Metal-Free Electron Donor-Acceptor Pair Enabled Long-Term Stability of Li-CO2 Battery.

The challenges of Lithium-carbon dioxide (Li-CO2) batteries for ensuring long-term cycling stability arise from the thermodynamically stable and electrically insulating discharge products (e.g., Li2CO3), which primarily rely on their interaction with the active materials. To achieve the optimized intermediates, the bifunctional electron donor-acceptor (D-A) pairs are proposed in cathode design to adjust such interactions in the case of B-O pairs. The inclusion of BC2O sites allows for the optimized redistribution of electrons via p-π conjugation. The as-obtained DO-AB pairs endow the enhanced interactions with Li+, CO2, and various intermediates, accompanied by the adjustable growth mode of Li2CO3. The shift from solvation-mediated mode into surface absorption mode in turn manipulates the morphology and decomposition kinetics of Li2CO3. Therefore, the corresponding Li-CO2 battery got twofold improved in both the capacity and reversibility. The cycling prolongs exceed 1300 h and well operates at a wide temperature range (20-50 °C) and different folding angles (0-180°). Such a strategy of introducing electron donor-acceptor pairs provides a distinct direction to optimize the lifetime of Li-CO2 battery from local structure regulation at the atomic scale, further inspiring in-depth understandings for developing electrochemical energy storage and carbon capture technologies.

Asymmetric Janus functionalization induced magnetization and switchable out-of-plane polarization in 2D MXene Mo2CXX'.

Exploring two-dimensional (2D) van der Waals materials with out-of-plane polarization and electromagnetic coupling is essential for the development of next-generation nano-memory devices. A novel class of 2D monolayer materials with predicted spin-polarized semi-conductivity, partially compensated antiferromagnetic (AFM) order, fairly high Curie temperature, and out-of-plane polarization is analyzed in this work for the first time. Based on density functional theory calculations, we systematically studied these properties in asymmetrically functionalized MXenes (Janus Mo2C)-Mo2CXX' (X, X' = F, O, and OH). Using ab initio molecular dynamics (AIMD) and phonon spectrum calculations, the thermal and dynamic stabilities of six functionalized Mo2CXX' were identified. Our DFT+U calculation results also provided a switching path for out-of-plane polarizations, where the reverse of electric polarization is driven by terminal-layer atom flipping. More importantly, strong coupling between magnetization and electric polarization originating from spin-charge interactions was observed in this system. Our results confirm that Mo2C-FO would be a novel monolayer electromagnetic material, and its magnetization can be modulated by electric polarization.

Visual Browse and Exploration in Motion Capture Data with Phylogenetic Tree of Context-Aware Poses.

Visual browse and exploration in motion capture data take resource acquisition as a human-computer interaction problem, and it is an essential approach for target motion search. This paper presents a progressive schema which starts from pose browse, then locates the interesting region and then switches to online relevant motion exploration. It mainly addresses three core issues. First, to alleviate the contradiction between the limited visual space and ever-increasing size of real-world database, it applies affinity propagation to numerical similarity measure of pose to perform data abstraction and obtains representative poses of clusters. Second, to construct a meaningful neighborhood for user browsing, it further merges logical similarity measures of pose with the weight quartets and casts the isolated representative poses into a structure of phylogenetic tree. Third, to support online motion exploration including motion ranking and clustering, a biLSTM-based auto-encoder is proposed to encode the high-dimensional pose context into compact latent space. Experimental results on CMU's motion capture data verify the effectiveness of the proposed method.

Energy Modeling of Neighbor Discovery in Bluetooth Low Energy Networks.

Given that current Internet of Things (IoT) applications employ many different sensors to provide information, a large number of the Bluetooth low energy (BLE) devices will be developed for IoT systems. Developing low-power and low-cost BLE advertisers is one of most challenging tasks for supporting the neighbor discovery process (NDP) of such a large number of BLE devices. Since the parameter setting is essential to achieve the required performance for the NDP, an energy model of neighbor discovery in BLE networks can provide beneficial guidance when determining some significant parameter metrics, such as the advertising interval, scan interval, and scan window. In this paper, we propose a new analytical model to characterize the energy consumption using all possible parameter settings during the NDP in BLE networks. In this model, the energy consumption is derived based on the Chinese remainder theorem (CRT) for an advertising event and a scanning event during the BLE NDP. In addition, a real testbed is set up to measure the energy consumption. The measurement and experimental results reveal the relationship between the average energy consumption and the key parameters. On the basis of this model, beneficial guidelines for BLE network configuration are presented to help choose the proper parameters to optimize the power consumption for a given IoT application.

[Analysis on medication rules of modern traditional Chinese medicines in treating palpitations based on traditional Chinese medicine inheritance support system].

To analyze the prescription and medication rules of Chinese medicines in the treatment of palpitations in the Chinese journal full text database(CNKI) by using traditional Chinese medicine inheritance system, and provide a reference for further research and development of modern traditional Chinese medicines(TCMs) in treatment of palpitations. In order to give better guidance for clinical mediation, prescriptions used for treatment of palpitations in CNKI were collected, and then were input to the TCM inheritance support system for establishing a Chinese medicine prescription database for palpitations. The software's revised mutual information, complex system entropy clustering and other data mining methods were adopted to analyze the prescriptions according to the frequencies of herbs, "four natures", "five flavors" and "meridians" of the high-frequency medicines in the database, identify the core herbs and application characteristics, and analyze the prescription rules and medication experience. Totally, 545 prescriptions used for palpitation were included in this study and involved 247 Chinese herbs. The analysis results showed that the herbs in prescriptions for palpitation mostly had the warm property, and the herbs in heart and spleen meridian accounted for a larger proportion, indicating that the treatment was mainly to nourish heart and strengthen spleen. The top 11 herbs in usage frequency were consistent with the high-frequency medicines in medication patterns of common herbal pairs; therefore, we considered that these 11 herbs were the core herbs; the core herbal combination included Cassia Twig, Licorice, fossil fragments, Ostreae decoction, and evolved into 9 new prescriptions for treating palpitation. Our results objectively presented the prescription and medication rules for treating palpitation and provided extremely effective guidance for the clinical therapy.

SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo.

Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent.

Research on adults with subthreshold depression after aerobic exercise: a resting-state fMRI study based on regional homogeneity (ReHo).

Objective: Subthreshold depression (StD)/subsyndromal depression refers to a threatening precursor to depression. Aerobic exercise is a promising self-supportive adjunctive intervention and an effective measure for StD. Our study utilizes regional homogeneity (ReHo) to investigate the impact of aerobic exercise on resting-state brain function. Methods: A total of 78 subjects, aged between 18 and 48 years, (StD group, n = 44; healthy control (HC) group, n = 34) engaged in moderate-intensity aerobic exercise 3-4 times per week for 8 weeks. Resting-state brain function and structural images were acquired before and after the exercise intervention. The ReHo method was employed to analyze abnormal changes in regional brain function, and a correlation analysis was performed using the Patient Health Questionnaire-9 (PHQ-9) and Self-Rating Anxiety Scale (SAS) scores. Results: The principal observation reveals synchronous abnormalities in the right anterior cingulate gyrus of the brain in StD subjects compared to HCs at baseline, with these differences dissipating after the implementation of aerobic exercise. After completing the aerobic exercise program, the StD group exhibited a difference in the right middle cingulate gyrus, while the left supplementary motor area (SMA) was altered in the HC group. Conclusion: Disparities in neural synchronization are evident between HCs and StD subjects, and the implementation of aerobic exercise intervention can effectively mitigate these distinctions, leading to a significant reduction in depressive symptoms among StD subjects. The primary mechanism of StD symptoms may involve the inhibition of the anterior cingulate gyrus, while the effects of aerobic exercise may be related to the modulation of neural synchronization of emotional reflexes. The discovery of these fMRI evidence findings may offer novel strategies for early detection and intervention in cases of StD.

TGF-ß promotes colorectal cancer cell growth in vitro and in vivo.

BACKGROUND/AIMS: TGF-ß has dual functions as a tumor promoter or a tumor suppressor. Recent studies suggest the roles of TGF-ß might change from a tumor suppressor to a tumor promoter, when lacking SMAD4 expression in CRC (colorectal cancer). However, the precise role of TGF-ß as tumor promoter in CRC is still unclear. METHODOLOGY: We evaluated the role of TGF-ß in SMAD4-null CRC SW620 cells. In vitro, we measured cell growth and cell cycle distribution by flow cytometry. In vivo, we implanted SW620 cells into mice and measured tumor weight after TGF-ß treatment. We also determined cell proliferation ability in tumor by immunohistochemistry of proliferating cell nuclear antigen (PCNA). RESULTS: Cell growth and DNA synthesis in S phase was remarkably enhanced by TGF-ß in vitro. Besides, TGF-ß-activated ERK1/2 MAPK signal was also observed. In vivo, TGF-ß enhanced tumor growth and cell proliferation in tumor. CONCLUSIONS: TGF-ß serves as a tumor promoter, which promotes CRC cell growth in vitro and in vivo. These suggest that TGF-ß might be developed as an effective therapeutic target for CRC patients.

Moulting behaviour in the trilobite Oryctocephalus indicus (Reed, 1910) from the Cambrian Miaolingian Series (Wuliuan Stage) of Jianhe, South China.

The accurate interpretation of trilobite moulting behaviour relies on a comprehensive understanding of their moult configurations, yet the focus has commonly been limited to a brief description of the exuviae, and how differences in moulting behaviour further impact the preservation of exuviae is often ignored. This study investigates the configuration, style, and process of moulting in Oryctocephalus indicus through analysis of 88 exuviae collected from the Kaili Formation (Cambrian, Wuliuan) in Guizhou Province, South China. The moult configurations of O. indicus are typically characterised by the lower cephalic unit (LCU), which comprises the librigenae and rostral-hypostomal plate connected as a whole, detached from the cephalon and positioned anterior to the thoracopygon, while the cranidium is mostly absent. From detailed observation and description of the available material, we believe that O. indicus completes its moult through an exuvial gape formed by disarticulation of the facial sutures, rostral sutures and/or sutures of the cephalothoracic joints. Although many exuviae exhibited an opening at the cephalothoracic joint-disjunction of which is usually accompanied by disarticulation of both the facial and rostral sutures-the Salter's configuration produced by the 'Salterian' mode of moulting was not observed. Additionally, the structural characteristics of Henningsmoen's configuration, Harrington's configuration, and Somersault's configuration are discussed based on the exuviae of O. indicus, and Henningsmoen's configuration has been categorised into three types according to the different states of fossil preservation. In this article, apart from promoting further research on moulting behaviour in O. indicus, we also provide a supplement for moult configuration based on the exuviae, which offers new materials for studying moulting behaviour in oryctocephalid trilobites.

Charge disproportionation-induced multiferroics and electric field control of magnetism in a 2D MXene - Mo2NCl2.

Two-dimensional (2D) magnetoelectric multiferroic materials with the coexistence of magnetization and ferroelectric polarization hold potential for application for the development of next-generation nano-memory devices. However, intrinsic 2D multiferroics with a high critical temperature and strong magnetoelectric coupling are still rare to date. Here, we propose a novel mechanism of 2D monolayer multiferroicity. Based on density functional theory (DFT), we predicted that in a Mo2NCl2 monolayer, the non-equilibrium charge disproportionation of Mo ions will induce an out-of-plane electric polarization, making this material a 2D monolayer multiferroic material. More importantly, the magnetic critical temperature is calculated to be ∼168 K, which is larger than those of the recently reported 2D multiferroic and ferromagnetic systems. Our findings also provide a promising platform to control the magnetic properties and electric behavior in 2D multiferroics using an external electric field.

PINK1/Parkin-mediated mitophagy in neurodegenerative diseases.

Mitochondria play key roles in bioenergetics, metabolism, and signaling; therefore, stable mitochondrial function is essential for cell survival, particularly in energy-intensive neuronal cells. In neurodegenerative diseases, damaged mitochondria accumulate in neurons causing associated bioenergetics deficiency, impaired cell signaling, defective cytoplasmic calcium buffering, and other pathological changes. Mitochondrial quality control is an important mechanism to ensure the maintenance of mitochondrial health, homeostasis, and mitophagy, the latter of which is a pathway that delivers defective mitochondria to the lysosome for degradation. Defective mitophagy is thought to be responsible for the accumulation of damaged mitochondria, which leads to cellular dysfunction and/or death in neurodegenerative diseases. PINK1/Parkin mainly regulates ubiquitin-dependent mitophagy, which is crucial for many aspects of mitochondrial physiology, particularly the initiation of autophagic mechanisms. Therefore, in the present review, we summarize the current knowledge of the conventional mitophagy pathway, focusing on the molecular mechanisms underlying mitophagy dysregulation in prion disease and other age-related neurodegenerative diseases, especially in relation to the PINK1/Parkin pathway. Moreover, we list the inducers of mitophagy that possess neuroprotective effects, in addition to their mechanisms related to the PINK1/Parkin pathway. These mechanisms may provide potential interventions centered on the regulation of mitophagy and offer therapeutic strategies for the treatment of neurodegenerative diseases.

Ultrafast Superfilling Construction of a Metal Artificial Interface for Long-Term Stable Zinc Anodes.

Zinc (Zn)-metal anodes are promising candidates for large-scale, highly safe energy-storage systems. However, their cycling life is associated with instability issues such as dendritic growth, corrosion, and hydrogen evolution. Introducing an artificial metal interface is expected to help overcome this challenge owing to the optimization of the absorption, nucleation, and growth of Zn2+ . In this study, an ultrafast, universal, and cost-effective superfilling approach is developed to construct a metal artificial interface decorated Zn anode in situ. Most zincophilic metals, including Sn, Cu, and Ag, can be used to construct a homogenous interface without any restrictions on the size, morphology, or curvature of the substrates. With Sn as a proof-of-concept demonstration, the as-obtained Sn@Zn anode is conducive for the homogenous Zn nuclei and 2D diffusion of Zn2+ ions. Symmetric cells with Sn@Zn electrodes can be operated for over 900 h at different current densities. This superior performance contributes to the attractive electrochemical characteristics of both coin and scaled-up Sn@Zn//ß-MnO2 cells. Given the facile and cost-effective fabrication and recyclability of the cells, this work enables the efficient design and exploration of Zn anodes for research, industrialization, and commercialization purposes.

RAB7A GTPase Is Involved in Mitophagosome Formation and Autophagosome-Lysosome Fusion in N2a Cells Treated with the Prion Protein Fragment 106-126.

Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP106-126. Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP106-126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome-lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP106-126-induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases. Proposed model of mitophagy regulated by RAB7A. (1) Accumulating PrP106-126 induced mitophagy. (2) RAB7A is recruited to mitochondria. (3) ATG5-12 and ATG9A (5) vesicles are recruited to the autophagosome formation sites in a RAB7A-dependent manner. The ATG5-12 complex recruits and anchors LC3-I to form active LC3-II (4), accelerating mitophagosomal formation. The ATG9A vesicles are thought to be a source of membranes for autophagosome assembly. The recruitment of proteins and lipids induces membrane expansion and subsequent closure to form the mitophagosome. (6) Maintenance of the normal low lysosomal PH depends on active (GTP-bound) RAB7A. (7) RAB7A recruits effector molecules responsible for tight membrane interactions, and directly or indirectly, the subsequent autophagosome merges with the lysosome, and the cargo is completely degraded.

Cardiolipin externalization mediates prion protein (PrP) peptide 106-126-associated mitophagy and mitochondrial dysfunction.

Proper mitochondrial performance is imperative for the maintenance of normal neuronal function to prevent the development of neurodegenerative diseases. Persistent accumulation of damaged mitochondria plays a role in prion disease pathogenesis, which involves a chain of events that culminate in the generation of reactive oxygen species and neuronal death. Our previous studies have demonstrated that PINK1/Parkin-mediated mitophagy induced by PrP106-126 is defective and leads to an accumulation of damaged mitochondria after PrP106-126 treatment. Externalized cardiolipin (CL), a mitochondria-specific phospholipid, has been reported to play a role in mitophagy by directly interacting with LC3II at the outer mitochondrial membrane. The involvement of CL externalization in PrP106-126-induced mitophagy and its significance in other physiological processes of N2a cells treated with PrP106-126 remain unknown. We demonstrate that the PrP106-126 peptide caused a temporal course of mitophagy in N2a cells, which gradually increased and subsequently decreased. A similar trend in CL externalization to the mitochondrial surface was seen, resulting in a gradual decrease in CL content at the cellular level. Inhibition of CL externalization by knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3 and NDPK-D, responsible for CL translocation to the mitochondrial surface, significantly decreased PrP106-126-induced mitophagy in N2a cells. Meanwhile, the inhibition of CL redistribution significantly decreased PINK1 and DRP1 recruitment in PrP106-126 treatment but had no significant decrease in Parkin recruitment. Furthermore, the inhibition of CL externalization resulted in impaired oxidative phosphorylation and severe oxidative stress, which led to mitochondrial dysfunction. Our results indicate that CL externalization induced by PrP106-126 on N2a cells plays a positive role in the initiation of mitophagy, leading to the stabilization of mitochondrial function.

A Review of Research Progress in Selective Laser Melting (SLM).

SLM (Selective Laser Melting) is a unique additive manufacturing technology which plays an irreplaceable role in the modern industrial revolution. 3D printers can directly process metal powder quickly to obtain the necessary parts faster. Shortly, it will be possible to manufacture products at unparalleled speeds. Advanced manufacturing technology is used to produce durable and efficient parts with different metals that have good metal structure performance and excellent metal thermal performance, to lead the way for laser powder printing technology. Traditional creative ways are usually limited by time, and cannot respond to customers' needs fast enough; for some parts with high precision and complexity, conventional manufacturing methods are inadequate. Contrary to this, SLM technology offers some advantages, such as requiring no molds this decreases production time and helps to reduce costs. In addition, SLM technology has strong comprehensive functions, which can reduce assembly time and improve material utilization. Parts with complex structures, such as cavities and three-dimensional grids, can be made without restricting the shape of products. Products or parts can be printed quickly without the use of expensive production equipment. The product quality is better, and the mechanical load performance is comparable to traditional production technologies (such as forging). This paper introduces in detail the process parameters that affect SLM technology and how they affect SLM, commonly used metal materials and non-metallic materials, and summarizes the current research. Finally, the problems faced by SLM are prospected.

Abnormalities of Gray Matter Volume and Its Correlation with Clinical Symptoms in Adolescents with High-Functioning Autism Spectrum Disorder.

Background: Previous studies have indicated abnormal gray matter volume (GMV) in individuals with autism spectrum disorder (ASD); however, there is little consistency across the findings within these studies, partly due to small sample size and great heterogeneity among participants between studies. Additionally, few studies have explored the correlation between clinical symptoms and GMV abnormalities in individuals with ASD. Here, the current study examined GMV alterations in whole brain and their correlations with clinical symptoms in a relatively large and homogeneous sample of participants with ASD matched typically developing (TD) controls. Methods: Forty-eight adolescents with high-functioning ASD and 29 group-matched TD controls underwent structural magnetic resonance images. Voxel-based morphometry was applied to investigate regional GMV alterations. The participants with ASD were examined for the severity of clinical symptoms with Autism Behavior Checklist (ABC). The relationship between GMV abnormalities and clinical symptoms was explored in ASD group using voxel-wise correlation analysis within brain regions that showed significant GMV alterations in individuals with ASD compared with TD controls. Results: We found increased GMV in multiple brain regions, including the inferior frontal gyrus, medial frontal gyrus, superior frontal gyrus, superior temporal gyrus, occipital pole, anterior cingulate, cerebellum anterior lobe, cerebellum posterior lobe, and midbrain, as well as decreased GMV in cerebellum posterior lobe in individuals with ASD. The correlation analysis showed the GMV in the left fusiform was negatively associated with the scores of sensory factor, and the GMV in the right cerebellum anterior lobe was positively associated with the scores of social self-help factor. Conclusion: Our results indicated that widespread GMV abnormalities of brain regions occurred in individuals with ASD, suggesting a potential neural basis for the pathogenesis and symptomatology of ASD.

The middle Cambrian Linyi Lagerstätte from the North China Craton: a new window on Cambrian evolutionary fauna.

The rapid appearance of major animal groups and complex marine communities during the Cambrian explosion is recorded in large part in Burgess Shale-type lagerstätten. However, the restricted temporal and spatial distribution of known lagerstätten continues to hinder the formation of a comprehensive perspective on Cambrian evolutionary faunas. Here we describe the Linyi Lagerstätte (ca. 504 mya), a new Cambrian Miaolingian lagerstätte from the Zhangxia Formation in Shandong Province, North China. The Linyi Lagerstätte contains a variety of well-preserved soft-bodied fossils, among which the non-trilobite arthropods, particularly the mollisoniids and radiodonts, are the most important groups. The new assemblage is remarkable for its excellent preservation of arthropod limbs, eyes and guts, as well as for its close similarity in taxonomic composition to Laurentian lagerstätten. The distinctive Linyi Lagerstätte holds great promise for providing additional insights into the morphological disparity, community structure and paleogeographic range of marine faunas during the middle Cambrian (Miaolingian).

Regional homogeneity of adolescents with high-functioning autism spectrum disorder and its association with symptom severity.

BACKGROUND AND PURPOSE: Previous studies have revealed abnormal regional homogeneity (ReHo) in individuals with autism spectrum disorder (ASD); however, there is little consistency across the findings within these studies, partly due to small sample size and great heterogeneity among participants between studies. Additionally, few studies have explored the association between ReHo aberrance and clinical symptoms in individuals with ASD. METHODS: Forty-eight adolescents with high-functioning ASD and 63 group-matched typically developing (TD) controls received functional magnetic resonance imaging at rest. Group-level analysis was performed to detect differences in ReHo between ASD and TD. Evaluation of symptom severity in individuals with ASD was based on the Autism Behavior Checklist (ABC). Voxel-wise correlation analysis was undergone to examine the correlations between the symptom severity and ReHo map in individuals with ASD within brain areas with ReHo abnormalities. RESULTS: Compared with the TD controls, individuals with ASD exhibited increased ReHo in the bilateral anterior cingulate cortex, left caudate, right posterior cerebellum (cerebellar tonsil), and bilateral brainstem and decreased ReHo in the left precentral gyrus, left inferior parietal lobule, bilateral postcentral gyrus, and right anterior cerebellum (culmen). The correlation analysis indicated that the ReHo value in the brainstem was negatively associated with the ABC total scores and the scores of Relating factor, respectively. CONCLUSIONS: Our findings indicated that widespread ReHo abnormalities occurred in ASD, shedding light on the underlying neurobiology of pathogenesis and symptomatology of ASD.

SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease.

Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106-126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106-126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease.

A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.