Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression ...remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.
Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a ...variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.
Detecting viable circulating tumor cells (CTCs) without disruption to their functions for in vitro culture and functional study could unravel the biology of metastasis and promote the development of ...personalized anti-tumor therapies. However, existing CTC detection approaches commonly include CTC isolation and subsequent destructive identification, which damages CTC viability and functions and generates substantial CTC loss. To address the challenge of efficiently detecting viable CTCs for functional study, we develop a nanosphere-based cell-friendly one-step strategy. Immunonanospheres with prominent magnetic/fluorescence properties and extraordinary stability in complex matrices enable simultaneous efficient magnetic capture and specific fluorescence labeling of tumor cells directly in whole blood. The collected cells with fluorescent tags can be reliably identified, free of the tedious and destructive manipulations from conventional CTC identification. Hence, as few as 5 tumor cells in ca. 1mL of whole blood can be efficiently detected via only 20min incubation, and this strategy also shows good reproducibility with the relative standard deviation (RSD) of 8.7%. Moreover, due to the time-saving and gentle processing and the minimum disruption of immunonanospheres to cells, 93.8±0.1% of detected tumor cells retain cell viability and proliferation ability with negligible changes of cell functions, capacitating functional study on cell migration, invasion and glucose uptake. Additionally, this strategy exhibits successful CTC detection in 10/10 peripheral blood samples of cancer patients. Therefore, this nanosphere-based cell-friendly one-step strategy enables viable CTC detection and further functional analyses, which will help to unravel tumor metastasis and guide treatment selection.
•CTCs and WBCs were efficiently and specifically labeled with different IFNs tags.•Simultaneous capture and identification of CTCs were realized by coupled IMNs and IFNs.•One-step strategy shortened time consumption and improved efficiency of CTC detection.•The strategy was cell-friendly to detect viable CTCs for culture and functional study.
Olfactory disturbance is one of the main symptoms of coronavirus disease-2019 (COVID-19). Various olfactory disorders caused by viral infections are treated with nasal corticosteroids. This study ...aimed to evaluate the safety and efficacy of nasal corticosteroids in the treatment of olfactory disorders caused by the severe acute respiratory syndrome coronavirus 2.
We searched the Web of Science, Embase, PubMed, and Cochrane Library databases for clinical trials of nasal corticosteroids for treating COVID-19 olfactory dysfunction.
We assessed the effect of nasal corticosteroids on olfactory function in COVID-19-affected individuals using a Meta-analysis of published studies, considering the number of patients who fully recovered from olfactory dysfunction, olfactory scores following treatment, and olfactory recovery time.
Seven studies involving 930 patients were analyzed. The Meta-analysis results revealed that the olfactory score of the experimental group was 1.40 points higher than that of the control group (standardized mean difference MD: 1.40, 95% confidence interval 95% CI: 0.34-2.47, P < .00001). However, the differences in the outcomes of cure rate (risk ratio: 1.18, 95% CI: 0.89-1.69, P = .21) and recovery time (MD: -1.78, 95% CI: -7.36 to 3.81, P = .53) were not statistically significant. Only 1 study reported adverse effects of nasal steroid treatment, namely tension, anger, and stomach irritation.
Although nasal steroid therapy does not result in significant adverse effects, it proves ineffective in the treatment of COVID-19 olfactory dysfunction.
A concept of measuring the quantum distance between two different quantum states that is called quantum information metric has been presented. The holographic principle (anti–de Sitter/conformal ...field theory) suggests that the quantum information metric Gλλ between perturbed state and unperturbed state in field theory has a dual description in the classical gravity. In this work we calculate the quantum information metric of a theory that is dual to a conical defect geometry and we show that it is n times the one of its covering space. We also give a holographic check for our result in the gravity side. Meanwhile, it was argued that Gλλ is dual to a codimension-one surface in spacetime and satisfies Gλλ=nd·Vol(Σmax)/Ld. We show that the coefficient nd for conical defect should be rescaled by n2 from the one for anti–de Sitter space. A limit case of conical defect-the massless Banados-Teitelboim-Zannelli (BTZ) black hole-is also considered. We show that the quantum information metric of a massless BTZ black hole disagrees with the one obtained by taking the vanishing temperature limit in BTZ black hole. This provides a new arena in differentiating the different phases between BTZ spacetime and its massless cousin.
ABSTRACT
Type Ia supernovae (SNe Ia) are successful cosmological distance indicators and important element factories in the chemical evolution of galaxies. They are generally thought to originate ...from thermonuclear explosions of carbon–oxygen white dwarfs in close binaries. However, the observed diversity among SNe Ia implies that they have different progenitor models. In this article, we performed the long-term evolution of NS+He star binaries with different initial He star masses ($M_{\rm He}^{\rm i}$) and orbital periods ($P_{\rm orb}^{\rm i}$) for the first time, in which the He star companions can explode as SNe Ia eventually. Our simulations indicate that after the He stars develop highly degenerate oxygen–neon (ONe) cores with masses near the Chandrasekhar limit, explosive oxygen burning can be triggered due to the convective Urca process. According to these calculations, we obtained an initial parameter space for the production of SNe Ia in the $\rm log\,$$P^{\rm i}_{\rm orb}{\text {--}}M^{\rm i}_{\rm He}$ plane. Meanwhile, we found that isolated mildly recycled pulsars can be formed after He stars explode as SNe Ia in NS+He star binaries, in which the isolated pulsars have minimum spin periods ($P_{\rm spin}^{\rm min}$) of ∼30–110 ms and final orbital velocities of ${\sim} \rm 60{\!-\!}360\, km\, s^{-1}$, corresponding to initial orbital periods of 0.07–10 d. Our work suggests that the NS+He star channel may contribute to the formation of isolated mildly recycled pulsars with velocity $\rm {\lesssim} 360\, km\, s^{-1}$ in observations, and such isolated pulsars should locate in the region of pulsars with massive white dwarf companions in the $P_{\rm spin} {\!-\!}\dot{P}_{\rm spin}$ diagram.
ABSTRACT
The disc instability mechanism (DIM) is widely accepted to account for the transient behaviour of dwarf novae (DNe), which experience short outbursts separated by long quiescence. The duty ...cycle (the ratio between the outburst duration and the recurrence time) determines the amount of accreted mass by the white dwarf (WDs) during outbursts, thus playing an important role in the long-term binary evolution. Employing the code of Modules for Experiments in Stellar Astrophysics, we systemically investigate the influence of the duty cycles on the evolution of DNe and the mass growth of accreting carbon-oxygen (CO) WDs. Our calculations show that, while the DIM can considerably influence the accretion process, efficient WD-mass growth requires a particular range of the duty cycle. For WDs with the initial masses of 0.6, 0.7, and 1.1 M⊙, these duty cycles are 0.006$\, \le$d$\, \le$0.007, d = 0.005, and, d = 0.003 and the accumulated mass of the WDs can reach 0.1, 0.13, and 0.21 M⊙, respectively. In all of our simulations, no CO WDs can grow their masses to the explosion mass of Type Ia supernovae of about 1.38 M⊙. Because of a much short time-scale of the outburst state, the final donor-star masses and orbital periods are insensitive to the duty cycles. Therefore, we propose that the DIM in DNe could alleviate the WD mass problem to some extent.
The reaction of racemic γ-substituted α,β-unsaturated γ-lactams rac-1 with arylboron reagents 2 in the presence of a chiral diene L1a–rhodium catalyst under basic conditions (3.0 equiv of NEt3) gave ...high yields of β,γ-disubstituted trans-γ-lactams 3 with both high diastereo- and enantioselectivity. Fast racemization of 1 by way of a dienolate generated with the base followed by kinetic resolution of 1 with the chiral rhodium catalyst realized this highly efficient dynamic kinetic resolution. The synthetic utility of the present method is demonstrated by the synthesis of key intermediates to biologically active compounds.
Vascular dementia (VaD), caused by stroke or small vessel disease, is the second‐most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is ...currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1‐42 in BCCAO rats by enzyme‐linked immunosorbent assay. Post‐translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl‐PTMs.
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•The gas flow hydrodynamics in the RPB under floating motions was studied.•The alternation of the turbulence-enhanced and turbulence-weakened zone was found.•The influence mechanism ...was analyzed based on the gas velocity vector.
As a typical process intensification device, a rotating packed bed (RPB) is promising for marine gas separation and purification. Previous studies have focused on the gas-phase characteristics of onshore RPBs without the function of floating motions. In this study, the effect of the six degrees of freedom floating motions on the gas-phase characteristics was investigated by experiments and simulation. Compared to the pressure drop under stationary conditions, the pressure drop under floating motions is generally lower and fluctuates. The heave motion causes a significant deviation and oscillation in the pressure drop. The simulation results revealed that the turbulence-enhanced zone (T-E zone) and the turbulence-weakened zone (T-W zone) appeared alternately and caused an evolution of the maldistribution factor. The floating motions enhance or weaken the radial, axial, and tangential slip velocities of the gas phase, which leads to the presence of a T-E/T-W zone and variation of flow direction. The results provided a deep understanding of offshore RPBs performance.
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