Summary Objective Hypoxia-inducible factor-2α (HIF-2α) transcriptionally upregulates Nampt in articular chondrocytes. NAMPT, which exhibits nicotinamide phosphoribosyltransferase activity, in turn ...causes osteoarthritis (OA) in mice by stimulating the expression of matrix-degrading enzymes. Here, we sought to elucidate whether HIF-2α activates the NAMPT-NAD+ -SIRT axis in chondrocytes and thereby contributes to the pathogenesis of OA. Methods Assays of NAD levels, SIRT activity, reporter gene activity, mRNA, and protein levels were conducted in primary cultured mouse articular chondrocytes. Experimental OA in mice was induced by intra-articular (IA) injection of adenovirus expressing HIF-2α (Ad- Epas1 ) or NAMPT (Ad- Nampt ). The functions of SIRT in OA were examined by IA co-injection of SIRT inhibitors or adenovirus expressing individual SIRT isoforms or shRNA targeting specific SIRT isoforms. Results HIF-2α activated the NAMPT-NAD+ -SIRT axis in chondrocytes by upregulating NAMPT, which stimulated NAD+ synthesis and thereby activated SIRT family members. The activated NAMPT-SIRT pathway, in turn, promoted HIF-2α protein stability by negatively regulating its hydroxylation and 26S proteasome-mediated degradation, resulting in increased HIF-2α transcriptional activity. Among SIRT family members (SIRT1–7), SIRT2 and SIRT4 were positively associated with HIF-2α stability and transcriptional activity in chondrocytes. This reciprocal regulation was required for the expression of catabolic matrix metalloproteinases (MMP3, MMP12, and MMP13) and OA cartilage destruction caused by IA injection of Ad- Epas1 Ad- Nampt. Conclusion The reciprocal regulation of HIF-2α and the NAMPT-NAD+ -SIRT axis in articular chondrocytes is involved in OA cartilage destruction caused by HIF-2α or NAMPT.
Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to ...be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.
We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.
Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.
Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.
The mechanism of superconductivity in cuprates remains one of the big challenges of condensed matter physics. High-Tc
cuprates crystallize into a layered perovskite structure featuring copper oxygen ...octahedral coordination. Due to the Jahn Teller effect in combination with the strong static Coulomb interaction, the octahedra in high-Tc
cuprates are elongated along the c axis, leading to a 3dx²-y² orbital at the top of the band structure wherein the doped holes reside. This scenario gives rise to 2D characteristics in high-Tc
cuprates that favor d-wave pairing symmetry. Here, we report superconductivity in a cuprate Ba₂CuO4-y, wherein the local octahedron is in a very exceptional compressed version. The Ba₂CuO4-y compound was synthesized at high pressure at high temperatures and shows bulk superconductivity with critical temperature (Tc
) above 70 K at ambient conditions. This superconducting transition temperature is more than 30 K higher than the Tc
for the isostructural counterparts based on classical La₂CuO₄. X-ray absorption measurements indicate the heavily doped nature of the Ba₂CuO4-y superconductor. In compressed octahedron, the 3d3z²-r² orbital will be lifted above the 3dx²-y² orbital, leading to significant 3D nature in addition to the conventional 3dx²-y² orbital. This work sheds important light on advancing our comprehensive understanding of the superconducting mechanism of high Tc
in cuprate materials.
In superconductors, electrons are paired and condensed into the ground state. An impurity can break the electron pairs into quasiparticles with energy states inside the superconducting gap. The ...characteristics of such in-gap states reflect accordingly the properties of the superconducting ground state. A zero-energy in-gap state is particularly noteworthy, because it can be the consequence of non-trivial pairing symmetry or topology. Here we use scanning tunnelling microscopy/spectroscopy to demonstrate that an isotropic zero-energy bound state with a decay length of ∼10 Å emerges at each interstitial iron impurity in superconducting Fe(Te,Se). More noticeably, this zero-energy bound state is robust against a magnetic field up to 8 T, as well as perturbations by neighbouring impurities. Such a spectroscopic feature has no natural explanation in terms of impurity states in superconductors with s-wave symmetry, but bears all the characteristics of the Majorana bound state proposed for topological superconductors, indicating that the superconducting state and the scattering mechanism of the interstitial iron impurities in Fe(Te,Se) are highly unconventional.
We report on the experimental studies of laser driven ion acceleration from a double-layer target where a near-critical density target with a few-micron thickness is coated in front of a ...nanometer-thin diamondlike carbon foil. A significant enhancement of proton maximum energies from 12 to ∼30 MeV is observed when a relativistic laser pulse impinges on the double-layer target under linear polarization. We attributed the enhanced acceleration to superponderomotive electrons that were simultaneously measured in the experiments with energies far beyond the free-electron ponderomotive limit. Our interpretation is supported by two-dimensional simulation results.
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U–Pb age, trace element and Hf isotope compositions of zircon were analysed for a metasedimentary rock and two amphibolites from the Kongling terrane in the northern part of the Yangtze Craton. The ...zircon shows distinct morphological and chemical characteristics. Most zircon in an amphibolite shows oscillatory zoning, high Th/U and 176Lu/177Hf ratios, high formation temperature, high trace element contents, clear negative Eu anomaly, as well as HREE‐enriched patterns, suggesting that it is igneous. The zircon yields a weighted mean 207Pb/206Pb age of 2857 ± 8 Ma, representing the age of the magmatic protolith. The zircon in the other two samples is metamorphic. It has low Th/U ratios, low trace element concentrations, variable HREE contents (33.8 ≥ LuN≥2213; 14.7 ≤ LuN/SmN ≤ 354) and 176Lu/177Hf ratios (0.000030–0.001168). The data indicate that the zircon formed in the presence of garnet and under upper amphibolite facies conditions. The metamorphic zircon yields a weighted mean 207Pb/206Pb age of 2010 ± 13 Ma. These results combined with previously obtained Palaeoproterozoic metamorphic ages suggest a c. 2.0 Ga Palaeoproterozoic collisional event in the Yangtze Craton, which may result from the assembly of the supercontinent Columbia. The zircon in two samples yields weighted mean two‐stage Hf model (TDM2) ages of 3217 ± 110 and 2943 ± 50 Ma, respectively, indicating that their protoliths were mainly derived from Archean crust.
The effect of transport stress on blood metabolism, glycolytic potential, and meat quality in broilers was investigated. Arbor Acres chicks (n = 360, 1 d old, males) were randomly allotted to 1 of 5 ...treatments: unstressed control, 45-min (short-term) transport with 45-min (short-term) recovery, 45-min transport with 3-h (long-term) recovery; 3 h (long-term) transport with 45-min recovery, and 3-h transport with 3-h recovery. Each treatment consisted of 6 replicates with 12 birds each. On d 46, all birds (except the control group) were transported according to a designed protocol. Transport time affected plasma glucose level (P < 0.05) and glycogen level (P = 0.06) in breast muscle as well as the area (P < 0.01) and density (P < 0.01) of IIa fibers. Glucose concentration increased slightly during the first 45 min of transport and then decreased dramatically in the long-term transported broilers (P < 0.05). Long-term transport decreased the concentration of breast glycogen (P = 0.06) and affected the size of IIa fibers in tibialis anterior by decreasing the area (P < 0.01) with an increase in density (P < 0.01). However, a long-term recovery after transport contributed to the homeostasis of blood corticosterone (CORT, P = 0.05) and low levels of glycogen (P < 0.05), lactate (P < 0.01), and glycolytic potential (P < 0.01) in thigh muscles. Interactions existed between transport and recovery time on area (P < 0.05) and density (P < 0.01) of IIa fibers. Furthermore, plasma nonesterified fatty acids increased significantly in the 3-h transport with 3-h recovery group (P < 0.05) in comparison with the control. These results suggested that transport induced the release of plasma CORT and glycopenia, which affected the contractive status of muscle fibers by changing their area and density, and enhanced glycolysis and even lipolysis. A long-term recovery after transport was beneficial in lowering plasma CORT levels and reducing muscle glycolysis, which might improve broiler meat quality.
This study aimed to explore the role of alanine aminotransferase (ALT) in the effects of urinary caffeine and its primary metabolites on cognitive function in elderly people.
In this investigation, ...we meticulously curated a cohort from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) database. Animal fluency emerged as the pivotal metric for assessing cognitive function within our study population. In order to navigate the intricacies of mixture analysis and circumvent potential complexities, we harnessed the power of Bayesian kernel machine regression (BKMR) models. This method allowed us to dissect the nuanced impacts of caffeine and its primary urinary metabolites on cognitive function. While accounting for caffeine and its metabolites, we analyzed the relationship between ALT and cognitive function through non-linear dynamics. Lastly, employing structural equation modeling, we probed the intriguing question of whether ALT mediates the influence of 3,7-dimethylxanthine on cognitive function. This comprehensive approach has unveiled a deeper understanding of the multifaceted interplay among these variables, offering invaluable insights into the determinants of cognitive function within our cohort.
After meticulous adjustment for various covariates, our linear regression analysis unveiled a noteworthy finding: 3,7-dimethylxanthine demonstrated a significant positive correlation with cognitive function (p < 0.05). Importantly, within the BKMR model employed, 3,7-dimethylxanthine emerged as the most influential factor within the compound, with posterior inclusion probabilities of 0.995 and 0.939. Furthermore, our single-exposure effect model confirmed its presence at the 25th, 50th, and 75th percentile concentrations of other components within the compound. Interestingly, bivariate concentration curves indicated no interaction within the compound, underscoring the prominent impact of 3,7-dimethylxanthine on cognitive function. Subsequently, through a test of Restricted Cubic Splines (RCS), we revealed a non-linear relationship between ALT and cognitive function at the 10th, 50th, and 90th percentiles (p < 0.05), indicating a heightened risk of diminished cognitive function in the low ALT group. Employing structural equation modeling, we meticulously examined the mediating role of ALT in relation to 3,7-dimethylxanthine and cognitive function. However, our study results did not yield significant evidence of a mediating effect. This comprehensive analysis elucidates the intricate interplay between these variables, unveiling the subtle mechanisms governing cognitive function.
In this study, a noteworthy positive correlation was observed between 3,7-dimethylxanthine and cognitive function. Additionally, a non-linear relationship was identified between ALT and cognitive function, with lower levels of ALT associated with a decline in cognitive function. The RCS trend suggested that higher levels of ALT may similarly lead to diminished cognitive performance. However, in our pursuit to ascertain potential mediation, we regrettably found no significant evidence supporting mediation among these factors involving ALT. This underscores the need for more comprehensive investigations and expanded clinical explorations into the intricate associations among these three pivotal elements.
Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT ...can be regulated by microRNAs (miRNAs). miR-148a is a liver-abundant miRNA. However, the role of miR-148a in the development of liver cancer remains largely unknown. In this study, we found that, compared with normal livers, miR-148a was significantly decreased in hepatocellular carcinoma (HCC) tissues, especially in those with the portal vein tumor thrombus. An in vitro transwell assay and an in vivo orthotopic liver xenograft model showed that the restoration of miR-148a expression significantly repressed the migration and pulmonary metastasis of hepatoma cells. Linear regression analysis revealed a positive correlation between the expression of miR-148a and the mRNA level of E-cadherin gene in human HCC tissues. Both gain- and loss-of-function studies disclosed that miR-148a promoted the expression of epithelial marker (E-cadherin) and reduced the levels of mesenchymal markers (N-cadherin, fibronectin or vimentin) in hepatoma cells. These data suggest that miR-148a may suppress EMT and cancer metastasis. Further mechanistic investigations showed that miR-148a directly inhibited Met expression by binding to its 3'-UTR. Moreover, the reintroduction of miR-148a attenuated the downstream signaling of Met, like activated phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3β-Ser9, and consequently reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT. Taken together, miR-148a may negatively regulate Met/Snail signaling and therefore inhibit the EMT and metastasis of hepatoma cells. These findings highlight the significance of miR-148a downregulation in tumor progression and implicate miR-148a as an attractive candidate for cancer therapy.
The amalgamation of South (SCB) and North China Blocks (NCB) along the Qinling‐Dabie orogenic belt involved several stages of high pressure (HP)‐ultra high pressure (UHP) metamorphism. The new ...discovery of UHP metamorphic rocks in the North Qinling (NQ) terrane can provide valuable information on this process. However, no precise age for the UHP metamorphism in the NQ terrane has been documented yet, and thus hinders deciphering of the evolution of the whole Qinling‐Dabie‐Sulu orogenic belt. This article reports an integrated study of U–Pb age, trace element, mineral inclusion and Hf isotope composition of zircon from an eclogite, a quartz vein and a schist in the NQ terrane. The zircon cores in the eclogite are characterized by oscillatory zoning or weak zoning, high Th/U and 176Lu/177Hf ratios, pronounced Eu anomalies and steep heavy rare earth element (HREE) patterns. The zircon cores yield an age of 796 ± 13 Ma, which is taken as the protolith formation age of the eclogite, and implies that the NQ terrane may belong to the SCB before it collided with the NCB. The ɛHf(t) values vary from −11.3 to 3.2 and corresponding two‐stage Hf model ages are 2402 to 1495 Ma, suggesting the protolith was derived from an enriched mantle. In contrast, the metamorphic zircon rims show no zoning or weak zoning, very low Th/U and 176Lu/177Hf ratios, insignificant Eu anomalies and flat HREE patterns. They contain inclusions of garnet, omphacite and phengite, suggesting that the metamorphic zircon formed under eclogite facies metamorphic conditions, and their weighted mean 206Pb/238U age of 485.9 ± 3.8 Ma was interpreted to date the timing of the eclogite facies metamorphism. Zircon in the quartz vein is characterized by perfect euhedral habit, some oscillatory zoning, low Th/U ratios and variable HREE contents. It yields a weighted mean U–Pb age of 480.5 ± 2.5 Ma, which registers the age of fluid activity during exhumation. Zircon in the schist is mostly detrital and U–Pb age peaks at c. 1950 to 1850, 1800 to 1600, 1560 to 1460 and 1400 to 1260 Ma with an oldest grain of 2517 Ma, also suggesting that the NQ terrane may have an affinity to the SCB. Accordingly, the amalgamation between the SCB and the NCB is a multistage process that spans c. 300 Myr, which includes: the formation of the Erlangping intra‐oceanic arc zone onto the NCB before c. 490 Ma, the c. 485 Ma crustal subduction and UHP metamorphism of the NQ terrane, the c. 430 Ma arc‐continent collision and granulite facies metamorphism, the 420 to 400 Ma extension and rifting in relation to the opening of the Palaeo‐Tethyan ocean, the c. 310 Ma HP eclogite facies metamorphism of oceanic crust and associated continental basement, and the final 250 to 220 Ma continental subduction and HP–UHP metamorphism.
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