The amino acid antiporter system Xc
is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ...ferroptosis). While the activity of system Xc
often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc
activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc
is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc
, depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc
and promote ferroptosis repressed by this antiporter.
AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were ...pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4℃ for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion.RESULTS: Postoperatively, serum transaminases were significantly ...
N6-methyladenosine (m6A) modification is the most frequently occurring internal modification in eukaryotic RNAs. By modulating various aspects of the RNA life cycle, it has been implicated in a wide ...range of pathological and physiological processes associated with human diseases. Ischemic stroke is a major cause of death and disability worldwide with few treatment options and a narrow therapeutic window, and accumulating evidence has indicated the involvement of m6A modifications in the development and progression of this type of stroke. In this review, which provides insights for the prevention and clinical treatment of stroke, we present an overview of the roles played by m6A modification in ischemic stroke from three main perspectives: (1) the association of m6A modification with established risk factors for stroke, including hypertension, diabetes mellitus, hyperlipidemia, obesity, and heart disease; (2) the roles of m6A modification regulators and their functional regulation in the pathophysiological injury mechanisms of stroke, namely oxidative stress, mitochondrial dysfunction, endothelial dysfunction, neuroinflammation, and cell death processes; and (3) the diagnostic and therapeutic potential of m6A regulators in the treatment of stroke.
Many-body entanglement is often created through the system evolution, aided by nonlinear interactions between the constituting particles. These very dynamics, however, can also lead to fluctuations ...and degradation of the entanglement if the interactions cannot be controlled. Here, we demonstrate near-deterministic generation of an entangled twin-Fock condensate of ~11,000 atoms by driving a rubidium-87 Bose-Einstein condensate undergoing spin mixing through two consecutive quantum phase transitions (QPTs). We directly observe number squeezing of 10.7 ± 0.6 decibels and normalized collective spin length of 0.99 ± 0.01. Together, these observations allow us to infer an entanglement-enhanced phase sensitivity of ~6 decibels beyond the standard quantum limit and an entanglement breadth of ~910 atoms. Our work highlights the power of generating large-scale useful entanglement by taking advantage of the different entanglement landscapes separated by QPTs.
Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models ...and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.
Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of ...high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma.
Light-mediated self-organization of nanoparticles (NPs) offers a route to study mesoscale electrodynamics interactions in many-body systems. Here we report the phase transition and self-stabilization ...of dynamic assemblies with up to 101 plasmonic metal NPs in optical fields. The spatial stability of self-organized NPs is strongly influenced by the laser intensity and polarization state, where phase transition occurs when the intensity increases and the polarization changes from linear to circular. Well-organized NP arrays can form in a circularly polarized laser beam, where the center of an array is less susceptible to thermal fluctuations than the edge. Moreover, larger arrays are self-protected from fluctuation-induced instability by incorporating more NP constituents. The dynamics of NP arrays can be understood by electrodynamic simulations coupled with thermal fluctuations and by examining their potential energy surfaces. This study clearly reveals the spatial inhomogeneity of optical binding interactions in a two-dimensional multiparticle system, which is important for building large-scale optical matter assemblies with NPs.
The screening performance of urine flow cytometry parameters (e.g., white blood cell and bacteria) for urinary tract infection (UTI) has been widely recognized. The majority of previous studies, ...however, investigated the screening performance of Sysmex UF-1000i urine flow cytometer. This study aimed to investigate the screening performance of Sysmex UF-5000 analyzer, a third-generation urinary flow cytometer, for UTI and its novel parameter named Gram flag for discriminating gram-positive and negative pathogens. Urine specimens sent to the clinical microbiology laboratory of our hospital for bacterial culture between September 13, 2021, and November 15, 2021, were prospectively and consecutively collected. The Sysmex UF-5000 analyzer was used to determine urine white blood cell (WBC) and bacteria simultaneously. A chemical strip was used to assess urine nitrate. UTI was defined as positive urine bacterial culture > 104 CFU /ml. The receiver operating characteristics (ROC) curve, nomogram, decision tree, and decision curve were used to determine the screening performance of urine WBC, nitrate, and bacterial. A total of 246 UTIs and 425 non-UTIs were enrolled. The areas under the ROC curve (AUCs) for WBC and bacterial were 0.74 and 0.86, respectively. The decision curve showed that urine bacteria had a higher benefit than WBC. The nomogram indicated that urine bacterial had the largest effect on the probability of UTI. The sensitivity and specificity of the decision tree were 0.69 and 0.95, respectively. The flag of Gram-negative had a positive predictive value (PPV) of 0.93 in patients with urine bacteria > 1367 /μl. Therefore, we conclude that urine bacteria determined by the Sysmex UF-5000 had higher screening performance and greater benefit than WBC. The decision tree can be used to improve the screening performance of routine urinary parameters. The flag of Gram-negative is a reliable indicator to confirm gram-negative bacteria infection in UTI patients.
The development of strain sensors featuring both ultra high sensitivity and high stretchability is still a challenge. We demonstrate that strain sensors based on fragmented single-walled carbon ...nanotube (SWCNT) paper embedded in poly(dimethylsiloxane) (PDMS) can sustain their sensitivity even at very high strain levels (with a gauge factor of over 107 at 50% strain). This record sensitivity is ascribed to the low initial electrical resistance (5–28 Ω) of the SWCNT paper and the wide change in resistance (up to 106 Ω) governed by the percolated network of SWCNT in the cracked region. The sensor response remains nearly unchanged after 10 000 strain cycles at 20% proving the robustness of this technology. This fragmentation based sensing system brings opportunities to engineer highly sensitive stretchable sensors.
In this paper, we are devoted to investigate the consensus-based distributed state estimation problems for a class of sensor networks within the unscented Kalman filter (UKF) framework. The ...communication status among sensors is represented by a connected undirected graph. Moreover, a weighted average consensus-based UKF algorithm is developed for the purpose of estimating the true state of interest, and its estimation error is bounded in mean square which has been proven in the following section. Finally, the effectiveness of the proposed consensus-based UKF algorithm is validated through a simulation example.
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