Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic ...lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance.
SYNOPSIS
Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.
The transcription factors YAP and TAZ stabilize ATF4 by promoting its nuclear import to cooperatively induce expression of SLC7A11, a cystine importer critical for glutathione synthesis.
Glutathione synthesis and homeostasis are required to repress ferroptosis and to maintain Sorafenib resistance in liver cancer cells.
Inhibition of Glutathione synthesis re‐sensitizes Sorafenib‐resistant cancer cells to Sorafenib therapy, which then induces ferroptosis and represses tumor growth in murine liver cancer models.
Pharmacological repression of the anti‐oxidant pathways regulated by YAP/TAZ and ATF4 could re‐sensitize therapy‐resistant liver cancers to Sorafenib treatment.
Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.
Superhydrophobic surfaces based on aluminium oxide coatings had been developed on glass substrates via solution based approach for solar panel cover glass applications. The fabricated surface was ...amorphous with an interconnected porous network of nanoflakes. The static contact angle of the prepared coatings was 161° and exhibited superior self–cleaning behaviour at a tilting angle less than 10°. The 300nm thick coating with refractive index value gradually decreased from air (n −1), through the fabricated coating (n −1.35) towards the glass substrate (n – 1.56) enabled it to acquire a high average transmittance of 95% with anti-reflecting property. The photovoltaic performance of commercially available solar cells covered with uncoated glass substrate and aluminium oxide coated glass substrate was measured under various conditions (such as – fabricated, artificially contaminated and self – cleaned conditions) and the results were compared. The uncoated glass substrate and aluminium oxide coated superhydrophobic glass substrate recovered the efficiency of saw dust contaminated solar panel by 67% and 91%, respectively, thereby enabling the fabricated superhydrophobic glass substrate to be effectively useful for self–cleaning cover glass applications.
•Transparent, anti-reflective and superhydrophobic aluminium oxide coatings were fabricated by chemical method.•The coatings were superhydrophobic with static water contact angle of 155°.•The fabricated superhydrophobic substrates were optically transparent.•The coated glass recovered the efficiency of contaminated solar panel by 91% and useful for cover glass applications.
Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs).sup.1. Activation of the ...inflammasome provides host defence against aspergillosis.sup.2,3, which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (DELTAgt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.
Abstract
We report the discovery of extremely low mass white dwarfs (ELM WDs) as a companion of blue straggler stars (BSSs) in the Galactic globular cluster NGC 362 using images from AstroSat's Ultra ...Violet Imaging Telescope (UVIT). Spectral energy distributions (SEDs) for 26 far-UV (FUV) bright member BSSs are created using data from the UVIT, the UltraViolet and Optical Telescope (UVOT), Gaia EDR3, and the 2.2 m ESO/MPI telescope. A single SED is fitted to 14 BSSs, whereas double-SED fits revealed ELM WDs as binary companions in 12 of the 26 BSSs studied. The effective temperature, radius, luminosity, and mass of the 12 ELM WDs are found to have a range of
T
eff
= 9750−18,000 K,
R
= 0.1−0.4
R
⊙
,
L
= 0.4−3.3
L
⊙
, and
M
= 0.16−0.20
M
⊙
. These suggest that 12 BSSs are post-mass-transfer systems formed through the case A/B mass transfer pathway. To the best of our knowledge, this is the first finding of ELM WDs as companions to BSSs in globular clusters. This cluster is known to have a binary BSS sequence, and the 12 binary and 14 single BSSs (as classified by the SEDs) follow the mass transfer and collisional sequence of BSSs in the color–magnitude diagram. The cooling ages of nine of the ELM WDs are found to be younger than 500 Myr. Though the binary BSSs may have formed during the core collapse (∼200 Myr) or as part of the dynamical evolution of the cluster, they provide new insights on the dynamics of this cluster.
Nucleation and growth of chemical conversion coating on Mg–4Zn alloy prepared by immersion in saturated NaHCO3 at ambient temperature and its corrosion behaviour in simulated body fluid (SBF) is ...investigated in this paper. Compact dense coating obtained up on 24 h of immersion at ambient temperature is found to provide complete coverage of the surface and a high initial corrosion resistance in SBF. With sustained exposure to SBF, the coating dissolves and slowly cracks to expose the substrate to the corrosion medium. The 24 h coated sample shows high levels of bio mineralisation, with flower shaped crystals of phosphates of Ca and Mg on the surface. The combined effects of slow first hydrogen evolution rate and precipitation of phosphates, and similarities to the carbonate coating developed in vivo makes the conversion coating discussed in this paper a suitable choice for Mg alloys for temporary bio implant applications.
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•Nucleation and growth of nesquehonite layer on Mg–4Zn alloy by 24 h treatment with saturated NaHCO3.•Complete surface coating leads to low H2 evolution of 1.099mlcm−2day−1 in simulated body fluid.•Coated sample shows lower corrosion and better bio mineralisation than bare substrate.•Partially coating leads to larger initial hydrogen evolution than bare substrate.
Tripartite multidrug efflux systems of Gram-negative bacteria are composed of an inner membrane transporter, an outer membrane channel and a periplasmic adaptor protein. They are assumed to form ...ducts inside the periplasm facilitating drug exit across the outer membrane. Here we present the reconstitution of native Pseudomonas aeruginosa MexAB-OprM and Escherichia coli AcrAB-TolC tripartite Resistance Nodulation and cell Division (RND) efflux systems in a lipid nanodisc system. Single-particle analysis by electron microscopy reveals the inner and outer membrane protein components linked together via the periplasmic adaptor protein. This intrinsic ability of the native components to self-assemble also leads to the formation of a stable interspecies AcrA-MexB-TolC complex suggesting a common mechanism of tripartite assembly. Projection structures of all three complexes emphasize the role of the periplasmic adaptor protein as part of the exit duct with no physical interaction between the inner and outer membrane components.
The breakup of the supercontinent Gondwanaland into Africa, Antarctica, Australia and India about 140 million years ago, and consequently the opening of the Indian Ocean, is thought to have been ...caused by heating of the lithosphere from below by a large plume whose relicts are now the Marion, Kerguelen and Réunion plumes. Plate reconstructions based on palaeomagnetic data suggest that the Indian plate attained a very high speed (18-20 cm yr(-1) during the late Cretaceous period) subsequent to its breakup from Gondwanaland, and then slowed to approximately 5 cm yr(-1) after the continental collision with Asia approximately 50 Myr ago. The Australian and African plates moved comparatively less distance and at much lower speeds of 2-4 cm yr(-1) (refs 3-5). Antarctica remained almost stationary. This mobility makes India unique among the fragments of Gondwanaland. Here we propose that when the fragments of Gondwanaland were separated by the plume, the penetration of their lithospheric roots into the asthenosphere were important in determining their speed. We estimated the thickness of the lithospheric plates of the different fragments of Gondwanaland around the Indian Ocean by using the shear-wave receiver function technique. We found that the fragment of Gondwanaland with clearly the thinnest lithosphere is India. The lithospheric roots in South Africa, Australia and Antarctica are between 180 and 300 km deep, whereas the Indian lithosphere extends only about 100 km deep. We infer that the plume that partitioned Gondwanaland may have also melted the lower half of the Indian lithosphere, thus permitting faster motion due to ridge push or slab pull.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated ...cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin's transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin's transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin's transcriptional activities upon stimulation with Wnt3a or during TGF-β-induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin-dependent transcription in malignant tumor progression of breast cancer.
In the present study, Gas Tungsten Arc Welding (GTAW) of Inconel 718 alloy has been carried out at different welding currents with and without ultrasonic vibration. In the absence of ultrasonic ...treatment, samples welded with a current of 80 A have shown a crack length of 15 mm which is found to increase to 35 mm for a welding current of 120 A. The slow solidification rate associated with high welding current causes increase in hot cracking length. Non-equilibrium Scheil solidification simulation of Inconel 718 based on CALPHAD approach suggests that the long freezing range of more than 175 °C, small fraction of eutectic, i.e., less than 10% in susceptible freezing range (SFR) and segregation of low melting point Laves and γ′′ (Ni3Nb) phases play critical roles in hot cracking behavior of Inconel 718 alloy. Ultrasonic treatment during solidification of weld metal has decreased the crack sensitivity and dendritic arm length of Inconel 718 alloy from 47.5% to 13.3% for the welding current of 120 A. There was a corresponding reduction in dendritic arm length from 1256 to 89 μm. Further, it was observed that the welding current has very limited role in the hot cracking behavior of Inconel 718 alloy in the presence of ultrasonic vibration. Dendritic fragmentation, grain refinement and reduction in solute segregation are recognized as the main factors that mitigate hot cracking tendency of Inconel 718 alloy by ultrasonic vibration.
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•Hot Cracking of Inconel 718 GTAW process was investigated during ultrasonic vibration.•Crack sensitivity found increased with welding current in the absence of ultrasonic vibration.•Non-equilibrium Scheil solidification model predicts the inherent hot cracking tendency of Inconel 718 alloy.•Ultrasonic treatment reduced the hot cracking length of Inconel 718 alloy by 70–80%.•Ultrasonic assisted dendritic fragmentation and reduction in solute segregation are responsible for reduction in hot cracking.
Herein, porous 1D n–p type ultra-long ZnO@Bi2O3 heterojunction nanorods have been synthesized by a solvothermal method and their complex charge transport characteristics pertaining to NO2 gas sensing ...properties have been investigated. The porous structure of the ZnO@Bi2O3 heterojunction nanorods assisted in achieving superior sensing properties compared to pristine ZnO nanorods. Temperature-dependent in situ electrical studies of the porous heterojunction nanorods explored the unique electron transport properties under different environments, which revealed the accumulation/depletion of electrons and charge carrier recombination leading to band bending at the metal oxide heterojunctions. The formation of electron depletion layers at n-ZnO/p-Bi2O3 interfaces is believed to increase the adsorption of oxidizing gas, resulting in a fast response time (10–12 s) and 10 times higher sensitivity than that of the ZnO nanorod-based sensor towards 500 ppb NO2. To study the structure–property correlation of the ultra-long ZnO@Bi2O3 heterojunction nanorods-based sensor, a crystallographic model supported by transmission electron microscopy analysis was adopted to understand the NO2 gas adsorption properties on the surface. The crystallographic model helps to visualize the dangling bonds and the ratio of metal to oxygen ions present at the exposed crystal planes. The results suggest that porous, ultralong n–p type ZnO@Bi2O3 heterojunction nanorods could be a promising candidate for a high performance NO2 sensor for real time applications.
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