Application of Se-Met to CdTe QDs significantly reduces toxicity by modulating redox balance and inhibiting apoptosis.

Cadmium tellurium quantum dots (CdTe QDs) as one of the most widely used QDs have been reported the toxicity and biosafety in recent years, little work has been done to reduce their toxicity however. Based on the mechanisms of toxicity of CdTe QDs on liver target organs such as oxidative stress and apoptosis previously reported by other researchers, we investigated the mechanism of action of trace element selenium (Se) to mitigate the hepatotoxicity of CdTe QDs. The experimental results showed that Se-Met at 40-140 µg L-1 could enhance the function of intracellular antioxidant defense system and the molecular structure of related antioxidant enzymes by reduce the production of ROS by 45%, protecting the activity of antioxidants and up-regulating the expression of selenoproteins with antioxidant functions, Gpx1 increase 225% and Gpx4 upregulated 47%. In addition, Se-Met could alleviate CdTe QDs-induced apoptosis by regulating two apoptosis-inducing factors, as intracellular caspase 3/9 expression levels were reduced by 70% and 87%, decreased Ca2+ concentration, and increased mitochondrial membrane potential measurements. Overall, this study indicates that Se-Met has a significant protective effect on the hepatotoxicity of CdTe QDs. Se-Met can be applied to the preparation of CdTe QDs to inhibit its toxicity and break the application limitation.

Ketogenic diet protects myelin and axons in diffuse axonal injury.

BACKGROUND: Ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after traumatic brain injury (TBI). Diffuse axonal injury (DAI) is a common type of traumatic brain injury that is characterized by delayed axonal disconnection. Previous studies showed that demyelination resulting from oligodendrocyte damage contributes to axonal degeneration in DAI. AIM: The present study tests a hypothesis that ketone bodies from the ketogenic diet confers protection for myelin and attenuates degeneration of demyelinated axon in DAI. METHODS: A modified Marmarou's model of DAI was induced in adult rats. The DAI rats were fed with KD and analyzed with western blot, transmission electron microscope, ELISA test and immunohistochemistry. Meanwhile, a co-culture of primary oligodendrocytes and neurons was treated with ketone body ß-hydroxybutryate (ßHB) to test for its effects on the myelin-axon unit. RESULTS: Here we report that rats fed with KD showed an increased fatty acid metabolism and ketonemia. This dietary intervention significantly reduced demyelination and attenuated axonal damage in rats following DAI, likely through inhibition of DAI-induced excessive mitochondrial fission and promoting mitochondrial fusion. In an in vitro model of myelination, the ketone body ßHB increased myelination significantly and reduced axonal degeneration induced by glucose deprivation (GD). ßHB robustly increased cell viability, inhibited GD-induced collapse of mitochondrial membrane potential and attenuated death of oligodendrocytes. CONCLUSION: Ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage. Ketogenic diet maybe a promising therapy for DAI.

Attention-guided duplex adversarial U-net for pancreatic segmentation from computed tomography images.

PURPOSE: Segmenting the organs from computed tomography (CT) images is crucial to early diagnosis and treatment. Pancreas segmentation is especially challenging because the pancreas has a small volume and a large variation in shape. METHODS: To mitigate this issue, an attention-guided duplex adversarial U-Net (ADAU-Net) for pancreas segmentation is proposed in this work. First, two adversarial networks are integrated into the baseline U-Net to ensure the obtained prediction maps resemble the ground truths. Then, attention blocks are applied to preserve much contextual information for segmentation. The implementation of the proposed ADAU-Net consists of two steps: 1) backbone segmentor selection scheme is introduced to select an optimal backbone segmentor from three two-dimensional segmentation model variants based on a conventional U-Net and 2) attention blocks are integrated into the backbone segmentor at several locations to enhance the interdependency among pixels for a better segmentation performance, and the optimal structure is selected as a final version. RESULTS: The experimental results on the National Institutes of Health Pancreas-CT dataset show that our proposed ADAU-Net outperforms the baseline segmentation network by 6.39% in dice similarity coefficient and obtains a competitive performance compared with the-state-of-art methods for pancreas segmentation. CONCLUSION: The ADAU-Net achieves satisfactory segmentation results on the public pancreas dataset, indicating that the proposed model can segment pancreas outlines from CT images accurately.

Multi-scale Selection and Multi-channel Fusion Model for Pancreas Segmentation Using Adversarial Deep Convolutional Nets.

Organ segmentation from existing imaging is vital to the medical image analysis and disease diagnosis. However, the boundary shapes and area sizes of the target region tend to be diverse and flexible. And the frequent applications of pooling operations in traditional segmentor result in the loss of spatial information which is advantageous to segmentation. All these issues pose challenges and difficulties for accurate organ segmentation from medical imaging, particularly for organs with small volumes and variable shapes such as the pancreas. To offset aforesaid information loss, we propose a deep convolutional neural network (DCNN) named multi-scale selection and multi-channel fusion segmentation model (MSC-DUnet) for pancreas segmentation. This proposed model contains three stages to collect detailed cues for accurate segmentation: (1) increasing the consistency between the distributions of the output probability maps from the segmentor and the original samples by involving the adversarial mechanism that can capture spatial distributions, (2) gathering global spatial features from several receptive fields via multi-scale field selection (MSFS), and (3) integrating multi-level features located in varying network positions through the multi-channel fusion module (MCFM). Experimental results on the NIH Pancreas-CT dataset show that our proposed MSC-DUnet obtains superior performance to the baseline network by achieving an improvement of 5.1% in index dice similarity coefficient (DSC), which adequately indicates that MSC-DUnet has great potential for pancreas segmentation.

Necrostatin-1 prevents the proapoptotic protein Bcl-2/adenovirus E1B 19-kDa interacting protein 3 from integration into mitochondria.

Necrostatin-1 (Nec-1) has previously been shown to protect neurons from death in traumatic and ischemic brain injuries. This study tests the hypothesis that Nec-1 protects neural cells against traumatic and ischemic brain injuries through inhibition of the Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3). We have used biochemical and morphological techniques to determine the inhibition of Nec-1 on BNIP3-induced cell death and to identify its mechanism of action in in vivo and in vitro models of neurodegeneration. Here we show that Nec-1 significantly increased neuronal viability following prolonged exposure to hypoxia in vitro, and attenuated myelin damage and neuronal death in traumatic brain injury and cerebral ischemia in Sprague-Dawley rats. Nec-1 alleviated traumatic brain injury-induced up-regulation of BNIP3 in mature oligodendrocytes. In isolated mitochondria, Nec-1 prevented BNIP3 from integrating into mitochondria by modifying its binding sites on the mitochondria. Consequently, Nec-1 robustly inhibited BNIP3-induced collapse of mitochondrial membrane potential and reduced the opening probability of mitochondrial permeability transition pores. Nec-1 also preserved mitochondrial ultrastructure and suppressed BNIP3-induced nuclear translocation of apoptosis-inducing factor. In conclusion, Nec-1 protects neurons and oligodendrocytes against traumatic and ischemic brain injuries by targeting the BNIP3-induced cell death pathway, and is a novel inhibitor for BNIP3. Cover Image for this issue: https://doi.org/10.1111/jnc.15056.

Accurate pancreas segmentation using multi-level pyramidal pooling residual U-Net with adversarial mechanism.

BACKGROUND: A novel multi-level pyramidal pooling residual U-Net with adversarial mechanism was proposed for organ segmentation from medical imaging, and was conducted on the challenging NIH Pancreas-CT dataset. METHODS: The 82 pancreatic contrast-enhanced abdominal CT volumes were split via four-fold cross validation to test the model performance. In order to achieve accurate segmentation, we firstly involved residual learning into an adversarial U-Net to achieve a better gradient information flow for improving segmentation performance. Then, we introduced a multi-level pyramidal pooling module (MLPP), where a novel pyramidal pooling was involved to gather contextual information for segmentation, then four groups of structures consisted of a different number of pyramidal pooling blocks were proposed to search for the structure with the optimal performance, and two types of pooling blocks were applied in the experimental section to further assess the robustness of MLPP for pancreas segmentation. For evaluation, Dice similarity coefficient (DSC) and recall were used as the metrics in this work. RESULTS: The proposed method preceded the baseline network 5.30% and 6.16% on metrics DSC and recall, and achieved competitive results compared with the-state-of-art methods. CONCLUSIONS: Our algorithm showed great segmentation performance even on the particularly challenging pancreas dataset, this indicates that the proposed model is a satisfactory and promising segmentor.

The wide distribution and horizontal transfers of beta satellite DNA in eukaryotes.

Beta satellite DNA (satDNA), also known as Sau3A sequences, are repetitive DNA sequences reported in human and primate genomes. It is previously thought that beta satDNAs originated in old world monkeys and bursted in great apes. In this study, we searched 7821 genome assemblies of 3767 eukaryotic species and found that beta satDNAs are widely distributed across eukaryotes. The four major branches of eukaryotes, animals, fungi, plants and Harosa/SAR, all have multiple clades containing beta satDNAs. These results were also confirmed by searching whole genome sequencing data (SRA) and PCR assay. Beta satDNA sequences were found in all the primate clades, as well as in Dermoptera and Scandentia, indicating that the beta satDNAs in primates might originate in the common ancestor of Primatomorpha or Euarchonta. In contrast, the widely patchy distribution of beta satDNAs across eukaryotes presents a typical scenario of multiple horizontal transfers.

Acquired tamoxifen resistance is surmounted by GW8510 through ribonucleotide reductase M2 downregulation-mediated autophagy induction.

Tamoxifen resistance is a major roadblock in the treatment of patients with breast cancer. Ribonucleotide reductase M2 (RRM2) was found to be involved in acquired resistance of breast cancer cells (BCCs) to tamoxifen. Here, we used GW8510, which has been identified as a potential RRM2 inhibitor, to evaluate the effect of RRM2 inhibition on reversing resistance of BCCs to tamoxifen and investigate its mechanisms. We showed that RRM2 overexpression played a key role in the development of acquired tamoxifen resistance in BCCs through downregulation of autophagy level. Combination treatment with tamoxifen and GW8510 significantly inhibited survival of the tamoxifen-resistant BCCs through induction of autophagic cell death compared to either of the two drugs. Furthermore, combination of tamoxifen and GW8510 resulted in marked growth inhibition of tamoxifen-resistant BBC xenograft tumor in vivo compared to tamoxifen or GW8510 alone. In conclusion, tamoxifen in combination with GW8510 can overcome acquired tamoxifen resistance in BCCs and may be a rational therapeutic approach against breast cancer with high RRM2 expression.

Comparative transcriptome profiling reveals cold stress responsiveness in two contrasting Chinese jujube cultivars.

BACKGROUND: Low temperature is a major factor influencing the growth and development of Chinese jujube (Ziziphus jujuba Mill.) in cold winter and spring. Little is known about the molecular mechanisms enabling jujube to cope with different freezing stress conditions. To elucidate the freezing-related molecular mechanism, we conducted comparative transcriptome analysis between 'Dongzao' (low freezing tolerance cultivar) and 'Jinsixiaozao' (high freezing tolerance cultivar) using RNA-Seq. RESULTS: More than 20,000 genes were detected at chilling (4 °C) and freezing (- 10 °C, - 20 °C, - 30 °C and - 40 °C) stress between the two cultivars. The numbers of differentially expressed genes (DEGs) between the two cultivars were 1831, 2030, 1993, 1845 and 2137 under the five treatments. Functional enrichment analysis suggested that the metabolic pathway, response to stimulus and catalytic activity were significantly enriched under stronger freezing stress. Among the DEGs, nine participated in the Ca2+ signal pathway, thirty-two were identified to participate in sucrose metabolism, and others were identified to participate in the regulation of ROS, plant hormones and antifreeze proteins. In addition, important transcription factors (WRKY, AP2/ERF, NAC and bZIP) participating in freezing stress were activated under different degrees of freezing stress. CONCLUSIONS: Our research first provides a more comprehensive understanding of DEGs involved in freezing stress at the transcriptome level in two Z. jujuba cultivars with different freezing tolerances. These results may help to elucidate the molecular mechanism of freezing tolerance in jujube and also provides new insights and candidate genes for genetically enhancing freezing stress tolerance.

Smart home for elderly care: development and challenges in China.

BACKGROUND: China's smart home for elderly care emerged in 2008, and had went through four developmental stages which consists of seed stage, start-up stage, development stage and popularization stage. MAIN TEXT: The status quo and development of smart home for elderly care in China is reviewed, and suggestions are provided on how to further develop China's smart home for elderly care. The focus of China's policies on smart home for elderly care were different during those four developmental stages. Compared with Western countries, China's smart home for elderly care is a policy-driven product rather than technology-driven or demand-driven one. In addition, it is quasi-public goods rather than private goods. These unique characteristics of China's smart home for elderly care not only become the driving force of its rapid development, but also bring many challenges to its development, such as the insufficient demand, the disorderly development, and the waste of public and private resources. CONCLUSIONS: Although great progress has been made in China's smart home care, much efforts are still needed to further advance its development. The technical standards for the elderly care services should be formulated as soon as possible and the existing public and private smart home for elderly care platforms should be combined. Enterprises involved in smart home care services should be encouraged to develop new technologies to reduce the cost of products and services provided by smart home for elderly care.

Nitric oxide blocks the development of the human parasite Schistosoma japonicum.

Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS-/-) Sprague-Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS-/- rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host-parasite interactions and drug development strategies against schistosomiasis.

Methamphetamine-induced toxic leukoencephalopathy: clinical, radiological and autopsy findings.

Toxic leukoencephalopathy represents a process of structural alteration of the white matter. It is caused by substance abuse including drugs such as heroin, cocaine, toluene and ethanol. We reported the clinical, radiological and autopsy findings of a rare case of toxic leukoencephalopathy following chronic methamphetamine (MA) usage. A 34-year-old man with a 3-year history of MA abuse experienced progressive sluggish state, limb weakness, inability to stand and eating disorders, followed by rapid progression to coma and death. Imaging revealed hypodense CT and long T1 and T2 signals in MRI in the white matter of the bilateral periventricular and centrum semiovale regions. Histologically, white matter rarefaction, loss of myelin and axonal injury were observed. This pattern of clinical presentation, radiological manifestations and histological findings show a certain degree of particularity in toxic leukoencephalopathy. Clinically, the condition may be easily misdiagnosed as withdrawal symptoms. In suspected cases, MRI is recommended for diagnosis. The case reported here reminds clinicians and forensic pathologist of the possibility of toxic leukoencephalopathy related to MA abuse.

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome.

Assembly of the inflammasome has recently been identified to be a critical event in the initiation of inflammation. However, its role in bacterial killing remains unclear. Our study demonstrates that Pseudomonas aeruginosa infection induces the assembly of the NLRP3 inflammasome and the sequential secretion of caspase1 and interleukin-1ß (IL-1ß) in human macrophages. More importantly, activation of the NLRP3 inflammasome reduces the killing of P. aeruginosa in human macrophages, without affecting the generation of antimicrobial peptides, reactive oxygen species, and nitric oxide. In addition, our results demonstrate that P. aeruginosa infection increases the amount of the LC3-II protein and triggers the formation of autophagosomes in human macrophages. The P. aeruginosa-induced autophagy was enhanced by overexpression of NLRP3, ASC, or caspase1 but was reduced by knockdown of these core molecules of the NLRP3 inflammasome. Treatment with IL-1ß enhanced autophagy in human macrophages. More importantly, IL-1ß decreased the macrophage-mediated killing of P. aeruginosa, whereas knockdown of ATG7 or Beclin1 restored the IL-1ß-mediated suppression of bacterial killing. Collectively, our study explores a novel mechanism employed by P. aeruginosa to escape from phagocyte killing and may provide a better understanding of the interaction between P. aeruginosa and host immune cells, including macrophages.

MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb.

Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhancing phagosome maturation. In the present study, we demonstrate a novel role of miR-155 in regulating the autophagy-mediated anti-mycobacterial response. Both in vivo and in vitro studies showed that miR-155 expression was significantly enhanced after mycobacterial infection. Forced expression of miR-155 accelerated the autophagic response in macrophages, thus promoting the maturation of mycobacterial phagosomes and decreasing the survival rate of intracellular mycobacteria, while transfection with miR-155 inhibitor increased mycobacterial survival. However, macrophage-mediated mycobacterial phagocytosis was not affected after miR-155 overexpression or inhibition. Furthermore, blocking autophagy with specific inhibitor 3-methyladenine or silencing of autophagy related gene 7 (Atg7) reduced the ability of miR-155 to promote autophagy and mycobacterial elimination. More importantly, our study demonstrated that miR-155 bound to the 3'-untranslated region of Ras homologue enriched in brain (Rheb), a negative regulator of autophagy, accelerated the process of autophagy and sequential killing of intracellular mycobacteria by suppressing Rheb expression. Our results reveal a novel role of miR-155 in regulating autophagy-mediated mycobacterial elimination by targeting Rheb, and provide potential targets for clinical treatment.

miR-155 suppresses bacterial clearance in Pseudomonas aeruginosa-induced keratitis by targeting Rheb.

miR-155 (microRNA-155) is an important noncoding RNA in regulating host inflammatory responses. However, its regulatory role in ocular infection remains unclear. Our study first explored the function of miR-155 in Pseudomonas aeruginosa-induced keratitis, one of the most common sight-threatening ocular diseases. We found that miR-155 expression was enhanced in human and mouse corneas after P. aeruginosa infection and was mainly expressed in macrophages but not neutrophils. In vivo studies demonstrated that miR-155 knockout mice displayed more resistance to P. aeruginosa keratitis, with a higher inducible nitric oxide synthase level and a lower bacterial burden. More importantly, in vitro data indicated that miR-155 suppressed the macrophage-mediated bacterial phagocytosis and intracellular killing of P. aeruginosa by targeting Rheb (Ras homolog enriched in brain). To the best of our knowledge, this is the first study to explore the role of miR-155 in bacterial keratitis, which may provide a promising target for clinical treatment of P. aeruginosa keratitis and other infectious diseases.

Research on the influencing factors of Chinese agricultural brand competitiveness based on DEMATEL-ISM.

Agricultural products are pivotal to the national economy, and a comprehensive analysis of brand competitiveness significantly contributes to the support of agricultural structural adjustment and modernization. Focusing on the Yangtze River Delta region of China, this study develops an evaluation index system encompassing four dimensions: core brand competitiveness, brand management, market competitiveness, and innovation in branding. Utilizing a DEMATEL-ISM model, this research elucidates the intrinsic relationships among factors that influence brand competitiveness, resulting in a four-tier hierarchical model. The analysis delineates key factors at superficial, intermediate, and profound levels that influence brand competitiveness. Notably, regional production bases, along with innovations in brand technology and systems, emerge as profound influencers. Drawing on these findings, the study recommends strategies to enhance production foundations, accurately define development trajectories, spearhead technological innovation to foster collective reform efforts, and advocate for institutional advancements to bolster healthy brand growth.

Metal-Organic Framework Nanomaterials as a Medicine for Catalytic Tumor Therapy: Recent Advances.

Nanomaterials, with unique physical, chemical, and biocompatible properties, have attracted significant attention as an emerging active platform in cancer diagnosis and treatment. Amongst them, metal-organic framework (MOF) nanostructures are particularly promising as a nanomedicine due to their exceptional surface functionalities, adsorption properties, and organo-inorganic hybrid characteristics. Furthermore, when bioactive substances are integrated into the structure of MOFs, these materials can be used as anti-tumor agents with superior performance compared to traditional nanomaterials. In this review, we highlight the most recent advances in MOFs-based materials for tumor therapy, including their application in cancer treatment and the underlying mechanisms.

OsRopGEF10 Attenuates Cytokinin Signaling to Regulate Panicle Development and Grain Yield in Rice.

Cytokinins, which play crucial roles in shoot development, substantially affect grain yield. In rice, the OsRopGEF10-OsRAC3 module is associated with cytokinin signaling and crown root development. However, the effects of RopGEF-mediated cytokinin signaling on rice shoot development and grain yield remain unclear. In this study, we investigated the role of OsRopGEF10 in SAM development and the underlying mechanism. We showed that overexpression of OsRopGEF10 inhibited SAM and panicle development, leading to decreased grain yield. Intriguingly, the overexpression of a specific amino acid mutant of OsRopGEF10, designated gef10-W260S, was found to promote panicle development and grain yield. Further analysis using the BiFC assay revealed that the gef10-W260S mutation disrupted the recruitment of rice histidine phosphotransfer proteins (OsAHP1/2) to the plasma membrane (PM), thereby promoting cytokinin signaling. This effect was corroborated by a dark-induced leaf senescence assay, which revealed an increased cytokinin response in the gef10-W260S ectopic expression lines, whereas the overexpression lines presented a suppressed cytokinin response. Moreover, we revealed that the enhanced panicle development in the gef10-W260S lines was attributable to the upregulated expression of several type-B response regulators (RRs) that are crucial for panicle development. Collectively, these findings revealed the negative regulatory function of OsRopGEF10 in the development of the shoot apical meristem (SAM) via interference with cytokinin signaling. Our study highlights the promising role of OsRopGEF10 as a potential target for regulating SAM and panicle development in rice, revealing a valuable breeding strategy for increasing crop yield.

Magnetostrictive-piezocatalytic CoFe2O4@UiO-66 nanohybrid and its potential for deep-seated tumor treatment.

Magnetostrictive CoFe2O4 (CFO) nanoparticles were encapsulated within a UiO-66 metal-organic-framework layer to form a CFO@UiO-66 nanohybrid. The deforming of CFO, in response to a high-frequency AC magnetic field, initiates the piezocatalytic property of UiO-66 to generate ˙OH radicals, which can kill cancer cells buried in thick tissues, showcasing bright potential for deep-seated tumor treatment.

ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging.

Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1G93A) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1WT). Transgenic mice carrying the hSOD1G93A gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1WT transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1G93A mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSODG93A transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.