Hongqiao Zhang's research while affiliated with University of Southern California and other places
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Publications (82)
Air pollution is associated with risks of dementia and accelerated cognitive decline. Rodent air pollution models have shown white matter vulnerability. This study uses diffusion tensor imaging (DTI) to quantify changes to white matter microstructure and tractography in multiple myelinated regions after exposure to diesel exhaust particulate (DEP)....
Background:
Epidemiological studies have variably linked air pollution to increased risk of Parkinson's disease (PD). However, there is little experimental evidence for this association. Alpha-synuclein (α-syn) propagation plays central roles in PD and glutamate receptor A1 (GluA1) is involved in memory and olfaction function.
Methods:
Each mous...
Exposure to urban air pollution particles is strongly associated with higher risks of accelerated cognitive decline, cerebral atrophy, and dementia in multiple population studies. Among possible mechanisms is the decrease of neurotrophins, shown for BDNF in human exposures, which have critical roles in regulating adult neurogenesis and synaptic pla...
Experimental animal exposures show neurotoxic effects of diesel in young mice even after short-term exposures. We hypothesize that neuroinflammatory effects of diesel exhaust particles (DEP) are mediated by toll-like receptor 4 (TLR4) activation in brain microglia. We studied both sexes of young (2 months) and middle-aged (18 months) TLR4 flx/flx (...
Understanding the nanoscale chemical speciation of heterogeneous systems in their native environment is critical for several disciplines such as life and environmental sciences, biogeochemistry, and materials science. Synchrotron-based x-ray spectromicroscopy tools are widely used to understand the chemistry and morphology of complex material syste...
Background:
Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer's disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions....
Background:
HNE (4-hydroxy-2-nonenal), a primary α, β-unsaturated aldehyde product of lipid peroxidation, is implicated in the pathogenesis and progression of Alzheimer's disease (AD). HNE level in the brain increases with aging and is higher in AD hippocampus than age-matched controls. Upon HNE exposure, cells usually can upregulate HNE detoxific...
Background:
Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood-brain barrier weakening, which may augment neurotoxic effec...
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mech...
Background:
Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer's disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown p...
4-hydroxynonenal (HNE, 4-hydroxy-2-nonenal) is a primary α,β-unsaturated aldehyde product of lipid peroxidation. The accumulation of HNE increases with aging and the mechanisms are mainly attributable to increased oxidative stress and decreased capacity of HNE elimination. In this review article, we summarize the studies on age-related change of HN...
Glutathione (GSH) plays critical roles in the inflammatory response by acting as the master substrate for antioxidant enzymes and an important anti-inflammatory agent. In the early phase of the inflammatory response of macrophages, GSH content is decreased due to the down regulation of the catalytic subunit of glutamate cysteine ligase (GCLC). In t...
The neurotoxicity of air pollution is undefined for sex and APOE alleles. These major risk factors of Alzheimer's disease (AD) were examined in mice given chronic exposure to nPM, a nano-sized subfraction of urban air pollution. In the cerebral cortex, female mice had twofold more genes responding to nPM than males. Transcriptomic responses to nPM...
4-Hydroxenonenal (HNE) is one of the major α,β-unsaturated aldehyde products of lipid peroxidation. HNE can form conjugates with macromolecules, including protein, and thereby alter their function. HNE and its conjugation with proteins are increased in aging and age-related diseases. To elucidate how HNE is involved in these aging-related pathophys...
Air pollution (AirP) is associated with many neurodevelopmental and neurological disorders in human populations. Rodent models show similar neurotoxic effects of AirP particulate matter (PM) collected by different methods or from various sources. However, controversies continue on the identity of the specific neurotoxic components and mechanisms of...
Exposure to urban ambient particulate matter (PM) is associated with risk of Alzheimer's disease and accelerated cognitive decline in normal aging. Assessment of the neurotoxic effects caused by urban PM is complicated by variations of composition from source, location, and season. We compared several in vitro cell-based assays in relation to their...
Nrf2 is the master transcription factor regulating the basal and inducible expression of antioxidant genes. With aging, the basal Nrf2 activity is increased but oxidant/electrophile-enhanced activation of Nrf2 signaling is diminished, and these changes are accompanied by an increased expression of Bach1, a repressor of Nrf2 signaling. In this limit...
The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O 2 , as a model of acceler...
In response to oxidative stress, cells usually expand a wide suite of defense mechanisms as part of adaptive homeostasis. Included in the array of adaptive responses is increased expression and activity of 20S proteasomes, immunoproteasomes, and PA28 (11S) proteasomal activator that enable efficient and rapid removal of oxidatively damaged proteins...
Rett syndrome is a rare, female-specific genetic disease that is caused by an X-linked dominant mutation of the methyl-CPG-binding protein 2 (MECP2) gene, involved in chromatin architecture and often functioning as transcriptional repressor. MECP2 mutation is the leading cause behind the most prevalent form of female-specific cognitive disability....
Evidence indicates that oxidative stress plays a central role in the pathogenesis of harmful effects caused by airborne nanoparticle (ANP), a health hazard associated with various diseases. Carbon nanoparticles are a major component of urban ANP, and usually adsorbs transition metals especially iron and organics on the surface. Nuclear factor eryth...
Glutathione (GSH), the most abundant non-protein antioxidant thiol in cells, also plays a key role in mediating the inflammatory response. Its content is reduced in the early phase of the inflammatory response of macrophages due to decreased expression of the catalytic subunit of glutamate cysteine ligase (GCLC). How GCLC is down regulated during t...
The elderly are more susceptible to sepsis, which is often fatal, and caused by infection and characterized by systemic inflammation and oxidative stress. Blood monocytes are effector immune cells that play critical roles in the pathogenesis of sepsis through producing large amount of pro-inflammatory cytokines and oxidants. In this study we examin...
Silica nanoparticles with iron on their surface (SiFeP) induce the production of oxidants and pro-inflammatory cytokines in epithelial cells. Crosstalk between the nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and NF-κB signaling was found in response to SiFeP exposure. However, little is known about the age-related change in interaction...
How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynt...
How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynt...
Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE...
Silica and iron are major constituents in ambient particulate matter, and iron is a common impurity in many engineered nanomaterials. The purpose of this work was to determine the pro-inflammatory and other biological effects and mechanism of particle size and iron presence under low dose, non-cytotoxic conditions that are likely to approximate act...
Silica nanoparticles with iron on their surface cause the production of oxidants and stimulate an inflammatory response in macrophages. Nuclear factor erythroid-derived 2 -like factor 2 (Nrf2) signaling and its regulated antioxidant genes play critical roles in maintaining redox homeostasis. In this study we investigated the regulation of four repr...
4-hydroxy-2-nonenal (HNE), a major non-saturated aldehyde product of lipid peroxidation, has been extensively studied as a signaling messenger. In these studies a wide range of HNE concentrations have been used, ranging from the unstressed plasma concentration to far beyond what would be found in actual pathophysiological condition. In addition, ac...
Studies have demonstrated that airborne nanoparticulate matter causes oxidative stress, inflammation, and induces an Nrf2-regulated adaptive response. However, the contribution of particulate components to these biologic effects and how Nrf2 signaling is activated need to be further clarified. In this study, we focused on silica and iron, two commo...
4-Hydroxy-2-nonenal (HNE), one of the major α, β-unsaturated aldehydes produced during lipid peroxidation, is a potent messenger in mediating signaling pathways. Lipid peroxidation and HNE production appear to increase with aging. Although the cause and effect relation remains arguable, aging is associated with significant changes in diverse signal...
Oxidation of critical signaling protein cysteines regulated by H2O2 has been considered to involve sulfenic acid (RSOH) formation. RSOH may subsequently form either a sulfenyl amide (RSNHR′) with a neighboring amide, or a mixed disulfide (RSSR′) with another protein cysteine or glutathione. Previous studies have claimed that RSOH can be detected as...
The balance of cellular antioxidant/inflammation shifts with aging, which results from increased pro‐inflammatory cytokines and inhibition of the Nrf2 pathway. Human small airway epithelial (SAE) cells were stimulated with lipopolysaccharide at 5 μg/ml and sulforaphane at 2 μM for 12 hours in vitro. The mRNA of cell inflammatory (NF‐κB‐dependent) a...
Increasing oxidative stress, a major characteristic of aging, has been implicated in variety of age-related pathologies. In aging, oxidant production from several sources is increased while antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins also declines. Impor...
Transforming growth factor-β1 (TGF-β) is involved in multiple cellular processes through Src activation. In the canonical pathway, Src activation is initiated by pTyr530 dephosphorylation followed by a conformational change allowing Tyr419 auto-phosphorylation. A non-canonical pathway in which oxidation of cysteine allows bypassing of pTyr530 depho...
Free Radical Biology and Medicine, 77 + (2014) 388-388. doi:10.1016/j.freeradbiomed.2014.09.022
Transforming growth factor-β (TGF-β1 is involved in multiple cellular processes including epithelial-mesenchymal transition (EMT), and many of them are mediated through activating Src kinase, a non-receptor tyrosine kinase. How TGF-β1activates Src remains largely unknown. In the classic pathway Src activation is initiated by dephosphorylation of pT...
Src is a critical enzyme involved in epithelial‐mesenchymal transition that contributes to metastasis and possibly fibrosis. Previous studies have demonstrated that oxidants are involved in Src activation by various stimuli. As glutathionylation of critical cysteine residues is an important mechanism of redox signaling, we studied the glutathionyla...
Although the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) regulated expression of multiple antioxidant and cytoprotective genes through the electrophile responsive element (EpRE) is well established, interaction of Nrf2/EpRE with Nrf1, a closely-related transcription factor, is less well understood. Due to either proteolysis or al...
3244
Introduction
The United States Armed Forces estimate that sickle cell trait (SCT) conveys a 30-fold risk of sudden cardiac death and a 200-fold risk of rhabdomyolysis following exertion in recruits during basic training. Catastrophic cardiovascular collapse in African Americans with SCT has been the leading cause of death in NCAA football pla...
Glutathione (GSH) is the most abundant antioxidant and a major detoxification agent in cells. It is synthesized through two-enzyme reaction catalyzed by glutamate cysteine ligase and glutathione synthetase, and its level is well regulated in response to redox change. Accumulating evidence suggests that GSH may play important roles in cell signaling...
Epithelial‐mesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, both associated with cigarette smoke (CS). CS, the major cause of lung cancer CS has been reported to promote EMT. Nonetheless, the mechanism whereby CS induces EMT remains largely unknown. We investigated the induction of EMT by CS and...
Many xenobiotic detoxifying (phase II) enzymes are induced by sublethal doses of environmental toxicants. However, these adaptive mechanisms have not been studied in response to vehicular-derived airborne nano-sized particulate matter (nPM). Because aging is associated with increased susceptibility to environmental toxicants, we also examined the e...
Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, two conditions associated with cigarette smoke (CS). CS has been reported to promote the EMT process. CS is the major cause of lung cancer and nearly half of lung cancer patients are active smokers. Nonetheless, the mechanism whereby CS...
The ability to adapt to acute oxidative stress (e.g. H(2)O(2), peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to in...
Multidrug-resistant protein-3 (MRP3), a membrane-bound transporter, facilitates efflux of toxic compounds, including certain chemotherapies, out of cells. Aberrant MRP3 expression has been linked to drug resistance in non-small cell lung carcinoma (NSCLC). We sought to determine if tumor MRP3 expression patterns correlate with the mutational status...
Resveratrol, a polyphenolic compound rich in grapes and red wine, has been reported to protect cells against oxidative damage and cell death by increasing cellular antioxidant/detoxification capacity. Cigarette smoking is a major risk factor for respiratory diseases and oxidative damage is implicated in its pathogenesis. Here we investigated the en...
The electrophile response element (EpRE) is essential for regulation of many genes involved in protection against toxic agents. Putative EpRE core sequences (TGAnnnnGC) are localized in 5'-flanking regions (5'-UTR) of these genes but specificity of the internal bases and whether location affects function has not been refined. The catalytic subunit...
gamma-Glutamyl transpeptidase (GGT) catalyzes the transfer of the glutamyl moiety from glutathione, and glutathione S-conjugates to acceptors to form another amide or to water to produce free glutamate. Functionally, GGT plays important roles in glutathione homeostasis and mercapturic acid metabolism. The expression of GGT is increased as an adapti...
Phase II enzymes are induced primarily through the common electrophile response element (EpRE) signaling. Studies performed in different cell types and with different inducer appear to indicate variation in the upstream signaling pathways involved in the induction of these phase II genes. Nonetheless, whether variation in signaling among phase II g...
Multidrug-resistant proteins (MRPs) are members of the ATP-binding cassette superfamily that facilitate detoxification by transporting toxic compounds, including chemotherapeutic drugs, out of cells. Chemotherapy, radiation, and other xenobiotic stresses have been shown to increase levels of select MRPs, although the underlying mechanism remains la...
Resveratrol has been shown to protect against oxidative stress through modulating antioxidant capacity. In this study, we investigated resveratrol-mediated induction of glutathione (GSH) and glutamate cysteine ligase (GCL), and the combined effect of resveratrol and 4-hydroxynonenal (HNE) on GSH synthesis in cultured HBE1 human bronchial epithelial...
This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSH and the sources...
During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactiv...
Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated...
Silica particle-associated inflammation is implicated in the genesis of several pulmonary diseases, including silicosis and lung cancer. In this study we investigated the role of phosphatidylcholine-specific phospholipase C (PC-PLC) in silica-stimulated induction of TNF-alpha and IL-1beta and how PC-PLC activity is regulated by silica in a rat alve...
4-Hydroxynonenal (HNE), a major electrophilic product of lipid peroxidation, is regarded as both a marker of oxidative stress and a mediator of oxidative damage. At subtoxic concentrations, however, this compound has been shown to be a signalling molecule that can induce the expression of various antioxidant/detoxification enzymes, including glutam...
The role of H2O2 as a second messenger in signal transduction pathways is well established. We show here that the NADPH oxidase-dependent production of O2*(-) and H2O2 or respiratory burst in alveolar macrophages (AM) (NR8383 cells) is required for ADP-stimulated c-Jun phosphorylation and the activation of JNK1/2, MKK4 (but not MKK7) and apoptosis...
Up-regulation of activity of gamma-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. In...
gamma-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNA V is controlled by promoter 5. Previously we found that GGT mRNA V-2 was responsible for the induction of GGT in rat...
Gamma-glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5'-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epi...
Glutathione (GSH) is the most abundant nonprotein thiol in cells and has multiple biological functions. Glutathione biosynthesis by way of the γ‐glutamyl cycle is important for maintaining GSH homeostasis and normal redox status. As the only enzyme of the cycle located on the outer surface of plasma membrane, γ‐glutamyl transpeptidase (GGT) plays k...
gamma-Glutamyl transpeptidase (GGT) plays key roles in the metabolism of glutathione. Previous studies have shown that GGT expression was increased by oxidants, but the mechanism remains unclear. In the present study, the effects of 4-hydroxy-2-nonenal (HNE), an electrophilic end product of lipid peroxidation, on GGT expression were investigated in...
Glutathione (GSH) is the most abundant nonprotein thiol in cells and has multiple biological functions. Glutathione biosynthesis by way of the gamma-glutamyl cycle is important for maintaining GSH homeostasis and normal redox status. As the only enzyme of the cycle located on the outer surface of plasma membrane, gamma-glutamyl transpeptidase (GGT)...
Glutathione (GSH) is the primary nonprotein thiol in the cell. It has many important roles in cell function, including regulating redox-dependent signal transduction pathways. The content of GSH within the cell varies with stress. In many cases, a process involving GSH synthesis results in adaptation to subsequent stressors. Sustained increases in...
Dietary use of curcumin, the active component of tumeric, one of the most widely used spices, is linked to several beneficial health effects, although the underlying molecular mechanisms remain largely unknown. Correlations have been established between curcumin exposure and increases in enzymes for glutathione synthesis, particularly glutamate-cys...
Glutathione is the most abundant non-protein thiol in the cell, with roles in cell cycle regulation, detoxification of xenobiotics, and maintaining the redox tone of the cell. The glutathione content is controlled at several levels, the most important being the rate of de novo synthesis, which is mediated by two enzymes, glutamate cysteine ligase (...
In A549 cell culture, significant variability was found in sensitivity to actinomycin D. Using limiting dilution, actinomycin D-susceptible (G4S) and -resistant (D3R) subclones were isolated. G4S cells were also susceptible to protein synthesis inhibitors, a redox cycling quinone, and an electrophile with concomitant activation of caspases 3 and 9....
Citations
... 10 In a second approach, we re-used the spectra of ferrihydrite and Fe(III) sulphate from Pattammattel et al ., which was measured with the same monochromator type as in this work, having similar line broadening. 32 Plots were done with Origin7 (OriginLab Corporation, Northampton, MA). Images were assembled with Affinity Designer [Serif (Europe) Ltd., 2020]. ...
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... The corpus callosum receives most axonal projections from layers 2, 3 and 5, while cortical layer 4 receives sensory inputs from subcortical structures and white matter regions. 22 We con rmed by histochemistry that elevated levels of degraded myelin basic protein (dMBP) were present in the corpus callosum 23 and demonstrated a similar increase in the external capsule following 8-week DEP exposure. We also showed reduction of MBP (healthy myelin) in both the corpus collosum and the internal capsule. ...
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... Previously white matter injury of the corpus callosum was reported in PM-exposed mice (Liu et al., 2021). By using IPA software analysis, we found that myelination signalling pathway is deregulated upon exposure in our study. ...
... While antioxidants have been studied in autoimmune diseases, 67-9 their effectiveness against reactive oxygen species is limited. 10 Hydrogen peroxide is a potent oxidising agent that is a byproduct of the mitochondrial electron transport chain. 11 Excess hydrogen peroxide levels in the cell trigger apoptosis. ...
... µM. The antifungal effect was found to be increased in a dosedependent manner and the chlorine atom possessed an important role in such activity according to the structureactivity relationship study (56). ...
... Unexpectedly the neurotoxicity of locally obtained nPM decreased after 2018 (Zhang et al., 2021). To obtain reliable responses of neurotoxicity, we have switched to DEP for rodent exposures which replicate most of our prior findings with nPM (Shkirkova et al., 2022). ...
... Reactive oxygen species (ROS), especially hydrogen peroxide (H 2 O 2 ) are recognized as associated with tumor metastasis [36][37][38]. TGF-β-related signaling promotes hydrogen peroxide production in several types of cells [39][40][41]. Simultaneously, H 2 O 2 enhances TGF-β-mediated EMT via SMAD and MEK/ERK signaling [42]. To determine if intracellular H 2 O 2 participate in the TGF-β1-related inhibition of cell migration, we first measured H 2 O 2 level in cells with LAE supplement for 48 hours. ...
... Nonetheless, the number of participants included in our work was adequately powered to detect the magnitude of difference in adipose 4HNE abundance observed between the groups, and it also closely matches that reported in other studies where the in-depth characterization of AT was performed [41][42][43]. Second, since the accumulation of HNE in some tissues increases with aging [44] and after hormonal changes (i.e., menopause) [45,46], one may argue that the older age and the menopausal status of the OBT2D patients might have also affected the results. On the other hand, in a multiple regression model (Table 2), the adipose cell size was the only variable that significantly predicted the adipose accumulation of 4-HNE, independent of age and sex (as confounding variables), suggesting that this molecule may well behave as a unique signature of "diabetic" fat, independent of ageing or menopause. ...
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... Glyoxylate and dicarboxylate metabolism bypass the TCA cycle, participate in energy metabolism, and are important in fungal infections [29]. Glutathione metabolism is involved in biological processes such as ferroptosis and antioxidation [30], and glutathione is a major antioxidant that maintains redox homeostasis, which is closely associated with in ammatory responses [31]. Steroid hormone biosynthesis and primary bile acid biosynthesis involved in pathogenesis of acute and chronic infections in mice [32]. ...
... Interestingly, our findings partially overlap with the transcriptomic data of Haghani et al (Haghani et al., 2020)., in which PM effects were analysed in mouse cortex. For example, we found mRNA of Ryr3, Sema6a and lgr5 to be upregulated in both studies, while expression of Slc13a3 and Suclg2 was inhibited upon exposure in both areas studied. ...
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