Objective
The dysfunction of the
CLCN4
gene can lead to X-linked intellectual disability and Raynaud–Claes syndrome (MRXSRC), characterized by severe cognitive impairment and mental disorders. This ...study aimed to investigate the genetic defects and clinical features of Chinese children with
CLCN4
variants and explore the effect of mutant ClC-4 on the protein expression level and subcellular localization through
in vitro
experiments.
Methods
A total of 401 children with intellectual disabilities were screened for genetic variability using whole-exome sequencing (WES). Clinical data, including age, sex, perinatal conditions, and environmental exposure, were collected. Cognitive, verbal, motor, and social behavioral abilities were evaluated. Candidate variants were verified using Sanger sequencing, and their pathogenicity and conservation were analyzed using
in silico
prediction tools. Protein expression and localization of mutant ClC-4 were measured using Western blotting (WB) and immunofluorescence microscopy. The impact of a splice site variant was assessed with a minigene assay.
Results
Exome analysis identified five rare
CLCN4
variants in six unrelated patients with intellectual disabilities, including two recurrent heterozygous
de novo
missense variants (p.D89N and p.A555V) in three female patients, and two hemizygous missense variants (p.N141S and p.R694Q) and a splicing variant (c.1390-12T > G) that are maternally inherited in three male patients. The p.N141S variant and the splicing variant c.1390-12(T > G were novel, while p.R694Q was identified in two asymptomatic heterozygous female patients. The six children with
CLCN4
variants exhibited a neurodevelopmental spectrum disease characterized by intellectual disability (ID), delayed speech, autism spectrum disorders (ASD), microcephaly, hypertonia, and abnormal imaging findings. The minigene splicing result indicated that the c.1390-12T > G did not affect the splicing of
CLCN4
mRNA.
In vitro
experiments showed that the mutant protein level and localization of mutant protein are similar to the wild type.
Conclusion
The study identified six probands with
CLCN4
gene variants associated with X-linked ID. It expanded the gene and phenotype spectrum of
CLCN4
variants. The bioinformatic analysis supported the pathogenicity of
CLCN4
variants. However, these
CLCN4
gene variants did not affect the ClC-4 expression levels and protein location, consistent with previous studies. Further investigations are necessary to investigate the pathogenetic mechanism.
Decidual polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are essential to immune tolerance during pregnancy. A reduction in the number of these cells is associated with unexplained ...recurrent pregnancy loss (URPL). In our previous study, we reported that PMN-MDSCs are a group of mature neutrophils that are activated by the decidua microenvironment. In the present study, we show that the decidua microenvironment induces substantial lipid accumulation in neutrophils during their differentiation to PMN-MDSCs. Lower levels of lipid accumulation are detected in PMN-MDSCs from URPL patients, and the amount of lipid in the PMN-MDSCs is positively correlated with the proportion of PMN-MDSCs. Next, we demonstrate that decidua-derived IL6 with the presence of arachidonic acid upregulates fatty acid-binding protein 5 (FABP5)
the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Fy -60ABP5 then continuously stimulates intracellular lipid accumulation. Increased intracellular lipid accumulation mediates arachidonic acid metabolism, a pathway that is significantly activated by the induction of the decidua microenvironment, to stimulate the synthesis of prostaglandin E2 (PGE2) and finally induce the differentiation of PMN-MDSCs. To summarize, decidua-derived IL6 facilitates the differentiation of PMN-MDSCs from neutrophils
the pSTAT3/FABP5/PGE2 pathway. Defects in the process may result in impaired differentiation and dysfunction of PMN-MDSCs in URPL. These findings enhance our understanding of the physiological mechanisms of immune tolerance in pregnancy and provide therapeutic options for URPL.
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•A simple off-on-off fluorescent copper nanoclusters (CHA-CuNCs) sensor for detecting Trp and Hg2+ was developed.•The mechanism of off-on-off detection system was studied.•CHA-CuNCs ...can recognize Trp and Hg2+ in living cells.•The strategy offers specifically determining endogenous Trp and recognizing cancer cell by enhanced fluorescence.•The established method is facile, eco-friendly, sensitive and efficient.
The abnormalities of Tryptophan (Trp) and mercury ions (Hg2+) not only easily activate diseases, including mental illness and cancer, but also seriously affect human wellbeing. Fluorescent sensors are profoundly attractive options for identifying amino acids and ions; however, most sensors remain challenging due to the multipliable cost and deviation from the asynchronous quenching detection. In particular, fluorescent copper nanoclusters with high stability that quantitatively monitoring Trp and Hg2+ successively have seldom been reported. Herein, we employ coal humus acid (CHA) as a protective ligand and successfully construct weak cyan fluorescent copper nanoclusters (CHA-CuNCs) by a rapid, environmentally benign and cost-effective method. Significantly, the fluorescence of CHA-CuNCs is obviously improved by introducing Trp, because the indole group of Trp enhances the radiative recombination and aggregation-induced emissions. Interestingly, CHA-CuNCs not only realizes the highly selective and specific detection of Trp with a linear range of 25–200 μM and a detection limit of 0.043 μM based on the turn-on fluorescence strategy, but also quickly achieves the consecutive turn-off detection of Hg2+ due to the chelation interaction between Hg2+ and pyrrole heterocycle in Trp. Moreover, this method is successfully applied in the analysis of Trp and Hg2+ in real samples. Furthermore, the confocal fluorescent imaging of tumor cells demonstrates that CHA-CuNCs can be used for bioimaging and cancer cell recognition with Trp and Hg2+ abnormalities. These findings provide new guidance for the eco-friendly synthesis of CuNCs with eminent sequential off-on-off optical sensing property, indicating good prospects in biosensing and clinical medicine applications.
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•A new fluorescent covalent organic frameworks was synthesized.•N, O-bidentate ligation was be used to combine difluoroboron.•50% B-COF exhibited red fluorescence under ultraviolet ...excitation.
The multi-dentate chelate ligands containing N and O atoms have good chelating ability to boron trifluoride and their complexes show good fluorescence properties. In this work, a fluorescent covalent organic framework (COF) with good crystallinity and porosity, 50% B-COF, was successfully synthesized by coordination of starting COFs 50% COF-OH with boron trifluoride diethyl etherate via N, O-bidentate ligation. Imine bonds are highly polarized. The coordination of nitrogen and boron changes the electron cloud distribution of imine bonds, causing the non-fluorescent 50% COF-OH to be transformed into fluorescent 50% B-COF. 50% B-COF exhibited red fluorescence under ultraviolet excitation. This work provides a new strategy for the design of fluorescent COFs.
Oridonin (Ori), extracted from Isodon rubescens (Hemsl.) H.Hara, is a well-known traditional Chinese herbal medicinal product that possesses antioxidant and anti-inflammatory activities. Oxidative ...stress and inflammation are the main pathophysiological mechanisms in hindlimb IR injury. However, whether Ori has a protective effect on hind limb IR injury is unknown.
The present study was designed to determine the effect of Ori on hindlimb IR injury and its relationship with oxidative stress and inflammation.
The hind limb IR injury model in mice was used to evaluate the protective effect and related mechanisms of Ori. Forty-eight C57BL/6 mice (n = 12 per group) were randomly divided into four groups: Sham group; IR group; IR + Ori (10 mg/kg) group and IR + Ori (20 mg/kg) group. Mice in the IR and IR + Ori groups were subjected to hindlimb IR injury, while mice in the Sham group were subjected to no hindlimb IR injury. HE staining, Masson's staining, TTC staining, DHE staining, TUNEL staining, western blotting analysis and quantitative real-time PCR were employed to explore the mechanisms by which Ori exerts a protective effect on a classical hindlimb IR model in mice.
We found that Ori pretreatment prevented muscle damage and decreased cell apoptosis levels compared with the vehicle control. Moreover, the SOD2, CAT, MDA and ROS levels in muscle showed that Ori could significantly reduce oxidative stress in hindlimb IR mice, while the IL-1β and TNF-α levels in muscle showed that Ori could significantly attenuate IR-induced inflammation. We also found that Ori could increase the expression of Nrf2 and its downstream protein HO-1 and inhibit the expression levels of NLRP3-related proteins (NLRP3, ASC and Caspase-1) in vivo.
Our study suggested that Ori has a protective effect on hindlimb IR injury, which may be related to Nrf2-mediated oxidative stress and NLRP3-mediated inflammasome activation.
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The progression of intervertebral disc degeneration (IDD) is multifactorial with the senescence of nucleus pulposus (NP) cells and closely related to inflammation in NP cells. Dehydrocostus lactone ...(DHE) is a natural sesquiterpene lactone isolated from medicinal plants that has anti-inflammatory properties. Thus, DHE may have a therapeutic effect on the progression of IDD. In this study, NP cells were used to determine the appropriate concentration of DHE
. The role of DHE in tumor necrosis factor-α (TNF-α)-induced activation of inflammatory signaling pathways and cellular senescence, together with anabolism and catabolism of extracellular matrix (ECM) in NP cells, was examined
. The therapeutic effect of DHE
was determined using a spinal instability model of IDD in mice. The TNF-α-induced ECM degradation and the senescence of NP cells were partially attenuated by DHE. Mechanistically, DHE inhibited the activation of NF-κB and MAPK inflammatory signaling pathways and ameliorated the senescence of NP cells caused by the activation of STING-TBK1/NF-κB signaling induced by TNF-α. Furthermore, a spinal instability model in mice demonstrated that DHE treatment could ameliorate progression of IDD. Together, our findings indicate that DHE can alleviate IDD changes and has a potential therapeutic function for the treatment of IDD.
A novel series of di-carbonyl analogs of curcumin (DACs) were prepared and evaluated for their anti-inflammatory properties. Preliminary results showed that a vast majority of compounds tested in ...this study could effectively suppress LPS-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Structure-activity relationships of the compounds were discussed. Compounds 5a27 and 5a28 showed the most potent anti-inflammatory activities and had higher structural stability and orally bioavailability than curcumin in vitro. Mechanistically, they inhibited the activation of macrophages via the blockade of mitogen-activated protein kinase (MAPK) signaling and nuclear translocation of NF-κB. In vivo, 5a27 and 5a28 markedly alleviated lipopolysaccharides (LPS)-induced acute lung injury (ALI). The wet/dry ratio of lungs was significantly normalized by the active compounds, which was consistent with the suppression of neutrophil infiltration and production of proinflammatory cytokines. Collectively, these results present a new series of curcumin analogs as promising anti-inflammatory agents for treatment of ALI.
Novel di-carbonyl analogs of curcumin (DACs) were designed, synthesized and evaluated for anti-inflammatory activities for the treatment of ALI. Display omitted
•29 novel di-carbonyl analogs of curcumin (DACs) were synthesized and evaluated for anti-inflammatory activity.•Active DACs 5a27 and 5a28 exhibited better structural stability, orally bioavailability and anti-inflammatory activity than curcumin.•Compound 5a27 and 5a28 could be lead compounds as an ALI therapeutic agent.
Cations with suitable sizes to occupy an interstitial site of perovskite crystals have been widely used to inhibit ion migration and promote the performance and stability of perovskite ...optoelectronics. However, such interstitial doping inevitably leads to lattice microstrain that impairs the long-range ordering and stability of the crystals, causing a sacrificial trade-off. Here, we unravel the evident influence of the valence states of the interstitial cations on their efficacy to suppress the ion migration. Incorporation of a trivalent neodymium cation (Nd3+) effectively mitigates the ion migration in the perovskite lattice with a reduced dosage (0.08%) compared to a widely used monovalent cation dopant (Na+, 0.45%). The photovoltaic performances and operational stability of the prototypical perovskite solar cells are enhanced with a trace amount of Nd3+ doping while minimizing the sacrificial trade-off.Ion migration has a detrimental effect on the performance and stability of halide perovskite optoelectronics. Here, the authors incorporated a small dosage of high-valence neodymium cation to suppress this, with a minimal impact on the lattice microstrain.
Trading for Status Hong, Harrison; Jiang, Wenxi; Wang, Na ...
The Review of financial studies,
11/2014, Letnik:
27, Številka:
11
Journal Article
Recenzirano
We show that Keeping-Up-with-the-Joneses preferences can explain several puzzling retail investor behaviors, including the excessive trading of small local stocks. Status concerns lead households, ...especially those living in affluent areas, to demand these stocks to track their neighbors' wealth. This demand varies procyclically with the stock market's value and generates household trading. Using Chinese data on local stock turnover, stock message boards, and brokerage account trading, we test and confirm this hypothesis by exploiting the uneven rise of affluence across Chinese cities between 1998 and 2012.
Trade market power serves as a significant indicator of pricing power within the trade market. This paper aims to examine the market structure of global forage trade from 1997 to 2020 and assess the ...market power of forage exporters in major importing countries, namely Japan, China, and South Korea, by utilizing an extended G-K model based on the theory of residual elasticity of demand. The findings of this analysis provide several key insights. Firstly, it is revealed that the United States and Australia hold a monopoly on forage trade, while China has emerged as the most pivotal market for worldwide forage trade. Notably, China’s growing demand for forage imports is profoundly influencing the global forage trade landscape. Secondly, the extent and effectiveness of exporting countries’ market power in forage-importing nations, such as China, varies considerably. Lastly, the market power of forage-exporting countries is determined by various factors, including the demand for forage in importing nations, export monopoly, import structure, demand elasticity, and the level of marketization.
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