Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.
The surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in maintaining a multitude of microglial activities, such as survival, proliferation, migration, metabolism, inflammation, and phagocytosis. However, the molecular mechanisms underlying TREM2-mediated microglial activities remain largely elusive. Herein, we found that TREM2 interacted with the type I transmembrane protein TMEM59, whose expression could facilitate autophagic flux through its carboxyl-terminus. TMEM59 expression was decreased upon lipopolysaccharide treatment. While downregulation of TMEM59 promoted anti-inflammatory factor expression and attenuated lipopolysaccharide treatment-induced inflammation. Importantly, we found that overexpression of TREM2 reduced TMEM59 protein levels through promoting its degradation, whereas TMEM59 levels were elevated in Trem2deficient microglia. Finally, impaired survival, proliferation, migration, and phagocytosis, as well as dysregulated autophagy and metabolism in Trem2-deficient microglia were attenuated upon TMEM59 silencing. Together, our findings reveal a novel function of TREM2 in mediating TMEM59 protein degradation and demonstrate the importance of TMEM59 homeostasis in maintaining TREM2-mediated microglial activities.
Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with cognitive deficits and synaptic impairments. Amyloid-β (Aβ) plaque deposition, dystrophic neurite accumulation and neurofibrillary tangles are pathological hallmarks of AD. TMEM59 has been implicated to play a role in AD pathogenesis; however, the underlying mechanism remains unknown. Herein, we found that overexpression of TMEM59 in the hippocampal region led to memory impairment in wild type mice, suggesting its neurotoxic role. Interestingly, while TMEM59 overexpression had no effect on worsening synaptic defects and impaired memory in the 5xFAD mouse model of AD, it significantly exacerbated AD-like pathologies by increasing levels of detergent-insoluble Aβ and Aβ plaques, as well as dystrophic neurites. Importantly, haploinsufficiency of TMEM59 reduced insoluble Aβ levels, Aβ plaques, and neurite dystrophy, thereby rescuing synaptic plasticity and memory deficits in 5xFAD mice. Moreover, the level of TMEM59 in the brain of 5xFAD mice increased compared to wild type mice during aging, further corroborating its detrimental functions during neurodegeneration. Together, these results demonstrate a novel function of TMEM59 in AD pathogenesis and provide a potential therapeutic strategy by downregulating TMEM59.
Kron reduction is a general tool of network simplification for flow calculation. With a growing number of flexible loads appearing in distribution networks, traditional Kron reduction cannot be widely used in control and scheduling due to the elimination of controllable and variable load buses. Therefore, this paper proposes an improved Kron reduction based on node ordering optimization whose principles guarantee that all the boundary nodes are retained eventually after eliminating the first row and the first column in every step according to the order, thereby making it possible to take full advantage of their potential to meet different requirements in power system calculation and dispatching. The proposed method is verified via simulation models of IEEE 5-bus and 30-bus systems through illustrating the dynamic consistency of the output active power of the generator nodes and the power flow data of preserved nodes before and after reduction.
As is known to all, the delivery industry is one of the world's largest industries nowadays. Moreover, China's delivery is thriving these days, and it has already developed over 30 years with the total number of delivery works achieved more than seven million. Sadly, there are several moral problems through the development of China's delivery industry. Low skill requirements and relatively high incomes make food delivery one of the ideal career options for China's migrant workers. But the attractions of flexible hours and pay are not all they seem. Most of them work more than ten hours a day, and their commissions on each order have plummeted. Besides, delivery workers are often under pressure to deal with overflowing orders, impatient customers and meet strict delivery time requirements. In this article, we focused on some unreasonable deductions of the salary of express employees. We analyzed this problem in four aspects. They are morality, legality, consequentialism, and deontology, and different aspects may give different results. At the end of the essay, we have also posed several proposals, such as improving China's labor union system and Establishing an intelligent review and complaint system. In conclusion, according to the research, we should think of more and better ways to improve the express industry and seek more benefits for the couriers.
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