-based oxygen sensor measurement. We also demonstrated spatially-resolved hypoxic signaling in cancer cells through immunostaining, gene expression assay, and hypoxia-targeted drug treatment. Our platform can accurately generate and control oxygen gradients, eliminates complex microfluidic handling, allows for incorporation of additional tumor components, and is compatible with high-content imaging and high-throughput applications. It is well suited for understanding hypoxia-mediated mechanisms in cancer disease and other biological processes, and discovery of new therapeutics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Summary Metabolism is a key regulator of hematopoietic stem cell (HSC) functions. There is a lack of real-time, non-invasive approaches to evaluate metabolism in single HSCs. Using fluorescence lifetime imaging microscopy, we developed a set of metabolic optical biomarkers (MOBs) from the auto-fluorescent properties of metabolic coenzymes NAD(P)H and FAD. The MOBs revealed the enhanced glycolysis, low oxidative metabolism, and distinct mitochondrial localization of HSCs. Importantly, the fluorescence lifetime of enzyme-bound NAD(P)H (τbound) can non-invasively monitor the glycolytic/lactate dehydrogenase activity in single HSCs. As a proof of concept for metabolism-based cell sorting, we further identified HSCs within the Lineage-cKit+Sca1+ (KLS) hematopoietic stem/progenitor population using MOBs and a machine-learning algorithm. Moreover, we revealed the dynamic changes of MOBs, and the association of longer τbound with enhanced glycolysis under HSC stemness-maintaining conditions during HSC culture. Our work thus provides a new paradigm to identify and track the metabolism of single HSCs non-invasively and in real time., Graphical Abstract, Highlights • Metabolic optical biomarkers non-invasively distinguish HSCs from early progenitors • NAD(P)H τbound reflects lactate dehydrogenase activity in single fresh/cultured HSCs • pHi correlates with τbound in hematopoietic populations, with HSCs being the highest • Optical biomarkers track metabolic changes and response to drugs in cultured HSCs, Optical Imaging; Biological Sciences; Cellular Physiology; Stem Cells Research

Heterogeneity of mitochondrial activities in cancer cells exists across different disease stages and even in the same patient, with increased mitochondrial activities associated with invasive cancer phenotypes and circulating tumor cells. Here, we use a micropatterned tumor-stromal assay (μTSA) comprised of MCF-7 breast cancer cells and bone marrow stromal cells (BMSCs) as a model to investigate the role of stromal constraints in altering the mitochondrial activities of cancer cells within the tumor microenvironment (TME). Using microdissection and RNA sequencing, we revealed a differentially regulated pattern of gene expression related to mitochondrial activities and metastatic potential at the tumor-stromal interface. Gene expression was confirmed by immunostaining of mitochondrial mass, and live microscopic imaging of mitochondrial membrane potential (ΔΨm) and optical redox ratio. We demonstrated that physical constraints by the stromal cells play a major role in ΔΨm heterogeneity, which was positively associated with nuclear translocation of the YAP/TAZ transcriptional co-activators. Importantly, inhibiting actin polymerization and Rho-associated protein kinase disrupted the differential ΔΨm pattern. In addition, we showed a positive correlation between ΔΨm level and metastatic burden in vivo in mice injected with MDA-MB-231 breast cancer cells. This study supports a new regulatory role for the TME in mitochondrial heterogeneity and metastatic potential.

Cathode catalysts without platinum group metals (PGMs) or carbon supports can reduce the price of proton exchange membrane fuel cells in automobiles, making them commercially competitive. In this paper, an inexpensive and PGM-free catalyst–amorphous nitrogen-doped TiO2-shell on TiN-core– was synthesized without carbon support. While existing PGM-free all-oxide catalysts without carbon support have shown moderate current densities (at the order of μA/cm2), the current density of this new catalyst is three orders of magnitude higher. Replacing commercial carbon support by hydrothermally synthesized Ti4O7 significantly enhanced the activity to be close to that of carbon-supported platinum. Although its conductivity and surface area were not sufficient for an accurate evaluation of its activity, these new results demonstrate the possibility of high-performance non-PGM catalysts without carbon supports.

Despite its revolutionary success in hematological malignancies, chimeric antigen receptor (CAR) T cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic studies of CAR-T cell biology in a physiological environment has been limited by the complexity of tumor-immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models. We have engineered a microdevice platform that recapitulates a three-dimensional tumor section with a gradient of oxygen and integrates fluidic channels surrounding the tumor for CAR-T cell delivery. Our design allows for the evaluation of CAR-T cell cytotoxicity and infiltration in the heterogeneous oxygen landscape of in vivo solid tumors at a previously unachievable scale in vitro.

Between 1950 and 2012, boreal summer (rainy season) rainfall in the Sahel changed from a multi-decadal decreasing trend to an increasing trend (positive trend shift) in the mid-1980s. We found that this trend shift was synchronous with similar trend shifts in global oceanic evaporation and in land precipitation on all continents except the Americas. The trend shift in oceanic evaporation occurred mainly in the Southern Hemisphere (SH) and the subtropical oceans of the Northern Hemisphere (NH). Because increased oceanic evaporation strengthens the atmospheric moisture transport toward land areas, the synchrony of oceanic evaporation and land precipitation is reasonable. Surface scalar winds over the SH oceans also displayed a positive trend shift. Sea surface temperature (SST) displayed a trend shift in the mid-1980s that was negative (increasing, then decreasing) in the SH and positive in the NH. Although SST had opposite trend shifts in both hemispheres, the trend shift in evaporation was positive in both hemispheres. We infer that because strong winds promote evaporative cooling, the trend shift in SH winds strengthened the trend shifts in both SST and evaporation in the SH. Because high SST promotes evaporation, the trend shift in NH SST strengthened the NH trend shift in evaporation. Thus differing oceanic roles in the SH and NH generated the positive trend shift in evaporation; however, the details of moisture transport toward the Sahel are still unclear, or perhaps there is no single determining influence.

Negative Arctic Oscillation (AO) and western Pacific (WP) indices persisted from October to December 2012 in the Northern Hemisphere. For the first time, the monthly AO and WP were both negative for three consecutive months since records have been kept. Although in general negative AO and WP phases cause Siberia, East Asia, and Japan to be abnormally cold, Japan was relatively warm in October 2012 even though both the AO and WP were strongly negative. The temperature of the Sea of Japan reached a record-breaking high in October 2012, and it was found that heating by these very warm waters, despite the small size of the Sea of Japan, overwhelmed the cooling effect of the strongly negative AO and WP in October. Linear regression analyses showed that Japan tends to be warm in years when the Sea of Japan is warm. Consequently, the temperature over Japan is controlled by interannual variations of small-scale oceanic phenomena as well as by large-scale atmospheric patterns. Previous studies have ignored such small-scale oceanic influences on island temperatures.

The polar night jet (PNJ) is a strong stratospheric westerly circumpolar wind at around 65∘ N in winter, and the strength of the climatological PNJ is widely recognized to increase from October through late December. Remarkably, the climatological PNJ temporarily stops increasing during late November. We examined this “short break” in terms of the atmospheric dynamical balance and the climatological seasonal march. We found that it results from an increase in the upward propagation of climatological planetary waves from the troposphere to the stratosphere in late November, which coincides with a maximum of the climatological Eliassen–Palm (EP) flux convergence in the lower stratosphere. The upward propagation of planetary waves at 100 hPa, which is strongest over Siberia, is related to the climatological strengthening of the tropospheric trough over Siberia. We suggest that longitudinally asymmetric forcing by land–sea heating contrasts caused by their different heat capacities can account for the strengthening of the trough.

Micromilling has great potential in producing microdevices for lab-on-a-chip and organ-on-a-chip applications, but has remained under-utilized due to the high machinery costs and limited accessibility. In this paper, we assessed the machining capabilities of a low-cost 3-D mill in polycarbonate material, which were showcased by the production of microfluidic devices. The study demonstrates that this particular mill is well suited for the fabrication of multi-scale microdevices with feature sizes from micrometers to centimeters.

Titanium dioxide (TiO2) has attracted significant attention for the use in various applications; photocatalysts, dye-sensitized solar cells, lithium/sodium ion batteries, sensors, etc. Since the discovery of high visible-light photocatalytic activity by Asahi et al. in 2001,1 substitution of oxygen atoms in TiO2 by heteroatoms has been the hot topic in these fields. Recent work of Ota et al. opened a new application of TiO2: oxygen deficient TiO x showed the oxygen reduction reaction (ORR) activity in acidic media that simulate polymer electrolyte fuel cell (PEFC) cathodes.2 Other oxide catalysts containing group 4 or 5 metals also showed ORR activity in acidic media, whereas TiO2 is the most promising from the viewpoint of natural abundance. The oxygen defects in oxide catalysts have been acknowledged as active sites for ORR and they have been incorporated using various routes such as the pyrolysis under reductive atmosphere containing hydrogen,2 so-called carbothermal-reduction3 and nitrogen-doping.4-8 Rutile is more active for ORR than anatase,3,6,7 and this trend is opposite to that in photocatalytic activity. In this work, oxygen defects were incorporated into nanoparticles of rutile TiO2 and other group 4 metal oxides by substitutional nitrogen-doping using a recently developed solution phase combustion route.7,8 X-ray photoelectron spectroscopy analyses on TiO2 catalysts revealed that (1) charge imbalance caused by doped nitrogen atoms were compensated by the incorporation of oxygen defects, not the decrease in the valence of titanium on the surface and (2) the surface rutile was formed on TiN, yielding a core-shell structure. Many transition metal nitrides are well known to be unstable in water or even in air moisture, except for Ta3N5;9,10 however, the surface rutile successfully protected the TiN-core in 0.1 mol dm–3 H2SO4 solution not to change the ORR mechanism represented by Tafel slope after 20,000 potential cycles between 0.6 and 1.0 V versus the reversible hydrogen electrode. The active sites will be discussed at the meeting by comparing the activity of TiO2 and other group 4 metal oxides. Acknowledgments The authors gratefully acknowledge Mr. Yusei Tsushima for his help with acquisition of transmission electron microscopy images. This work was partially supported by a Grant-in-Aid for Scientific Research (C) (26420132) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan; an Adaptable and Seamless Technology Transfer Program through Target-driven R&D grant (AS262Z02037) from the Japan Science and Technology Agency; a research grant from the Takahashi Industrial and Economic Research Foundation of Japan; a research grant from the Naoji Iwatani Foundation of Japan; and a grant for chemical research from the Foundation for Japanese Chemical Research. The X-ray photoelectron spectra were acquired with the support by Nanotechnology Platform, 12024046 of the MEXT of Japan. References (1) R. Asahi, T. Morikawa, T. Ohwaki, K. Aoki, and Y. Taga, Science, 293, 269 (2001). (2) J. H. Kim, A. Ishihara, S. Mitsushima, N. Kamiya, and K. Ota, Electrochim. Acta, 52, 2492 (2007). (3) M. Chisaka and N. Itagaki, Electrochim. Acta, in press. Doi:10.1016/j.electacta.2015.10.184. (4) M. Chisaka, H. Sasaki and H. Muramoto, Phys. Chem. Chem. Phys., 16, 20419 (2014). (5) M. Chisaka, A. Ishihara, K. Suito, K. Ota and H. Muramoto, Electrochim. Acta, 88, 697 (2013). (6) M. Chisaka and H. Muramoto, ChemElectroChem, 1, 544 (2014). (7) M. Chisaka, Y. Ando and H. Muramoto, Electrochim. Acta, 183, 100 (2015) (8) M. Chisaka, Y. Ando and N. Itagaki, J. Mater Chem. A, in press. Doi:10.1039/C5TA08235H (9) M. Hara, E. Chiba, A. Ishikawa, T. Takata, J. N. Kondo and K. Domen, J. Phys. Chem. B, 107, 13441 (2003). (10) M. Chisaka, A. Ishihara, N. Uehara, M. Matsumoto and K. Ota, J. Mater Chem. A, 3, 16414 (2015).

Melanoma has a 5-year survival rate of