LMNA-related muscular dystrophy involving myoblast proliferation and apoptosis through the FOXO1/GADD45A pathway.

LMNA-related muscular dystrophy is a major disease phenotype causing mortality and morbidity in laminopathies, but its pathogenesis is still unclear. To explore the molecular pathogenesis, a knock-in mouse harbouring the Lmna-W520R mutation was modelled. Morphological and motor functional analyses showed that homozygous mutant mice revealed severe muscular atrophy, profound motor dysfunction, and shortened lifespan, while heterozygotes showed a variant arrangement of muscle bundles and mildly reduced motor capacity. Mechanistically, the FOXO1/GADD45A pathway involving muscle atrophy processes was found to be altered in vitro and in vivo assays. The expression levels of FOXO1 and its downstream regulatory molecule GADD45A significantly increased in atrophic muscle tissue. The elevated expression of FOXO1 was associated with decreased H3K27me3 in its gene promotor region. Overexpression of GADD45A induced apoptosis and cell cycle arrest of myoblasts in vitro, and it could be partially restored by the FOXO1 inhibitor AS1842856, which also slowed the muscle atrophy process with improved motor function and prolonged survival time of homozygous mutant mice in vivo. Notably, the inhibitor also partly rescued the apoptosis and cell cycle arrest of hiPSC-derived myoblasts harbouring the LMNA-W520R mutation. Together, these data suggest that the activation of the FOXO1/GADD45A pathway contributes to the pathogenesis of LMNA-related muscle atrophy, and it might serve as a potential therapeutic target for laminopathies.

Supt16 Haploinsufficiency Impairs PI3K/AKT/mTOR/Autophagy Pathway in Human Pluripotent Stem Cells Derived Neural Stem Cells.

The maintenance of neural stem cells (NSCs) plays a critical role in neurodevelopment and has been implicated in neurodevelopmental disorders (NDDs). However, the underlying mechanisms linking defective human neural stem cell self-renewal to NDDs remain undetermined. Our previous study found that Supt16 haploinsufficiency causes cognitive and social behavior deficits by disrupting the stemness maintenance of NSCs in mice. However, its effects and underlying mechanisms have not been elucidated in human neural stem cells (hNSCs). Here, we generated Supt16+/- induced pluripotent stem cells (iPSCs) and induced them into hNSCs. The results revealed that Supt16 heterozygous hNSCs exhibit impaired proliferation, cell cycle arrest, and increased apoptosis. As the RNA-seq analysis showed, Supt16 haploinsufficiency inhibited the PI3K/AKT/mTOR pathway, leading to rising autophagy, and further resulted in the dysregulated expression of multiple proteins related to cell proliferation and apoptotic process. Furthermore, the suppression of Supt16 heterozygous hNSC self-renewal caused by autophagy activation could be rescued by MHY1485 treatment or reproduced in rapamycin-treated hNSCs. Thus, our results showed that Supt16 was essential for hNSC self-renewal and its haploinsufficiency led to cell cycle arrest, impaired cell proliferation, and increased apoptosis of hNSCs by regulating the PI3K/AKT/mTOR/autophagy pathway. These provided a new insight to understand the causality between the Supt16 heterozygous NSCs and NDDs in humans.

Supt16 haploinsufficiency causes neurodevelopment disorder by disrupting MAPK pathway in neural stem cells.

Chromatin regulators constitute a fundamental means of transcription regulation, which have been implicated in neurodevelopment and neurodevelopment disorders (NDDs). Supt16, one of candidate genes for NDDs, encodes the large subunit of facilitates chromatin transcription. However, the underlying mechanisms remain poorly understood. Here, Supt16+/- mice was generated, modeling the neurodevelopment disorder. Abnormal cognitive and social behavior was observed in the Supt16  +/- mice. Simultaneously, the number of neurocytes in the cerebral cortex and hippocampus is decreased, which might be resulted from the impairment of mouse neural stem cells (mNSCs) in the SVZ. Supt16 haploinsufficiency affects the proliferation and apoptosis of mNSCs. As the RNA-seq and chromatic immunoprecipitation sequencing assays showed, Supt16 haploinsufficiency disrupts the stemness of mNSCs by inhibiting MAPK signal pathway. Thus, this study demonstrates a critical role of Supt16 gene in the proliferation and apoptosis of mNSCs and provides a novel insight in the pathogenesis of NDDs.

Deforestation embodied in global trade: Integrating environmental extended input-output method and complex network analysis.

As deforestation has become an increasingly urgent issue worldwide, global initiatives and national policies have been launched to reduce deforestation. However, existing measures pay little attention to indirect deforestation and consumers' responsibilities, overlooking the different roles played by countries in the trading network. Therewith, to identify the producer's and consumers' responsibilities for deforestation, and reveal the roles and interrelations of those countries in the trading system, this study applies input-output analysis to find the main producers and consumers of embodied deforestation and complex network method to construct a network to illustrate the interrelations of the countries and identify their roles in the network. The results show the United States, China, Germany and other developed countries are the main consumers while Canada, Brazil, Indonesia and other heavily forested countries are the critical providers of embodied deforestation. Further studies find these countries have the highest level of degree, strength, and centrality, dominating the trade activities in the network. Additionally, the network features small-world nature and heterogeneity, illustrating the close connection of the network and the decisive roles of key nodes. This analysis provides findings to help policymakers more effectively address deforestation worldwide, by highlighting the flow of resources to and from key economies which have previously been overlooked.

The photodegradation of 17 alpha-ethinylestradiol in water containing iron and dissolved organic matter.

17 alpha-ethinylestradiol (EE2) in natural waters can seriously harm ecosystems and human health. Dissolved organic matter (DOM) and iron minerals are ubiquitous in natural waters, and they can shorten the half-life of EE2 in the natural environment. The interaction between dissolved organics and iron affects pollutants' transformation pathways. The mechanism of EE2's adsorption on hematite, magnetite and pyrite was studied. A photo-Fenton system was constructed in which humic acid (HA) and iron minerals degraded EE2 under simulated natural light conditions. Pyrite showed the best adsorption and degradation in acidic conditions (52%) for 5 h. Hydroxyl radical was found to be the main active substance in the photodegradation. The degradation products of EE2 were identified and possible degradation pathways were inferred. These results can contribute to the understanding of the transformation pathways of persistent organic pollutants in natural waters.

Photocatalytic degradation of dye by Ag/TiO2 nanoparticles prepared with different sol-gel crystallization in the presence of effluent organic matter.

TiO2 nanoparticle-doped Ag (Ag/TNPs) have good photocatalytic properties based on localized surface plasmon resonance (LSPR) effect. The effluent organic matter (EfOM) can be easily activated by photo-excitation to promote pollutant photodegradation, but excessive EfOM has an inactive effect. Herein, the purpose of this paper is to investigate the changes of photocatalytic performance by Ag/TNPs in the presence of EfOM. Three Ag/TNPs made by condensation crystallization or rotary evaporation crystallization using the sol-gel method were conducted in photocatalytic degradation of methyl orange (MO). The Ag/TNPs crystallized by condensation had greater separation rate of photogenerated electron-hole pairs and photocatalytic degradation of MO with high load rates of binding Ag and TiO2 than those formed by rotary evaporation crystallization. Indeed, EfOM could be excited to produce the active substances under illumination resulting in the promotion of MO degradation. However, contrary to previous speculation, no additive effect of MO photodegradation was observed with the addition both of EfOM and Ag/TNPs at different pH values (5~9) and ion strength (0~0.4 mol L-1). It can be explained that the EfOM changed the morphology and active sites in Ag/TNPs' surface. Meanwhile, EfOM could be consumed and degraded by Ag/TNP photocatalysis leading to the concentration of free radicals to decrease. This study revealed a nonsynergistic effect between nanomaterial and EfOM for photocatalysis. EfOM would have a negative effect on photocatalytic degradation of organic compounds by Ag/TNPs in the aquatic environment. Graphical abstract .

Dissolved organic matter mediates in the anaerobic degradation of 17α-ethinylestradiol in a coupled electrochemical and biological system.

Dissolved organic matter (DOM) can act as an electron shuttle in biogeochemical redox reactions to affect the fate of contaminants. Herein DOMs were tested for their ability to mediate in the degradation of 17α-ethinylestradiol (EE2) in a coupled electrochemical and biological system. Fulvic acid (FA) and Sigma humic acid (SHA) were found to promote degradation by the electro-domesticated micro-organisms in the coupled system. Analyses of superoxide dismutase levels, microbial community and clusters of orthologous groups of proteins showed that electrical stimulation promoted their growth and metabolism. It was confirmed that electron transfer in the coupled system was promoted in the presence of DOM as their protein-like components were converted into aromatic substances. The electrical stimulation improved the microorganisms' effectiveness in subsequent biodegradation under anaerobic condition. Stimulated micro-organisms seemed to increase their environmental tolerance and degrade EE2 effectively. These findings provide evidence about the fate of estrogens in bioelectrochemical water treatment.

The Purification, Characterization, and Biological Activity of New Polyketides from Mangrove-Derived Endophytic Fungus Epicoccum nigrum SCNU-F0002.

Six new polyketides, including one coumarin (1), two isocoumarins (2 and 3), dihydroradicinin (4), and two benzofuranone derivatives (7 and 8), together with seven known analogues (5-6 and 9-13) were isolated from the culture of the mangrove endophytic fungus Epicoccum nigrum SCNU-F0002. The structures were elucidated on the interpretation of spectroscopic data. The absolute configuration of Compounds 2 and 3 were determined by comparison of their ECD spectra with the data of their analogue dihydroisocoumarins described in the literature. The absolute configuration of 4 was determined by single-crystal X-ray diffraction. All the compounds were screened for their antioxidant, antibacterial, anti-phytopathogenic fungi and cytotoxic activities. Using a DPPH radical-scavenging assay, Compounds 10-13 showed potent antioxidant activity with IC50 values of 13.6, 12.1, 18.1, and 11.7 µg/mL, respectively. In addition, Compounds 6 and 7 showed antibacterial effects against Bacillus subtilis (ATCC 6538), Escherichia coli (ATCC 8739), and Staphylococcus aureus (ATCC 6538), with MIC values in the range of 25-50 µg/mL.