Hippocampal Long-Term Depression in the Presence of Calcium-Permeable AMPA Receptors

The GluA2 subunit of AMPA glutamate receptors (AMPARs) has been shown to be critical for the expression of NMDA receptor (NMDAR)-dependent long-term depression (LTD). However, in young GluA2 knockout (KO) mice, this form of LTD can still be induced in the hippocampus, suggesting that LTD mechanisms may be modified in the presence of GluA2-lacking, Ca2+ permeable AMPARs. In this study, we examined LTD at the CA1 synapse in GluA2 KO mice by using several well-established inhibitory peptides known to block LTD in wild type (WT) rodents. We showed that while LTD in the KO mice is still blocked by the protein interacting with C kinase 1 (PICK1) peptide pepEVKI, it becomes insensitive to the N-ethylmaleimide-sensitive factor (NSF) peptide pep2m. In addition, the effects of actin and cofilin inhibitory peptides were also altered. These results indicate that in the absence of GluA2, LTD expression mechanisms are different from those in WT animals, suggesting that there are multiple molecular processes enabling LTD expression that are adaptable to physiological and genetic manipulations

SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.

The secretory pathway of eukaryotic cells packages cargo proteins into COPII-coated vesicles for transport from the endoplasmic reticulum (ER) to the Golgi. We now report that complete genetic deficiency for the COPII component SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in COPII vesicle formation and cargo recruitment. However, these animals exhibit markedly reduced plasma cholesterol, with mutations in Apoe and Ldlr epistatic to Sec24a, suggesting a receptor-mediated lipoprotein clearance mechanism. Consistent with these data, hepatic LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER. Our findings also identify partial overlap in cargo selectivity between SEC24A and SEC24B, suggesting a previously unappreciated heterogeneity in the recruitment of secretory proteins to the COPII vesicles that extends to soluble as well as trans-membrane cargoes. DOI:http://dx.doi.org/10.7554/eLife.00444.001

Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress

Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems

Abnormal Spine Morphology and Enhanced LTP in LIMK-1 Knockout Mice

AbstractIn vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function

Plant-based diets and body composition in Chinese omnivorous children aged 6–9 years old: A cross-sectional study

Evidence suggests that plant-based diets are beneficial for alleviating metabolic diseases. Childhood is a crucial period for body growth and development. However, it is unknown whether adherence to a plant-based diet is related to a healthy body composition in children. We aimed to assess the relationship between a plant-based diet and body composition in children. A total of 452 Chinese children aged 6–9 years old participated in this cross-sectional study. Lean mass (LM), fat mass, and fat mass percentage (FMP) were assessed via dual-energy X-ray absorptiometry. An age- and sex-specific abdominal FMP ≥85th percentile was defined as abdominal obesity. Handgrip strength was measured using a hydraulic hand dynamometer. A validated 79-item food frequency questionnaire was used to collect dietary information. Overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI) scores were calculated. After adjusting for potential covariates, a higher hPDI score (per 10-score increment) was associated with a higher LM in the android area (0.038 kg, 3.2%), gynoid area (0.048 kg, 1.9%), and trunk (0.102 kg, 1.2%) and with a lower FMP (1.18%) in the android area. In contrast, a higher uPDI score (per 10-score increment) was associated with a lower LM in the trunk (0.091 kg, 1.1%) and android area (0.023 kg, 1.9%) and with a higher FMP (0.74%) in the android area. No significant associations were observed between the overall PDI and body composition or abdominal obesity. After stratifying by sex, higher (vs. lower) hPDI scores was associated with lower abdominal obesity risk in girls and higher handgrip strength in boys. In conclusion, in this cross-sectional study, we found that stronger adherence to a healthful plant-based diet, and less adherence to an unhealthful plant-based diet was associated with better body composition in Chinese omnivorous children aged 6–9 years old. Our results highlight the need to distinguish between healthy and unhealthy plant foods within investigating how to obtain a healthy body composition in children

Outlook on ecologically improved composites for aviation interior and secondary structures

Today, mainly man-made materials such as carbon and glass fibres are used to produce composite parts in aviation. Renewable materials such as natural fibres or bio-sourced resin systems have not found their way into aviation, yet. The project ECO-COMPASS aims to evaluate the potential applications of ecologically improved composite materials in the aviation sector in an international collaboration of Chinese and European partners. Natural fibres such as flax and ramie will be used for different types of reinforcements and sandwich cores. Furthermore, the bio-based epoxy resins to substitute bisphenol-A based epoxy resins in secondary structures are under investigation. Adapted material protection technologies to reduce environmental influence and to improve fire resistance are needed to fulfil the demanding safety requirements in aviation. Modelling and simulation of chosen eco-composites aims for an optimized use of materials while a life cycle assessment aims to prove the ecological advantages compared to synthetic state-of-the-art materials. In this paper, the status of selected ecologically improved materials will be presented with an outlook for potential application in interior and secondary structures

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

Background/Aims: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma. Methods: In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting. Results: The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus. Conclusion: These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment