Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the ...precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.
Insect life cycle is coordinated by hormones and their downstream effectors. Krüppel homolog1 (Kr-h1) is one of the crucial effectors which mediates the actions of the two critical hormones of ...insects, the juvenile hormone (JH) and 20-hydroxyecdysone (20E). It is a transcription factor with a DNA-binding motif of eight C
H
zinc fingers which is found to be conserved among insect orders. The expression of
is fluctuant during insect development with high abundance in juvenile instars and lower levels in the final instar and pupal stage, and reappearance in adults, which is governed by the coordination of JH, 20E, and miRNAs. The dynamic expression pattern of
is closely linked to its function in the entire life of insects. Over the past several years, accumulating studies have advanced our understanding of the role of
during insect development. It acts as a universal antimetamorphic factor in both hemimetabolous and holometabolous species by directly inhibiting the transcription of 20E signaling genes
(
) and
(
), and steroidogenic enzyme genes involved in ecdysone biosynthesis. Meanwhile, it promotes vitellogenesis and ovarian development in the majority of studied insects. In addition, Kr-h1 regulates insect behavioral plasticity and caste identity, neuronal morphogenesis, maturation of sexual behavior, as well as embryogenesis and metabolic homeostasis. Hence, Kr-h1 acts as a cornerstone regulator in insect life.
Genetic and genomic studies have advanced our knowledge of inherited Parkinson's disease (PD), however, the etiology and pathophysiology of idiopathic PD remain unclear. Herein, we perform a ...meta-analysis of 8 PD postmortem brain transcriptome studies by employing a multiscale network biology approach to delineate the gene-gene regulatory structures in the substantia nigra and determine key regulators of the PD transcriptomic networks. We identify STMN2, which encodes a stathmin family protein and is down-regulated in PD brains, as a key regulator functionally connected to known PD risk genes. Our network analysis predicts a function of human STMN2 in synaptic trafficking, which is validated in Stmn2-knockdown mouse dopaminergic neurons. Stmn2 reduction in the mouse midbrain causes dopaminergic neuron degeneration, phosphorylated α-synuclein elevation, and locomotor deficits. Our integrative analysis not only begins to elucidate the global landscape of PD transcriptomic networks but also pinpoints potential key regulators of PD pathogenic pathways.
The low intrinsic activity of Fe/N/C oxygen catalysts restricts their commercial application in the fuel cells technique; herein, we demonstrated the interface engineering of plasmonic induced ...Fe/N/C-F catalyst with primarily enhanced oxygen reduction performance for fuel cells applications. The strong interaction between F and Fe-N
4
active sites modifies the catalyst interfacial properties as revealed by X-ray absorption structure spectrum and density functional theory calculations, which changes the electronic structure of Fe-N active site resulting from more atoms around the active site participating in the reaction as well as super-hydrophobicity from C-F covalent bond. The hybrid contribution from active sites and carbon support is proposed to optimize the three-phase microenvironment efficiently in the catalysis electrode, thereby facilitating efficient oxygen reduction performance. High catalytic performance for oxygen reduction and fuel cells practical application catalyzed by Fe/N/C-F catalyst is thus verified, which offers a novel catalyst system for fuel cells technique.
Abstract
Soft magneto-active machines capable of magnetically controllable shape-morphing and locomotion have diverse promising applications such as untethered biomedical robots. However, existing ...soft magneto-active machines often have simple structures with limited functionalities and do not grant high-throughput production due to the convoluted fabrication technology. Here, we propose a facile fabrication strategy that transforms 2D magnetic sheets into 3D soft magneto-active machines with customized geometries by incorporating origami folding. Based on automated roll-to-roll processing, this approach allows for the high-throughput fabrication of soft magneto-origami machines with a variety of characteristics, including large-magnitude deploying, sequential folding into predesigned shapes, and multivariant actuation modes (e.g., contraction, bending, rotation, and rolling locomotion). We leverage these abilities to demonstrate a few potential applications: an electronic robot capable of on-demand deploying and wireless charging, a mechanical 8-3 encoder, a quadruped robot for cargo-release tasks, and a magneto-origami arts/craft. Our work contributes for the high-throughput fabrication of soft magneto-active machines with multi-functionalities.
Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the ...most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation
impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of
(
), a gene that is associated with recessive Parkinsonism. Combining
and
does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1
, resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of
and
pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis.
Understanding midbrain dopaminergic (DAergic) neuron-selective vulnerability in PD is essential for the development of targeted therapeutics. We report, for the first time, a nerve terminal impairment in SV trafficking selectively in MB neurons but not cortical neurons caused by two PARK genes:
(PARK8) and
(PARK20). We demonstrate that the enhanced kinase activity resulting from the most frequent
mutation in
is the key to this impairment. We provide evidence suggesting that
and
loss of function share a similar pathogenic pathway in deregulating DAergic neuron SV endocytosis and that they play additive roles in facilitating each other's pathogenic functions in PD.
Soft electromagnetic devices have great potential in soft robotics and biomedical applications. However, existing soft-magneto-electrical devices would have limited hybrid functions and suffer from ...damaging stress concentrations, delamination or material leakage. Here, we report a hybrid magnetic-mechanical-electrical (MME) core-sheath fiber to overcome these challenges. Assisted by the coaxial printing method, the MME fiber can be printed into complex 2D/3D MME structures with integrated magnetoactive and conductive properties, further enabling hybrid functions including programmable magnetization, somatosensory, and magnetic actuation along with simultaneous wireless energy transfer. To demonstrate the great potential of MME devices, precise and minimally invasive electro-ablation was performed with a flexible MME catheter with magnetic control, hybrid actuation-sensing was performed by a durable somatosensory MME gripper, and hybrid wireless energy transmission and magnetic actuation were demonstrated by an untethered soft MME robot. Our work thus provides a material design strategy for soft electromagnetic devices with unexplored hybrid functions.
Abstract
Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown ...to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.
•A high frequency AC heater based on two switched capacitors is proposed.•A optimization method based on PSO algorithm is introduced to optimize the heating frequency.•The heating results are ...validated under different heating frequencies and different SOC.•Fast heating speed and less cell energy loss are realized without external energy supply.
Lithium-ion batteries suffer from significant performance deterioration at subzero temperatures, which brings difficulty to the promotion of electric vehicles. In this paper, a high frequency alternating current (AC) heater based on switched capacitors is proposed which can heat batteries with fast speed and good uniformity without external energy supply. The optimal heating frequency is determined based on particle swarm optimization to obtain the fastest heating speed. The proposed heating topology only needs one pair of pulse width modulation signals to drive four MOSFETs to circulate an alternating current between the batteries and switched capacitors, leading to easy control with simple structure and low cost. The effectiveness of the proposed AC heater is validated under different heating frequencies at initial temperature −20°C and –25°C, respectively. Experimental results show that by circulating an alternating current with the optimal heating frequency of 10 kHz, the proposed heater can heat lithium-ion batteries from -20°C to 0°C within 2.2min, consuming only 5.4% cell energy, and can heat lithium-ion batteries from -25°C to 0°C within 9 min, consuming only 7.8% cell energy.
Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the ...disparity of the changes confounds the role of autophagy in AD.
To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production.
We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model.
Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.
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