Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/-) male mice exhibited the core symptoms of autism. Rfwd2+/- male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/- female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/- male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

Notoginsenoside R1 targets PPAR-γ to inhibit hepatic stellate cell activation and ameliorates liver fibrosis.

BACKGROUND: Hepatic fibrosis, a common pathological process that occurs in end-stage liver diseases, is a serious public health problem and lacks effective therapy. Notoginsenoside R1 (NR1) is a small molecule derived from the traditional Chinese medicine Sanqi, exhibiting great potential in treating diverse metabolie disorders. Here we aimed to enquired the role of NR1 in liver fibrosis and its underlying mechanism in hepatoprotective effects. METHODS: We investigated the anti-fibrosis effect of NR1 using CCl4-induced mouse mode of liver fibrosis as well as TGF-ß1-activated JS-1, LX-2 cells and primary hepatic stellate cell. Cell samples treated by NR1 were collected for transcriptomic profiling analysis. PPAR-γ mediated TGF-ß1/Smads signaling was examined using PPAR-γ selective inhibitors and agonists intervention, immunofluorescence staining and western blot analysis. Additionally, we designed and studied the binding of NR1 to PPAR-γ using molecular docking. RESULTS: NR1 obviously attenuated liver histological damage, reduced serum ALT, AST levels, and decreased liver fibrogenesis markers in mouse mode. Mechanistically, NR1 elevated PPAR-γ and decreased TGF-ß1, p-Smad2/3 expression. The TGF-ß1/Smads signaling pathway and fibrotic phenotype were altered in JS-1 cells after using PPAR-γ selective inhibitors and agonists respectively, confirming PPAR-γ played a pivotal protection role inNR1 treating liver fibrosis. Further molecular docking indicated NR1 had a strong binding tendency to PPAR-γ with minimum free energy. CONCLUSIONS: NR1 attenuates hepatic stellate cell activation and hepatic fibrosis by elevating PPAR-γ to inhibit TGF-ß1/Smads signalling. NR1 may be a potential candidate compound for reliving liver fibrosis.

Plant economics spectrum governs leaf nitrogen and phosphorus resorption in subtropical transitional forests.

BACKGROUND: Leaf nitrogen (N) and phosphorus (P) resorption is a fundamental adaptation strategy for plant nutrient conservation. However, the relative roles that environmental factors and plant functional traits play in regulating N and P resorption remain largely unclear, and little is known about the underlying mechanism of plant functional traits affecting nutrient resorption. Here, we measured leaf N and P resorption and 13 plant functional traits of leaf, petiole, and twig for 101 representative broad-leaved tree species in our target subtropical transitional forests. We integrated these multiple functional traits into the plant economics spectrum (PES). We further explored whether and how elevation-related environmental factors and these functional traits collectively control leaf N and P resorption. RESULTS: We found that deciduous and evergreen trees exhibited highly diversified PES strategies, tending to be acquisitive and conservative, respectively. The effects of PES, rather than of environmental factors, dominated leaf N and P resorption patterns along the elevational gradient. Specifically, the photosynthesis and nutrient recourse utilization axis positively affected N and P resorption for both deciduous and evergreen trees, whereas the structural and functional investment axis positively affected leaf N and P resorption for evergreen species only. Specific leaf area and green leaf nutrient concentrations were the most influential traits driving leaf N and P resorption. CONCLUSIONS: Our study simultaneously elucidated the relative contributions of environmental factors and plant functional traits to leaf N and P resorption by including more representative tree species than previous studies, expanding our understanding beyond the relatively well-studied tropical and temperate forests. We highlight that prioritizing the fundamental role of traits related to leaf resource capture and defense contributes to the monitoring and modeling of leaf nutrient resorption. Therefore, we need to integrate PES effects on leaf nutrient resorption into the current nutrient cycling model framework to better advance our general understanding of the consequences of shifting tree species composition for nutrient cycles across diverse forests.