Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.
Objective To explore a performance standard for hemolytic toxins in harmful bloom algae. Methods Using Chattonella marina as hemolytic substances producing organism, methods and conditions were compared and optimized including cell breakage, distillation temperature, blood origin and storage of algal pellets in extraction and activity determination of hemolytic toxins. Results The hemolytic activity of C. marina broken by supersonic method was 288.23 HU/L, higher than that by freezing--thawing method (94.89 HU/L), suggesting that supersonic method could be more optimal to break microalgal cells. When the supersonic treatment times were 5, 10, 20 and 30 min, the hemolytic activities were 80.57, 157.45, 288.23 and 279.17 HU/L, respectively, indicating that 20 min of supersonic treatment was suitable. When the distillation temperature were 40, 60 and 80 degrees C, the hemolytic activities were 288.23, 124.97 and 120.68 HU/L, respectively, meaning that high distillation temperature in extraction of hemolytic substances lowed the hemolytic activities of samples. Bloods from various animals such as human, fish, rat and rabbit exhibited different sensitivity to the hemolytic toxins, of which rabbit erythrocyte was the most sensitive. The hemolytic activities to human, fish, rat and rabbit were 244.98, 288.23, 266.35 and 195.47HU/L, respectively. The storage of algal pellets for 3 days at the temperature of 0 degrees C did not reveal a significant loss in hemolytic activity, while significant losses were observed at the temperature of 20 degrees C or -20 degrees C only after one day. Conclusion Supersonic method could be more optimal to break cell in comparison with freeze-thaw method. Optimal conditions for broken algal cells by supersonic method were 200 W for 20 min at the temperature of 4 degrees C. The distillation temperature in extraction of hemolytic substances should be maintained under the temperature of 40 degrees C. The rabbit erythrocyte could be the most optimal blood to detect hemolytic activity due to its high sensitivity. The algal pellets could be kept at the temperature of 0 degrees C for 3 days before determination of activity.
Abstract Repeated column chromatography of the EtOAc-soluble fraction of the aerial parts of Dodonaea viscosa led to the isolation of two new modified clerodanes, methyl dodovisate A (1) and methyl dodovisate B (2), two new prenylated flavonoids, 5,7,4′-trihydroxy-3′,5′-di(3-methylbut-2-enyl)-3,6-dimethoxyflavone (10) and 5,7,4′-trihydroxy-3′-(4-hydroxy-3-methylbutyl)-5′-(3-methylbut-2-enyl)-3,6-dimethoxyflavone (11), together with eight known compounds, dodonic acid (3), hautriwaic acid (4), hautriwaic lactone (5), (+)-hardwickiic acid (6), 5α-hydroxy-1,2-dehydro-5,10-dihydroprintzianic acid methyl ester (7), strictic acid (8), dodonolide (9), and aliarin (12). The structures of the new compounds were elucidated by spectroscopic data analysis. Compounds 1–9 and 11 were evaluated on larvicidal activity against the fourth-instar larvae of Aedes albopictus and Culex pipens quinquefasciatus. Keywords: Sapindaceae Dodonaea viscosa clerodane diterpenoidsprenylated flavonoids Acknowledgements This work was funded by the grants of the Ministry of Education of China through its 111 and 985 projects (B08044 and MUC 985-3-3), the Ministry of Science and Technology of China (2008FY110400-2-2 and 2005DKA21006), and the Knowledge Innovation Program of the Chinese Academy of Sciences.
Rectal cancer (RC) is the leading cause of tumor-related death among both men and women. The efficacy of immunotherapy for rectal cancer is closely related to the immune infiltration level. The N6-methyladenosine (m6A) modification may play a pivotal role in tumor-immune interactions. However, the roles of m6A-related genes in tumor-immune interactions of rectal cancer remain largely unknown. After an evaluation on the expression levels of m6A-related genes and their correlations with the prognosis of rectal cancer patients, we found that METTL14 was the only gene to be significantly correlated with prognosis in rectal cancer patients. Therefore, we further observed the impact of METTL14 expression and m6A modification on the immune infiltration in rectal cancer. Our study indicates that low expression of the m6A “writer” gene METTL14 in rectal cancer may lead to the downregulation of m6A RNA modification, thus reducing the level of immune cell infiltration and resulting in poor prognosis. METTL14 expression level is an independent prognostic factor in rectal cancer and is positively correlated with the immune infiltration level. Our study identified METTL14 as a potential target for enhancing immunotherapy efficacy in rectal cancer.
Cognition of climate change risk is defined as an individual or group’ objective understanding of climate change characterized by global warming and assessment and judgment of possibility of influence or damage caused by global warming, which can be evaluated from the following aspects: public’s cognition of risk events related to climate change, cognition of risk sources, cognition of risk consequence and cognition of risk responsibility. The questionnaire survey on urban residents’ cognition of climate change risk in Guangzhou shows that public cognition of source of climate change risk is higher than that of risk events related to climate change; the public has higher level of cognition of climate change’s consequences, and unsustainable and catastrophic risk consequences have the highest level of recognition by the public; governments and enterprises are considered to shoulder the most important responsibility to address climate change. Survey on urban residents’ cognition of climate change risk provides reference for popularization of climate change knowledge, and helps promote the public’s participation in the mitigation and adaption of global warming.
Developing therapeutic approaches that target neuronal differentiation will be greatly beneficial for the regeneration of neurons and synaptic networks in neurological diseases. Protein synthesis (mRNA translation) has recently been shown to regulate neurogenesis of neural stem/progenitor cells (NSPCs). However, it has remained unknown whether engineering translational machinery is a valid approach for manipulating neuronal differentiation. The present study identifies that a bivalent securinine compound SN3-L6, previously designed and synthesized by our group, induces potent neuronal differentiation through a novel translation-dependent mechanism. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis in Neuro-2a progenitor cells revealed that SN3-L6 upregulated a group of neurogenic transcription regulators, and also upregulated proteins involved in RNA processing, translation, and protein metabolism. Notably, puromycylation and metabolic labeling of newly synthesized proteins demonstrated that SN3-L6 induced rapid and robust activation of general mRNA translation. Importantly, mRNAs of the proneural transcription factors Foxp1, Foxp4, Hsf1, and Erf were among the targets that were translationally upregulated by SN3-L6. Either inhibition of translation or knockdown of these transcription factors blocked SN3-L6 activity. We finally confirmed that protein synthesis of a same set of transcription factors was upregulated in primary cortical NPCs. These findings together identify a new compound for translational activation and neuronal differentiation, and provide compelling evidence that reprogramming transcriptional regulation network at translational levels is a promising strategy for engineering NSPCs.
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