Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin's anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin. Endometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed. In women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response. Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin

Evaluación de la conectividad estructural y funcional en el corredor de conservación Podocarpus-Yacuambi, Ecuador

Con el objetivo de determinar el grado de conectividad estructural en el corredor de conectividad Podocarpus-Yacuambi (Yawi-sumak) en el sur del Ecuador, se evaluaron métricas del paisaje y se analizó la conectividad funcional en tres especies de mamíferos con requerimientos ecológicos contrastantes: Tapirus pinchaque, Sturnira erythromos y Cebus albifrons. El corredor tiene una extensión de 315346 hectáreas, la cobertura con la mayor proporción es el bosque (71%), paisaje correspondiente a un tipo de alteración “jaspeada”; sin embargo, este uso del suelo tuvo una de las mayores densidades de fragmento (0,25/100 ha), la mayor densidad de borde, contraste de borde y uno de los más bajos índices de conectividad, lo cual es indicativo de fragmentación. A nivel de paisaje, el índice de contagio fue de 74% y la conectividad con un umbral de distancia de 40 Km alcanzó el 74%. El hábitat óptimo para el Tapirus pinchaque abarcó la mayor proporción del corredor (78%), para Sturnira erythromos fue de 72%, mientras que Cebus albifrons obtuvo (29%). Los fragmentos de hábitat que pueden servir como puentes de paso para las tres especies se encuentran principalmente en los poblados de Tutupali, 28 de mayo e Imbana, por lo que es necesario priorizar estas áreas para hacer proyectos de producción sostenible y conservación. Aunque el bosque abarca una gran proporción de la zona, la conectividad estructural es baja debido a la fragmentación. La conectividad funcional para el tapir y el murciélago es óptima; no obstante, existen cuellos de botella en las zonas fragmentadas.In order to determine the degree of structural connectivity in the Podocarpus-Yacuambi (Yawi-sumak) ecological corridor in southern Ecuador, landscape metrics were evaluated and functional connectivity was analyzed for three mammalian species with contrasting ecological requirements: Tapirus pinchaque, Cebus albifrons, and Sturnira erythromos. The corridor is a variegated landscape with an area of 315346 hectares, of which 71 percent is forest. However, the forest is highly fragmented with high patch density (0.25/100 ha), high edge density and edge contrast index and low levels of connectivity. At the landscape level, the contagion index was 74 percent and connectivity with a threshold distance of 40 Km reached 74 percent. The optimal habitat for Tapirus pinchaque spanned the largest proportion (78%) of the corridor compared to Sturnira erythromos (72%) and Cebus albifrons (29%). Habitat patches that can serve as “stepping stones” for the three species are found mainly in the districts of Tutupali, 28 de Mayo and Imbana, so it is necessary to prioritize these areas for sustainable production and conservation projects. The study suggests that although forest cover is high, structural connectivity is low due to fragmentation. Functional connectivity for the tapir and the bat is optimal; however, there are bottlenecks in fragmented areas

Witness: The Modern Writer as Witness

Editor\u27s Note [Excerpt] The United States, as a society, is on the brink of profound and positive change. Demographically and culturally, things are improving, and the reason is obvious to people who study history: Conflict pushes us to be better, to strive for principled goals. Consider the inspired eco-advocacy of Greta Thunberg. Or the swearing in of most diverse class of lawmakers in history into the 116th Congress. Or billionaire Robert F. Smith’s pledge to pay off every Morehouse College (in Atlanta, Georgia) student’s debt. Indeed, there are many good people helping and great moments happening in spite of a bleak 24-hour news cycle designed to ruin happiness and to limit our understanding of our human potential. We at Witness see this yearning for transformation in the works we selected. The doorway must be crossed, and the voices and characters we featured in our Winter 2019 issue stand at the vestibule, ready for the light to warm them, primed to fight for that necessary illumination.https://digitalscholarship.unlv.edu/witness/1000/thumbnail.jp

Prevention of lithium-ion battery thermal runaway using polymer-substrate current collectors

Isolating electronically conducting material from internal short circuits is a promising way to prevent the onset of thermal runaway within lithium-ion cells. Here, a metal-coated polymer current collector, which is designed to disconnect internal short circuits by withdrawing from the heating region, is tested in 18650 cells. In addition to having lower mass and manufacturing costs, cells with metal-coated polymer current collectors demonstrate a reduced risk of thermal runaway during nail penetration. High-speed synchrotron X-ray radiography of 18650 cells during nail-penetration testing, in tandem with pre- and post-mortem X-ray computed tomography, provides insights into the function of the current collectors. The results are compared with those of 18650 cells with standard commercial aluminum and copper current collectors. Cells with aluminum-coated polymer current collectors demonstrated 100% success in thermal runaway prevention during nail penetration, retaining a cell voltage >4.00 V, while standard cells consistently experienced thermal runaway

Correlative acoustic time-of-flight spectroscopy and X-ray imaging to investigate gas-induced delamination in lithium-ion pouch cells during thermal runaway

It remains difficult to detect internal mechanical deformation and gas-induced degradation in lithium-ion batteries, especially outside specialized diagnostics laboratories. In this work, we demonstrate that electrochemical acoustic time-of-flight (EA-ToF) spectroscopy can be used as an insightful and field-deployable diagnostic/prognostic technique to sense the onset of failure. A 210 mAh commercial lithium-ion cell undergoing thermal abuse testing is probed with in situ and operando EA-ToF spectroscopy, together with simultaneous fractional thermal runaway calorimetry (FTRC) and synchrotron X-ray imaging. The combination of X-ray imaging and EA-ToF analysis provides new understanding into the through-plane mechanical deformation in lithium-ion batteries through direct visualisation and the acoustic ToF response. Internal structural changes, such as gas-induced delamination, are identified using EA-ToF spectroscopy due to variations in the attenuation and signal peak shifts. This is corroborated using X-ray imaging, demonstrating EA-ToF spectroscopy as a promising technique for detecting onset of battery failure

Evaluating microstructure evolution in an SOFC electrode using digital volume correlation

Degradation mechanisms within solid oxide fuel cells (SOFC) during thermal cycling limit operational start-up times and cell lifetime, and must therefore be better understood and mitigated. This work explores such mechanisms using digital volume correlation (DVC) techniques applied to lab-based X-ray tomograms where the microstructural evolution is evaluated during the operational cycling of a Ni-YSZ/YSZ cell. To emulate reduced start-up times, five tomograms were collected over four operational thermal cycles to 750 °C at various ramp-rates: 3, 10, 20 and 30 °C min-1. Two key features are observed in the 3D strain profiles. Firstly, during low ramp-rates the material produces microscopic channels towards cluster-points. This is thought to be caused by the ceramic skeleton inhibiting the effects of sintering. Secondly, previously unseen macroscopic 'waves' developed after high-rate cycling, consisting of linear regions of compression and tension throughout the sample. These wave features decay away from a heterogeneous defect which is thought to be responsible for the non-uniform strain profile. This work demonstrates the first use of sub-micron DVC computations applied to an SOFC exposed to operationally relevant temperatures. These findings will assist in the development of new electrode materials from their fabrication to operation, ultimately supporting commercial viability of SOFCs

4D nano-tomography of electrochemical energy devices using lab-based X-ray imaging

Electrochemical energy devices offer a variety of alternate means for low-carbon, multi-scale energy conversion and storage. Reactions in these devices are supported by electrodes with characteristically complex microstructures. To meet the increasing capacity and lifetime demands across a range of applications, it is essential to understand microstructural evolutions at a cell and electrode level which are thought to be critical aspects influencing material and device lifetime and performance. X-ray computed tomography (CT) has become a highly employed method for non-destructive characterisation of such microstructures with high spatial resolution. However, sub-micron resolutions present significant challenges for sample preparation and handling particularly in 4D studies, (three spatial dimensions plus time). Here, microstructural information is collected from the same region of interest within two electrode materials: a solid oxide fuel cell and the positive electrode from a lithium-ion battery. Using a lab-based X-ray instrument, tomograms with sub-micron resolutions were obtained between thermal cycling. The intricate microstructural evolutions captured within these two materials provide model examples of 4D X-ray nano-CT capabilities in tracking challenging degradation mechanisms. This technique is valuable in the advancement of electrochemical research as well as broader applications for materials characterisatio

Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer

Metastasis is the leading cause of cancer-related death. This multistage process involves contribution from both tumour cells and the tumour stroma to release metastatic cells into the circulation. Circulating tumour cells (CTCs) survive circulatory cytotoxicity, extravasate and colonise secondary sites effecting metastatic outcome. Reprogramming the transcriptomic landscape is a metastatic hallmark, but detecting underlying master regulators that drive pathological gene expression is a key challenge, especially in childhood cancer. Here we used whole tumour plus single-cell RNA-sequencing in primary bone cancer and CTCs to perform weighted gene co-expression network analysis to systematically detect coordinated changes in metastatic transcript expression. This approach with comparisons applied to data collected from cell line models, clinical samples and xenograft mouse models revealed mitogen-activated protein kinase 7/matrix metallopeptidase 9 (MAPK7/MMP9) signalling as a driver for primary bone cancer metastasis. RNA interference knockdown of MAPK7 reduces proliferation, colony formation, migration, tumour growth, macrophage residency/polarisation and lung metastasis. Parallel to these observations were reduction of activated interleukins IL1B, IL6, IL8 plus mesenchymal markers VIM and VEGF in response to MAPK7 loss. Our results implicate a newly discovered, multidimensional MAPK7/MMP9 signalling hub in primary bone cancer metastasis that is clinically actionable

Polychaetoid/ZO-1 strengthens cell junctions under tension while localizing differently than core adherens junction proteins

During embryonic development, dramatic cell shape changes and movements reshape the embryonic body plan. These require robust but dynamic linkage between the cell–cell adherens junctions and the force-generating actomyosin cytoskeleton. Our view of this linkage has evolved, and we now realize linkage is mediated by mechanosensitive multiprotein complexes assembled via multivalent connections. Here we combine genetic, cell biological, and modeling approaches to define the mechanism of action and functions of an important player, Drosophila polychaetoid, homologue of mammalian ZO-1. Our data reveal that Pyd reinforces cell junctions under elevated tension, and facilitates cell rearrangements. Pyd is important to maintain junctional contractility and in its absence cell rearrangements stall. We next use structured illumination microscopy to define the molecular architecture of cell–cell junctions during these events. The cadherin–catenin complex and Cno both localize to puncta along the junctional membrane, but are differentially enriched in different puncta. Pyd, in contrast, exhibits a distinct localization to strands that extend out from the region occupied by core junction proteins. We then discuss the implications for the protein network at the junction–cytoskeletal interface, suggesting different proteins localize and function in distinct ways, perhaps in distinct subcomplexes, but combine to produce robust connections

Resolving the Discrepancy in Tortuosity Factor Estimation for Li-Ion Battery Electrodes through Micro-Macro Modeling and Experiment

Battery performance is strongly correlated with electrode microstructural properties. Of the relevant properties, the tortuosity factor of the electrolyte transport paths through microstructure pores is important as it limits battery maximum charge/discharge rate, particularly for energy-dense thick electrodes. Tortuosity factor however, is difficult to precisely measure, and thus its estimation has been debated frequently in the literature. Herein, three independent approaches have been applied to quantify the tortuosity factor of lithium-ion battery electrodes. The first approach is a microstructure model based on three-dimensional geometries from X-ray computed tomography (CT) and stochastic reconstructions enhanced with computationally generated carbon/binder domain (CBD), as CT is often unable to resolve the CBD. The second approach uses a macro-homogeneous model to fit electrochemical data at several rates, providing a separate estimation of the tortuosity factor. The third approach experimentally measures tortuosity factor via symmetric cells employing a blocking electrolyte. Comparisons have been made across the three approaches for 14 graphite and nickel-manganese-cobalt oxide electrodes. Analysis suggests that if the tortuosity factor were characterized based on the active material skeleton only, the actual tortuosities would be 1.35–1.81 times higher for calendered electrodes. Correlations are provided for varying porosity, CBD phase interfacial arrangement and solid particle morphology