The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, ...the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Present-day heat flow model of Mars Parro, Laura M; Jiménez-Díaz, Alberto; Mansilla, Federico ...
Scientific reports,
04/2017, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
Until the acquisition of in-situ measurements, the study of the present-day heat flow of Mars must rely on indirect methods, mainly based on the relation between the thermal state of the lithosphere ...and its mechanical strength, or on theoretical models of internal evolution. Here, we present a first-order global model for the present-day surface heat flow for Mars, based on the radiogenic heat production of the crust and mantle, on scaling of heat flow variations arising from crustal thickness and topography variations, and on the heat flow derived from the effective elastic thickness of the lithosphere beneath the North Polar Region. Our preferred model finds heat flows varying between 14 and 25 mW m
, with an average value of 19 mW m
. Similar results (although about ten percent higher) are obtained if we use heat flow based on the lithospheric strength of the South Polar Region. Moreover, expressing our results in terms of the Urey ratio (the ratio between total internal heat production and total heat loss through the surface), we estimate values close to 0.7-0.75, which indicates a moderate contribution of secular cooling to the heat flow of Mars (consistent with the low heat flow values deduced from lithosphere strength), unless heat-producing elements abundances for Mars are subchondritic.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Animal reproductive success implies the performance of several behaviours, such as courting, mate searching, copulation, offspring production and care. These behaviours usually have high energetic ...and ecological costs. Therefore, to maximise their reproductive success, animals should make choices throughout their lives, such as deciding how much energy to invest in different activities, according to their conditions and needs. In temperate estuaries, the fiddler crab L. uruguayensis has a short reproductive period, with two synchronous spawning events. Considering that reproductive behaviours incur high energetic cost to fiddler crabs, we estimated how this species manages its activity budget throughout the reproductive period, to quantify trade-offs between the time spent on reproductive behaviours versus time spent on other activities. By analysing videos of females and males recorded in the field at different moments of the reproductive period, we observed that pre-copulatory behaviours, such as female wandering and male waving were more intense at the beginning of the reproductive period, suggesting that most matings occurred before the first spawning event but not before the second one. The ecological conditions during the breeding season and the individual strategies adopted by males and females mostly determine when and how much time to spend on courtship behaviours, and behavioural plasticity can be expected whenever the conditions change. The strategy used by L. uruguayensis for energy management, females’ ability to store male gametes and environmental temperatures might have been the main factors determining the relative time spent in courtship behaviours during the reproductive period.
•In temperate estuaries, Leptuca uruguayensis spawns twice in the reproductive period.•Reproductive behaviours were more intense at the beginning of the reproductive period.•Females searched for mates more intensely before the first spawning event.•Males waved the major cheliped more intensely before the first spawning event.•Pre-copulatory behaviours did not predict the spawning pattern of L. uruguayensis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Reactive oxidative species (ROS) and S‐glutathionylation modulate the activity of plant cytosolic triosephosphate isomerases (cTPI). Arabidopsis thaliana cTPI (AtcTPI) is subject of redox ...regulation at two reactive cysteines that function as thiol switches. Here we investigate the role of these residues, AtcTPI‐Cys13 and At‐Cys218, by substituting them with aspartic acid that mimics the irreversible oxidation of cysteine to sulfinic acid and with amino acids that mimic thiol conjugation. Crystallographic studies show that mimicking AtcTPI‐Cys13 oxidation promotes the formation of inactive monomers by reposition residue Phe75 of the neighboring subunit, into a conformation that destabilizes the dimer interface. Mutations in residue AtcTPI‐Cys218 to Asp, Lys, or Tyr generate TPI variants with a decreased enzymatic activity by creating structural modifications in two loops (loop 7 and loop 6) whose integrity is necessary to assemble the active site. In contrast with mutations in residue AtcTPI‐Cys13, mutations in AtcTPI‐Cys218 do not alter the dimeric nature of AtcTPI. Therefore, modifications of residues AtcTPI‐Cys13 and AtcTPI‐Cys218 modulate AtcTPI activity by inducing the formation of inactive monomers and by altering the active site of the dimeric enzyme, respectively. The identity of residue AtcTPI‐Cys218 is conserved in the majority of plant cytosolic TPIs, this conservation and its solvent‐exposed localization make it the most probable target for TPI regulation upon oxidative damage by reactive oxygen species. Our data reveal the structural mechanisms by which S‐glutathionylation protects AtcTPI from irreversible chemical modifications and re‐routes carbon metabolism to the pentose phosphate pathway to decrease oxidative stress.
Significance Statement
Reactive oxidative species (ROS) and glutathione regulate plant cytosolic triosephosphate isomerases (cTPI) by targeting two reactive cysteines that function as thiol switches. Here we present the structural basis for cTPI inactivation by ROS and S‐glutathionylation regulation. Our structures show how S‐glutathionylation protects AtcTPI from irreversible chemical modifications while re‐routing carbon metabolism aimed to decrease oxidative stress.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Newly emerged proteomic methodologies, particularly data‐independent acquisition (DIA) analysis–related approaches, would improve current gene expression–based classifications of colorectal cancer ...(CRC). Therefore, this study was aimed to identify protein expression signatures using SWATH‐MS DIA and targeted data extraction, to aid in the classification of molecular subtypes of CRC and advance in the diagnosis and development of new drugs. For this purpose, 40 human CRC samples and 7 samples of healthy tissue were subjected to proteomic and bioinformatic analysis. The proteomic analysis identified three different molecular CRC subtypes: P1, P2 and P3. Significantly, P3 subtype showed high agreement with the mesenchymal/stem‐like subtype defined by gene expression signatures and characterized by poor prognosis and survival. The P3 subtype was characterized by decreased expression of ribosomal proteins, the spliceosome, and histone deacetylase 2, as well as increased expression of osteopontin, SERPINA 1 and SERPINA 3, and proteins involved in wound healing, acute inflammation and complement pathway. This was also confirmed by immunodetection and gene expression analyses. Our results show that these tumours are characterized by altered expression of proteins involved in biological processes associated with immune evasion and metastasis, suggesting new therapeutic options in the treatment of this aggressive type of CRC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hirayama disease is a rare neuromuscular disease, which classically presents as lower motor neuron weakness and atrophy in the upper limbs and specifically the C7-T1 myotomes. Proposed pathogenesis ...relates to microcirculatory dysfunction in the territory of the anterior spinal artery caused by epidural venous plexus engorgement with forward displacement of the posterior dura and spinal cord during neck flexion, leading to chronic ischemic changes in the lower cervical anterior horn cells. Diagnosis hinges upon clinical and radiographic findings, and treatment is generally conservative given the self-limited nature of the disease. Here, we present a case with classic radiologic findings of Hirayama disease with lower limb myelopathic findings alone. This case raises the question of whether the pathophysiology leading to focal anterior cervical myelopathy in forward flexion could present along a broader clinical spectrum than previously recognized, from complete asymptomaticity, to classic Hirayama disease with C7-T1 atrophy, to cervical myelopathy with long tract signs.
Partially observed functional data are frequently encountered in applications and are the object of an increasing interest by the literature. We here address the problem of measuring the centrality ...of a datum in a partially observed functional sample. We propose an integrated functional depth for partially observed functional data, dealing with the very challenging case where partial observability can occur systematically on any observation of the functional dataset. In particular, differently from many techniques for partially observed functional data, we do not request that some functional datum is fully observed, nor we require that a common domain exist, where all of the functional data are recorded. Because of this, our proposal can also be used in those frequent situations where reconstructions methods and other techniques for partially observed functional data are inapplicable. By means of simulation studies, we demonstrate the very good performances of the proposed depth on finite samples. Our proposal enables the use of benchmark methods based on depths, originally introduced for fully observed data, in the case of partially observed functional data. This includes the functional boxplot, the outliergram and the depth versus depth classifiers. We illustrate our proposal on two case studies, the first concerning a problem of outlier detection in German electricity supply functions, the second regarding a classification problem with data obtained from medical imaging.
Supplementary materials
for this article are available online.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
This paper reports a simple method for the preparation of suitable graphene quantum dots after surface passivation, to be used for the determination of carbaryl in juice samples. A comparison of ...synthetic conditions for the preparation of graphene quantum dots following the top‐down approach is described. In the one‐step route selected, evaluation of diverse reaction time for cutting and modulating the oxidizing sites in the broken pieces of the initial graphene layer is conducted with a mixture of concentrated acids. Exploring the passivation effect on the purified graphene quantum dots, we demonstrated the suitability of the selected graphene quantum dots for practical application in the detection of carbaryl using fluorometric detection. Higher sensitivity was achieved after 8 min of contact, in which graphene quantum dots promotes the degradation of carbaryl into naphthol, being the latter responsible for the analytical signal. The detection and quantification limits were 0.36 and 1.21 μg/L, respectively, being the response linear up to 26 μg/L with excellent precision (better than 3.2% at the limit of detection). The recovery of the analyte from commercial juice samples (91.4–96.7%) testifies to the applicability of the proposal for the analytical problem selected.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dietary restriction is a frequent strategy for weight loss, but adherence is difficult and returning to poor dietary habits can result in more weight gain than that previously lost. How weight loss ...due to unrestricted intake of a healthy diet affects the response to resumption of poor dietary habits is less studied. Moreover, whether this response differs between the sexes and if the insulin-like growth factor (IGF) system, sex dependent and involved in metabolic control, participates is unknown. Mice received rodent chow (6% Kcal from fat) or a high-fat diet (HFD, 62% Kcal from fat) for 4 months, chow for 3 months plus 1 month of HFD, or HFD for 2 months, chow for 1 month then HFD for 1 month. Males and females gained weight on HFD and lost weight when returned to chow at different rates (p < 0.001), but weight gain after resumption of HFD intake was not affected by previous weight loss in either sex. Glucose metabolism was more affected by HFD, as well as the re-exposure to HFD after weight loss, in males. This was associated with increases in hypothalamic mRNA levels of IGF2 (p < 0.01) and IGF binding protein (IGFBP) 2 (p < 0.05), factors involved in glucose metabolism, again only in males. Likewise, IGF2 increased IGFBP2 mRNA levels only in hypothalamic astrocytes from males (p < 0.05). In conclusion, the metabolic responses to dietary changes were less severe and more delayed in females and the IGF system might be involved in some of the sex specific observations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent discoveries of shale gas reserves have promoted a renewed interest in gas-to-liquid technologies for the production of fuels and chemicals. One option of particular interest for the chemical ...industry is the production of methanol. In this work, an economic and environmental analysis for the production of methanol from shale gas is presented. Four reforming technologies, partial oxidation, steam methane reforming, autothermal reforming, and a combined reforming, are considered for the production of the syngas to be fed to the methanol plant. Process simulations are used to assess the performance of each resulting flowsheet. The results identify partial oxidation and autothermal reforming as the most suitable options for methanol production from an economic viewpoint, but the use of the combined reforming turned out to be the best sustainable alternative from an environmental viewpoint.
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