An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in ...fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these ...transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
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► Glycogen metabolism is upregulated by hypoxia in cancer cells in vitro and in vivo ► Synthesis versus degradation enzymes have a marked difference in temporal induction ► Metabolism of glucose via glycogen sustains the pentose phosphate pathway ► Depletion of PYGL induces senescence and inhibits tumor growth
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Yardangs are streamlined ridges that form in arid environments on Earth and Mars through wind‐driven abrasion of consolidated substrates. Currently, there is limited consensus on the mechanisms that ...initiate and establish patterns of yardangs on the landscape. In this work, we examine the spatial organization of yardangs in the Campo de Piedra Pómez ignimbrite deposit of north‐western Argentina and identify evidence of antecedent controls on yardang patterns and formation. We mapped 14,826 yardangs in the region using a high‐resolution digital elevation model (DEM) and satellite imagery. We classified yardangs as points using a two‐stage decision rule based on morphology and spectral characteristics. Point pattern analysis shows that yardangs in the study area are not randomly distributed and commonly exhibit directional anisotropy in point pattern. The anisotropic pattern manifests as bands of closely‐spaced yardangs oriented transverse to the dominant northwesterly wind direction. We hypothesize that banding is controlled by pre‐existing antecedent topography in the bedrock, such as fumaroles or ridges associated with pyroclastic flow deposits. We present evidence from other locations on Earth and Mars to illustrate that the transverse banding is a common pattern in yardang landscapes.
Point pattern analysis of 14,826 yardangs in the Campo de Piedra Pómez (CPP) ignimbrite deposit of north‐western Argentina demonstrates the spatial signature of yardang distribution, density, and orientation across the CPP is indicative of a non‐random pattern suggesting the influence of an underlying spatial process. A directional anisotropic pattern manifests as bands of closely‐spaced yardangs oriented transverse to the dominant northwesterly wind direction. We hypothesize antecedent topography exerts control on the initiation and development of yardangs in the CPP.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Lysosomes are membrane-surrounded cytoplasmic organelles filled with a powerful cocktail of hydrolases. Besides degrading cellular constituents inside the lysosomal lumen, lysosomal hydrolases ...promote tissue remodeling when delivered to the extracellular space and cell death when released to the cytosol. Here, we show that spatially and temporally controlled lysosomal leakage contributes to the accurate chromosome segregation in normal mammalian cell division. One or more chromatin-proximal lysosomes leak in the majority of prometaphases, after which active cathepsin B (CTSB) localizes to the metaphase chromatin and cleaves a small subset of histone H3. Stabilization of lysosomal membranes or inhibition of CTSB activity during mitotic entry results in a significant increase in telomere-related chromosome segregation defects, whereas cells and tissues lacking CTSB and cells expressing CTSB-resistant histone H3 accumulate micronuclei and other nuclear defects. These data suggest that lysosomal leakage and chromatin-associated CTSB contribute to proper chromosome segregation and maintenance of genomic integrity.
Spatially and temporally variable suspended sediment transport from upstream sources was investigated in the West River (unofficial name) at the Cape Bounty Arctic Watershed Observatory (CBAWO) on ...Melville Island, Nunavut (74°55′ N, 109°35′ W), a river with nearly a decade of hydrological and sediment transport research in the Canadian Arctic and subject to recent permafrost disturbances, such as soil skin flows on slopes, massive ground ice melt in the channel, and substantial climate change. During the 2012 season, a survey was undertaken during the nival period to identify areas of the river where the flow was isolated from the channel bed by snow and where it progressively reached the bed. During the nival period, and throughout the rest of the season, suspended sediment transport data were collected from a primary outlet station and six upstream locations to identify the sources and sinks of sediment in the various reaches of the West River. An inferred sediment budget approach was used to identify the storage and release dynamics in each reach. Nival event-scale hysteresis and seasonal diurnal hysteresis patterns for 2012 were primarily anticlockwise, suggesting that sources of sediment were not readily available for transport during peak flows but became available as discharge waned. Analysis of diurnal hysteresis relationships for the years 2004–2012 (excluding 2011) signals a shift in daily sediment-discharge hysteresis from primarily clockwise to anticlockwise following an episode of permafrost disturbance and enhanced erosion in 2007. Consistent sediment storage in the upper catchment from this disturbance is interpreted to have contributed to the shift to anticlockwise daily hysteresis. Results provide insights into the fluvial and geomorphological response to changes in sediment availability in Arctic rivers and how these changes in turn affect sediment transport in these environments.
•Sediment yield analysis between 2004 and 2012 with pre- and post-disturbance conditions•Rapid depletion of in-channel snow and resultant sediment transport•Budget and hysteresis analysis highlight long-term source/sink areas of the river.•Fluvial system mitigates the downstream impacts of catchment permafrost disturbance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis.
In human cancer cell lines and ...tumours, we found that miR-210 targets the mitochondrial iron sulfur scaffold protein ISCU, required for assembly of iron-sulfur clusters, cofactors for key enzymes involved in the Krebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygen species (ROS) in hypoxia. ISCU suppression reduced mitochondrial complex 1 activity and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. Cancers with low ISCU had a worse prognosis.
Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A deep learning (DL) terrain classification system, the Novelty and Anomaly Hunter - HiRISE (NOAH-H) was used to produce a terrain map of Mawrth Vallis, Mars. With it, we digitised the extent and ...distribution of transverse aeolian ridges (TARs), a common type of martian aeolian bedform. We present maps of the site, classifying terrain into descriptive classes and interpretive groups. TAR density maps are calculated, and the network output is compared to a manually produced map of TAR density, highlighting the differences in approach and results between these methods. Even when mapping on a small scale, humans must divide the terrain into coherent patches in order to map a large area in a reasonable time frame. Conversely, the speed of DL systems enables mapping on the pixel scale, producing a more detailed product, but one which is also "noisier", and less immediately informative. There are pros and cons to both approaches.
A morphological map of Marth Vallis, Mars, has been created, classifying variations in surface texture into 14 descriptive classes.
A deep learning (DL) convolutional neural network was trained to predict these classes in further HiRISE images, which had not been used for training.
The resulting classified rasters were orthorectified and mosaicked using ArcGIS.
Appropriate classes from the resulting map were compared with manual digitisation of the spatial densities of Transverse Aeolian Ridges (TARs).
This comparison highlights the different scales at which human and DL mapping takes place, and that the two datasets have different strengths and weaknesses.
The speed at which the network can complete its task allows it to attempt a higher level of fidelity than is possible for a human.
Derived maps of the density of boulders and TARs were also produced using both the DL and manual datasets.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Slope disturbances are key sources of sediment, and the impact and recovery of disturbance on downslope erosion is poorly understood. We measured the erosional response of varying extents of slope ...disturbance in small permafrost catchments for 5 years following disturbance by active layer detachments. Initial erosion rates increased with the size of disturbance, but subsequent fluxes depended on specific morphological evolution of disturbances. Varying degrees of (i) channel density within the disturbances, (ii) downstream channel connectivity, and (iii) geomorphic evolution of disturbances lead to significant differences in catchment response to disturbance. Our results indicate that new equilibrium states of sediment erosion are achieved within the most disturbed and channelized catchments and contribute to greater heterogeneity of erosion on the landscape.
Key Points
Initially, sediment concentrations and yields scale with disturbed area
Postdisturbance internal channelization sustains greater sediment flux
Evolution of disturbance and channels generates long‐term, heterogeneous yields
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We applied a deep learning terrain classification system, the 'Novelty or Anomaly Hunter - HiRISE' (NOAH-H), originally developed for the ExoMars landing sites in Oxia Planum and Mawrth Vallis, to ...the Mars 2020 Perseverance rover landing site in Jezero crater. NOAH-H successfully classified the terrain in four HiRISE images of Jezero even though the landforms in the Jezero study area were slightly different from those in the training dataset. We mosaicked the NOAH-H classified rasters and compared them with a manually generated photogeological map, and with Perseverance rover and Ingenuity helicopter images. We find that grouped NOAH-H classes correspond well with the humanmade map and that individual classes are corroborated by the available ground-truth images. We conclude that our NOAH-H products can be refined for feeding into traversability analysis of the ExoMars Rosalind Franklin rover landing site at Oxia Planum and that they can also be used to aid the photogeological mapping process.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the High Arctic, late summer rainfall events have the potential to increase discharge and transport substantial amounts of sediment. Past studies have not considered the role of antecedent soil ...moisture with respect to rainfall-runoff response, particularly in the context of changing climate. We investigate these processes through multiple major rainfall events and the associated discharge and suspended sediment response, measured in a small watershed at ape ounty, elville sland, unavut. Fluvial and sedimentological responses to two major rainfall events on 9 ul. and 23 ul., 2012, totaling 35.4 and 10.6 mm, respectively, resulted in negligible responses in discharge and suspended sediment mobilization. The magnitude and intensity of these events were not unusual in this region, but the lack of response was substantial when compared with past events of similar magnitudes. The two-week antecedent period leading up to the 9 ul. rainfall was characterized by exceptional temperatures and high solar radiation, decreasing soil moisture and increasing infiltration potential, all of which substantially diminished the runoff and resultant suspended sediment transport. These results demonstrate that antecedent catchment conditions may substantially attenuate suspended sediment transport responses to multiple major rainfall events and decrease runoff ratios and characterization of these conditions is necessary to accurately model catchment response.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, KISLJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
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