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Ideal 3-dimensional imaging of many complex samples, such as biological tissues made up of micro-scale structures extending over millimeter- to centimeter-scale tissue samples and organisms, requires both a wide field-of-view and high resolution. With existing optics and detectors used for micro-CT imaging, sub-micron pixel resolution can only be achieved for fields-of-view of Daphnia magna were imaged on Beamline 8.3.2 of the Advanced Light Source. Volumes of 10,000 × 10,000 × 7,096 isotropic 0.5 μm voxels were reconstructed over a 5.0 × 3.5 mm field-of-view. Measurements in the projection domain confirmed a 1.182 μm measured spatial resolution that is largely Nyquist-limited. This unprecedented combination of field-of-view and resolution dramatically reduces the need for sectional scans and computational stitching for large samples, ultimately offering the means to elucidate change in tissue and cellular morphology in the context of larger whole, intact model organisms and specimens. This development is also anticipated to benefit micro-CT imaging in materials science, microelectronics, agricultural science, and biomedical engineering.SynopsisA custom wide-field lens and a new-generation megapixel camera enabled microCT scanning over a 3.5 × 5 mm field-of-view at a 1 μm resolution / 0.5 μm pixel size at the Berkeley Lawrence Advanced Light Source using a phantom with micron scale features. This novel combination of resolution and field-of-view will be broadly applicable to any setting in which micron-scale structures need to be characterized comprehensively in 3 dimensions over mm to cm scale.

Background Cervical cancer is the fourth most common cancer among women worldwide, with an estimate of 570,000 new cases and about 311,000 deaths annually. Low-resource countries, including those in sub-Saharan Africa, have the highest-burden with an estimate of 84 % of all cervical cancers. This study examines the prevalence and socio-demographic-economic factors associated with cervical cancer screening in sub-Saharan Africa. Methods A weighted population-based cross-sectional study using Demographic and Health Surveys data. We used available data on cervical cancer screening between 2011 and 2018 from the Demographic and Health Surveys for five sub-Saharan African countries (Benin, Ivory Coast, Kenya, Namibia, and Zimbabwe). The study population included women of childbearing age, 21–49 years (n = 28,976). We fit a multivariable Poisson regression model to identify independent factors associated with cervical cancer screening. Results The overall weighted prevalence of cervical cancer screening was 19.0 % (95 % CI: 18.5 %–19.5 %) ranging from 0.7 % in Benin to 45.9 % in Namibia. Independent determinants of cervical cancer screening were: older age (40−49 years) adjusted prevalence ratio (aPR) = 1.77 (95 % CI: 1.64, 1.90) compared with younger age (21−29 years), secondary/higher education (aPR = 1.51, 95 CI: 1.28–1.79) compared with no education, health insurance (aPR = 1.53, 95 % CI: 1.44–1.61) compared with no insurance, and highest socioeconomic status (aPR = 1.39, 95 % CI: 1.26–1.52) compared with lowest. Conclusion The prevalence of cervical cancer screening is substantially low in sub-Saharan Africa countries and shows a high degree of between-country variation. Interventions aimed at increasing the uptake of cervical cancer screening in sub-Saharan Africa are critically needed.

BackgroundBlocking the PD-L1 immune checkpoint axis with therapeutic antibodies against either the ligand or PD-1 has proven to be an effective treatment modality for multiple cancer histologies. Small molecules targeting the PD-L1/PD-1 axis represent an alternate modality of blocking this pathway. INCB090244 is a small molecule that blocks the PD-L1/PD-1 interaction and restores T cell function similar to the clinical stage PD-L1 inhibitor INCB086550.MethodsMDA-MB-231 or CHO cells overexpressing PD-L1 were used to investigate effects of INCB090244 on PD-L1 dimerization, and intracellular trafficking. In vivo, CD34+ humanized mice harboring MDA-MB-231 tumors or C57Bl/6 mice bearing GL261 subcutaneous or orthotopic tumors were used to investigate the efficacy, biodistribution, and pharmacodynamic effects of INCB090244. Human specific gene expression changes in tumors from MDA-MB-231 bearing humanized mice were analyzed by RNA sequencing.ResultsIn vitro, INCB090244 potently disrupted the PD-L1:PD-1 interaction, induced PD-L1 dimerization, and inhibited PD-1-mediated negative signaling, resulting in enhanced IFN gamma and IL-2 production in primary human immune cells. Following dimerization, INCB090244 induced internalization of PD-L1 resulting in co-localization with the Golgi apparatus and partial localization in the nucleus. After cell treatment and washing, full restoration of PD-L1 at the cell surface was observed after 5 days of culture in vitro. In vivo, INCB090244 reduced tumor growth in CD34+ humanized mice bearing MDA-MB-231 tumors, to similar levels as atezolizumab. Antitumor activity was completely abrogated in immunodeficient mice, confirming the pharmacologic dependency on a competent immune system. RNA sequencing analysis on tumors from these mice demonstrated similar T cell activation gene signatures as clinical checkpoint blockade antibodies. Biodistribution studies in mice bearing both subcutaneous and orthotopically implanted GL261 glioma tumors demonstrated higher accumulation of INCB090244 in tumor tissue compared to PD-L1 antibodies.ConclusionsINCB090244 effectively disrupted the PD-L1/PD-1 interaction, induced dimerization and internalization of PD-L1, restored immunity in in vitro and in vivo tumor models, and is a suitable surrogate for the clinical candidate INCB086550. RNA sequencing demonstrated T cell activation signatures similar to those observed in patients receiving checkpoint blockade antibodies. Biodistribution studies demonstrated higher subcutaneous and brain tumor penetration by INCB090244 compared to PD-L1 antibodies, suggesting a potential advantage of small molecule PD-L1 inhibitors in accessing intratumoral regions. These data further support the clinical evaluation of small molecule PD-L1 inhibitors as an alternative approach to immune therapy.

The anaerobic corrosion of steel was monitored under simulated Swiss low-/intermediate-level waste repository conditions. Steel was studied both as bare rods and cast in cement, in water vapour, si...

Secondary electron detector (SED) plays a vital role in a focused ion beam (FIB) system. A successful circuit edit requires a good effective detector. Novel approach is presented in this paper to improve the performance of such a detector, making circuit altering for the most advanced integrated circuit (IC) possible.

The oxidation of nickel powder under a controlled gas and temperature environment was studied using synchrotron-based full-field transmission X-ray microscopy. The use of this technique allowed for the reaction to be imaged in situ at 55 nm resolution. The setup was designed to fit in the limited working distance of the microscope and to provide the gas and temperature environments analogous to solid oxide fuel cell operating conditions. Chemical conversion from nickel to nickel oxide was confirmed using X-ray absorption near-edge structure. Using an unreacted core model, the reaction rate as a function of temperature and activation energy were calculated. This method can be applied to study many other chemical reactions requiring similar environmental conditions.

International audience; Synchrotron X-ray computed nanotomography (nCT) and Focused Ion Beam-Scanning Electron Microscope nanotomography (FIB-nT) were used to characterize baked-out and sintered nickel (Ni) electrode-Multilayer Ceramic Capacitors. The three-dimensional microstructures obtained by two different tomography techniques were quantified and correlated. X-ray nCT is sufficient to reveal the pore characteristics, whereas the FIB-nT enables the particles in the initial packings to be identified. In the dielectric ceramic layers, pores preferentially orient horizontally in the layer and the regions near the Ni/BT interface are denser than the inner regions. This anisotropy is possibly caused by compressive stress induced during the heating stage.

This study set out to explore the relationship between female media use behavior and agreement with agenda-specific publicly promoted health messages. A random digit dial telephone cross-sectional survey was conducted using a nationally representative sample of female residents aged 25 and over. Respondents’ agreement with health messages was measured by a six-item Health Information Scale (HIS). Data were analyzed using chi-square tests and multiple logistic regression. This survey achieved a response rate of 86% (n = 1074). In this study the longest duration of daily television news watching (OR = 2.32), high self-efficacy (OR = 1.56), and greater attention to medical and health news (OR = 5.41) were all correlates of greater agreement with the selected health messages. Surprisingly, Internet use was not significant in the final model. Many women that public health interventions need to be targeting are not receptive to health information that can be accessed through Internet searches. However, they may be more readily targeted by television campaigns. Agenda-specific public health campaigns aiming to empower women to serve as nodes of information transmission and achieve efficient trickle down through the family unit might do better to invest more heavily in television promotion.

CD137 (4-1BB) is a transmembrane costimulatory receptor on T and NK cells that enhances adaptive immune responses and is a critical mediator of antitumor immunity. The development of CD137 targeted agents for cancer therapy has been hampered by on-target off-tumor toxicity in the case of agonist monospecific, bivalent mAbs or limited antitumor activity in the case of crosslinking mAbs. Here we have developed an Fc-silenced bispecific IgG1 antibody to CD137 and PD-L1 with monovalent binding specificity to each target. MCLA-145 drives transactivation of CD137 in the vicinity of cells expressing PD-L1, such as in the immunosuppressive tumor microenvironment. The degree of CD137 agonistic activity in T cells correlated with the expression level of PD-L1 on neighboring cells, as demonstrated in transactivation assays whereby reporter T cells were co-cultured with cells expressing different levels of PD-L1. PD-L1 expression as low as 6000 receptors per cell was sufficient to activate CD137 in neighboring T cells. In contrast, MCLA-145 blocked PD-1 signaling without requirement for CD137 binding in a PD-1/PD-L1 reporter assay. CD137 signaling was induced by MCLA-145 in multiple primary human immune cell assays including the mixed lymphocyte reaction, human PBMC, and whole blood SEB stimulation assays. MCLA-145 reversed T cell suppression mediated by M2 macrophages or Tregs, in vitro. In addition, MCLA-145 enhanced Ag-specific expansion and differentiation of human naïve CD8+ T cells in vitro. In vivo, MCLA-145 treatment resulted in significant tumor immune activation and antitumor responses in two separate humanized mouse tumor models. In one model, human T cells expressing NY-ESO specific TCR were adoptively transferred to mice bearing A549 tumors which expressed NY-ESO antigen and human PD-L1. MCLA-145 treatment at 5 mg/kg resulted in 54% tumor growth inhibition (TGI) as compared to T cell only treated mice. In the tumors of MCLA-145 treated mice, the percentage of NY-ESO specific CD8+ T cells were significantly increased compared to controls. In a second model, mice engrafted with human CD34+ cells were implanted with the breast tumor cell line MDA-MB-231. MCLA-145 at 0.5 mg/kg and 5 mg/kg induced significant tumor growth inhibition (55 and 57% respectively) as compared to vehicle control or Fc-silenced huIgG1 controls. Additionally, two out of nine animals in the 5 mg/kg MCLA-145-treated group had complete tumor regression. MCLA-145 increased the number of infiltrating CD8+ T cells, as well as the percentage of central memory CD8+ T cells. The cured animals were then re-challenged with MDA-MB-231 tumor cells, and tumors of previously cured mice were rejected as compared to no growth inhibition in treatment-naïve CD34+ NSG mice. In conclusion, these data support the clinical evaluation of MCLA-145 as a novel, PD-L1 dependent CD137 agonist immune therapy. Citation Format: Patrick Mayes, Paul Tacken, Steve Wang, Pieter-Fokko van Loo, Thomas Condamine, Hans van der Maaden, Eric Rovers, Steef Engels, Floris Fransen, Ashwini Kulkarni, Yao-bin Liu, Arpita Mondal, Leslie Hall, Soyeon Kim, Marina Martinez, Shaun O'Brien, Edmund Moon, Steven Albelda, Peggy Scherle, Gregory Hollis, Reid Huber, Mark Throsby, Cecile A. Geuijen. A bispecific Fc-silenced IgG1 antibody (MCLA-145) requires PD-L1 binding to activate CD137 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 539.

CD137 (4-1BB) is a transmembrane costimulatory receptor on T and NK cells that enhances adaptive immune responses and is a critical mediator of antitumor immunity. CD137 signaling requires receptor clustering normally facilitated by the trimeric CD137 ligand (CD137L). Alternatively, CD137 signaling can be triggered either directly by agonistic monoclonal antibodies (mAbs) or indirectly via crosslinking of CD137 binding mAbs by Fcγ receptors on neighboring cells. The development of CD137 targeted agents for cancer therapy has been hampered by on-target off-tumor toxicity in the case of agonist, monospecific, bivalent mAbs or limited antitumor activity in the case of crosslinking mAbs. To address the issues of toxicity and efficacy a highly selective and potent CD137xPD-L1 bispecific antibody (bAb) was identified by applying an unbiased functional screening approach. Collections of common light chain Fabs recognizing CD137 and PD-L1 were produced based on antibody panels from immunized MeMo® mice. A large and diverse panel of CD137xPD-L1 bAbs was then produced by combining different CD137 and PD-L1 Fabs based on epitope and sequence diversity in the IgG1 Biclonics® format. The bAbs were screened for activity in reporter cell lines expressing the receptors. This unbiased combinatorial screening identified a CD137xPD-L1 bAb (MCLA-145) for which CD137 mediated activation is dependent on the presence of PD-L1 on a neighboring cell and, as such, the antibody acts in ‘trans’. Flow cytometry experiments demonstrated that MCLA-145 is fully cross-reactive to cynomolgus monkey CD137 and PD-L1. The CD137 Fab arm blocks the interaction of CD137 with CD137L as demonstrated in a competition assay by flow cytometry. The PD-L1 Fab arm blocks the interaction between PD-1 and PD-L1 as demonstrated in ELISA. Binding epitopes were mapped by shotgun mutagenesis using a flow-based screen. In addition, hydrogen-deuterium exchange experiments were performed to map the binding domain on CD137. Data show that MCLA-145 binds the ligand binding domain of CD137 domain (CRDII). The PD-L1 Fab arm binds PD-L1 in the PD-1 binding N-terminal V domain. Both epitope mapping data sets are consistent with the CD137 and PD-L1 ligand blocking activity of MCLA-145. Monovalent binding affinities were measured by surface plasma resonance (SPR) and radioactive iodine labeling and demonstrated affinities in the low nM (CD137) and subnanomolar (PD-L1) range. SPR experiments also confirmed that MCLA-145 was able to bind simultaneously to both CD137 and PD-L1 recombinant proteins. The unique binding properties of MCLA-145 may result in an increased therapeutic window by specifically activating CD137 expressing cells in the tumor niche where PD-L1 is expressed while simultaneously blocking inhibitory input from the PD-1/PD-L1 axis. Citation Format: Cecile A. Geuijen, Paul Tacken, Rinse Klooster, Horacio Nastri, Shaun Stewart, Jing Zhou, Steve Wang, Cheng-Yen Huang, Arjen Kramer, Linda Kaldenberg-Hendriks, John de Kruif, Renate den Blanken-Smit, Vanessa Zondag-van de Zande, Abdul Basmeleh, Willem Bartelink, Patrick Mayes, Gregory Hollis, Reid Huber, Mark Throsby. An unbiased screen identifies a CD137xPD-L1 bispecific IgG1 antibody with unique T cell activation and binding properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 541.

As the competitive nature of tennis grows, so do the demands placed on the growing athlete. Their bodies are not as mature as adult professional athletes, and their ligaments, growth plates, and bones are not as strong, predisposing pediatric athletes to injury. Muscles may not be as well developed and imbalances make them prone to injury. Other risk factors for injury include the volume of play, grip position, grip size, racket size, stroke mechanics, body conditioning, neuromuscular training, and flexibility. The majority of injuries associated with tennis playing are due to force overload of the muscle-tendon-bone unit, rather than acute trauma.

Despite stringent power consumption requirements in many applications, over years organic light‐emitting diode (OLED) displays still suffer unsatisfactory energy efficiency due to poor light extraction. Approaches have been reported for OLED light out‐coupling, but they in general are not applicable for OLED displays due to difficulties in display image quality and fabrication complexity and compatibility. Thus to date, an effective and feasible light extraction technique that can boost efficiencies and yet keep image quality is still lacking and remains a great challenge. Here, a highly effective and scalable extraction‐enhancing OLED display pixel structure is proposed based on embedding the OLED inside a three‐dimensional reflective concave structure covered with a patterned high‐index filler. It can couple as much internal emission as possible into the filler region and then redirect otherwise confined light for out‐coupling. Comprehensive multi‐scale optical simulation validates that ultimately high light extraction efficiency approaching ≈80% and excellent viewing characteristics are simultaneously achievable with optimized structures using highly transparent top electrodes. This scheme is scalable and wavelength insensitive, and generally applicable to all red, green, and blue pixels in high‐resolution full‐color displays. Results of this work are believed to shed light on the development of future generations of advanced OLED displays.

Library is one of the learning resources centre, it stores varieties of information, provides support for teaching and research and satisfies student needs in learning. With the university's academic and practical development, the library also keeps up with more collection on relative practical books, actively train student in information literacy, with the aim to educate students in lifelong learning and independent learning; OCU's library provides better service and other professional functions, to collaborate with university courses' syllabus, researches, reading, etc. The establishment of the learning resource centre benefits the lecturers and students as it stores and supplies countless type of knowledge depends on their needs. In recent years, the Ministry of Education promotes institutional research based on statistics to provide reference to any institution for strategy planning. The aim of this study is to analyse the relationship between efficiency of book lending and student result, based on the number of book lending, type of book and the time of return of the book.

Immune checkpoint blockade has shown considerable therapeutic promise in the clinic. However, single agent activity is compromised by the presence of suppressive myeloid cells, including myeloid derived suppressor cells (MDSC), tumor associated macrophages (TAM) and polymorphonuclear (PMN) cells, in the tumor microenvironment. Epigenetic alterations can significantly contribute to the development of the immunosuppressive tumor microenvironment and recent data have suggested that combining epigenetic-based therapies with immunotherapeutic agents can lead to improved efficacy in preclinical models. Since Lysine Specific Demethylase 1 (LSD1) has been shown to play a critical role in hematopoiesis, we hypothesized that inhibition of LSD1 could have a direct effect on myeloid cell differentiation and potentially restore normal myelopoiesis in cancer patients. To test this hypothesis, we evaluated INCB059872, a potent, selective and orally available FAD-directed covalent inhibitor of LSD1 in several experimental models. In an in vitro differentiation assay, the majority of CD34+ progenitor cells were driven to a monocytic phenotype in the presence of INCB059872, while control treated cells differentiated toward granulocytic PMN cells. Similar results were observed in vivo. Using the orthotopic 4T1 mammary cancer model, the myeloid compartment was characterized in tumor tissues following treatment with INCB059872. Notably, the population of PMN-MDSC was significantly decreased in tumor tissues following oral administration of INCB059872, whereas the macrophage population was increased. These data suggest that INCB059872 can redirect myeloid differentiation toward monocyte/macrophages and inhibit the differentiation of PMN-MDSC in this syngeneic tumor microenvironment. Consistently, intratumoral T lymphocyte infiltration was increased following INCB059872 treatment. The combination of INCB059872 and α-PD-L1 antibody enhanced anti-tumor efficacy in the 4T1 orthotopic tumor model. Collectively, these data suggest that inhibition of LSD1 with INCB059872 can directly affect myeloid differentiation to reduce the accumulation of myeloid suppressive cells, restoring the tumor microenvironment to be more responsive to PD-1/PD-L1 axis blockade. This study supports the therapeutic potential for the combination of an LSD1 inhibitor with immuno-therapeutic agents to improve overall clinical response in cancer patients. Citation Format: Thomas Condamine, Steve Wang, Melody Diamond, Leslie Hall, Huiqing Liu, Antony Chadderton, Jin Lu, Chunhong He, Liangxing Wu, Timothy Burn, Wenqing Yao, Gregory Hollis, Reid Huber, Bruce Ruggeri, Peggy Scherle, Holly Koblish, Sang Hyun Lee. The LSD1 Specific Inhibitor INCB059872 enhances the activity of immune checkpoint blockade by reshaping the myeloid compartment in the syngeneic 4T1 mouse mammary tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4635. doi:10.1158/1538-7445.AM2017-4635

Reduction-oxidation (redox) cycling of Ni-based electrodes for solid oxide fuel/electrolysis cell irreversibly alters their microstructure and can cause the fracture of the electrolyte. Non-destructive 3-D imaging techniques enable tracking the microstructural changes that occur during the cycling [1]. Despite the recent advances, the understanding of how local 3-D geometrical features in the heterogeneous electrode material contribute to the material degradation remains incomplete. Absorption contrast X-ray nanotomography (XNT) of a same Ni(O)-yttria-stabilized zirconia (YSZ) sample was performed at the NiO K-edge white-line peak (8348 eV), before and after exposure to air at 800°C during 45 minutes. A complimentary XNT at 8376 eV confirmed a degree of oxidation in the range of 98%. The morphology of the Ni(O) phase was as expected completely different after re-oxidation. The spatial resolution in the range of 20 nm [2] further enabled the detection of cracks in the brittle YSZ phase. 3-D local curvature measurements were first performed to identify and characterize the crack initiation sites. Then, the capabilities of simple fracture mechanics models combined with curvature measurements were tested in the view of rapidly pinpointing the locations vulnerable to redox cycling. Finally, the detrimental effects of the cracks on the effective 3-D transport pathways in the Ni-YSZ anode under polarization was investigated using a skeleton-based discrete representation of the imaged volume and an analytical electrochemical fin model [3]. Topological properties, effective ionic conductivity and polarization resistance were calculated before and after oxidation. For the latter estimate, the effect of cracked YSZ network was considered first alone; that of the spatial re-distribution of triple-phase boundaries induced by re-oxidation will be included in the future. [1] A. M. Kiss, W. M. Harris, S. Wang, J. Vila-Comamala, A. Deriy and W. K. S. Chiu, Applied Physics Letters 102 (2013) 053902. [2] J. Vila-Comamala, Y. Pan, J. J. Lombardo, W. M. Harris, W. K. S. Chiu, C. David, Y. Wang, J. Synchrotron Rad. 19 (2012), 705–709. [3] G. J. Nelson, A. Nakajo, B. N. Cassenti, M. B. DeGostin, K. R. Bagshaw, A A. Peracchio, G. Xiao, S. Wang, F. Chen, W. K. S. Chiu, Journal of Power Sources 246 (2014) 322-334.