Whole-Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is characterized by slow, progressive bulbar and limb muscle weakness; however, the pattern of progression of muscle fat infiltration remains unclear. We assessed the progression of muscle involvement in 81 patients with SBMA using whole-body muscle magnetic resonance imaging (MRI), alongside clinical and laboratory findings. METHODS: This prospective study included patients with genetically confirmed SBMA who underwent whole-body muscle MRI. We analyzed muscle fat infiltration and the pattern of involved muscles using cluster analysis, visualizing the sequential progression of fat infiltration. Muscle clusters demonstrated correlation with clinical scales and laboratory findings. Additionally, linear regression analysis was performed to identify the MRI section most strongly associated with 6-minute walk test (6MWT). RESULTS: We included 81 patients with SBMA (age = 54.3 years). After categorizing the patients into 6 clusters based on the pattern of muscle fat infiltration, we observed that muscle involvement began in the posterior calf and progressed to the posterior thigh, pelvis, trunk, anterior thigh, medial thigh, anterior calf, and upper extremity muscles. These muscle clusters correlated significantly with disease duration (τ = 0.47, p < 0.001), 6MWT (τ = -0.49, p < 0.001), and serum creatinine level (τ = -0.46, p < 0.001). The whole-body MRI indicated the thigh as the section most significantly correlated with 6MWT. INTERPRETATION: We used whole-body muscle MRI to determine the sequential progression of the fat infiltration in SBMA. Our findings may enable the identification of objective and reliable imaging outcome measures in the study of the natural history or future clinical trials of SBMA. ANN NEUROL 2024;95:596-606.

Air pollution and survival in patients with malignant mesothelioma and asbestos-related lung cancer: a follow-up study of 1591 patients in South Korea.

BACKGROUND: Despite significant advancements in treatments such as surgery, radiotherapy, and chemotherapy, the survival rate for patients with asbestos-related cancers remains low. Numerous studies have provided evidence suggesting that air pollution induces oxidative stress and inflammation, affecting acute respiratory diseases, lung cancer, and overall mortality. However, because of the high case fatality rate, there is limited knowledge regarding the effects of air pollution exposures on survival following a diagnosis of asbestos-related cancers. This study aimed to determine the effect of air pollution on the survival of patients with malignant mesothelioma and asbestos-related lung cancer. METHODS: We followed up with 593 patients with malignant mesothelioma and 998 patients with lung cancer identified as asbestos victims between 2009 and 2022. Data on five air pollutants-sulfur dioxide, carbon monoxide, nitrogen dioxide, fine particulate matter with a diameter < 10 µm, and fine particulate matter with a diameter < 2.5 µm-were obtained from nationwide atmospheric monitoring stations. Cox proportional hazard models were used to estimate the association of cumulative air pollutant exposure with patient mortality, while adjusting for potential confounders. Quantile-based g-computation was used to assess the combined effect of the air pollutant mixture on mortality. RESULTS: The 1-, 3-, and 5-year survival rates for both cancer types decreased with increasing exposure to all air pollutants. The estimated hazard ratios rose significantly with a 1-standard deviation increase in each pollutant exposure level. A quartile increase in the pollutant mixture was associated with a 1.99-fold increase in the risk of malignant mesothelioma-related mortality (95% confidence interval: 1.62, 2.44). For lung cancer, a quartile increase in the pollutant mixture triggered a 1.87-fold increase in the mortality risk (95% confidence interval: 1.53, 2.30). CONCLUSION: These findings support the hypothesis that air pollution exposure after an asbestos-related cancer diagnosis can negatively affect patient survival.

Efficacy of leuprorelin in spinal and bulbar muscular atrophy: a 3-year observational study.

OBJECTIVE: This study aimed to investigate the long-term effects and functional outcomes of androgen suppression therapy using leuprorelin among Korean patients with spinal and bulbar muscular atrophy (SBMA). METHODS: This observational study enrolled patients with genetically confirmed SBMA who provided informed consent. Leuprorelin was administered via subcutaneous injection every 12 weeks. The primary outcome measure was the change in total Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) scores. RESULTS: A total of 48 SBMA patients were evaluated in this study. Among them, 39 patients underwent androgen suppression therapy over a 3-year period. The total SBMAFRS score decreased from 41.72 ± 5.55 to 36.74 ± 7.74 (p < 0.001) in patients who completed their treatment. The subgroup with a baseline SBMAFRS score of ≥ 42 had a significantly lower decline in SBMAFRS score than did those with a baseline SBMAFRS score of ≤ 41. We determined that at a baseline, SBMAFRS cutoff value of 41.5 could predict good prognosis, with a corresponding area under the curve of 0.689. CONCLUSION: Despite androgen suppression therapy, all enrolled participants exhibited a decrease in the overall SBMAFRS score. However, those with a baseline SBMAFRS of ≥ 42 showed a mild decrease in scores, indicating a more favorable prognosis. These findings suggest that a higher baseline motor function was a key prognostic indicator in SBMA treatment and that initiating early leuprorelin treatment in patients with high baseline function may lead to good clinical outcomes.

Neurofilament light chain as a biomarker in neuromyelitis optica spectrum disorder: a comprehensive review and integrated analysis with glial fibrillary acidic protein.

BACKGROUND: In the context of neuromyelitis optica spectrum disorder (NMOSD), there are several measures that serve as a biomarker. However, each of the methods has the intrinsic limitations. While neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have emerged as an additional biomarker for NMOSD, a thorough investigation of their role remains incomplete. Our aim is to provide a comprehensive review of the current literature regarding NfL and GFAP as a biomarker and explore their potential utility in NMOSD. METHODS: We performed a comprehensive search using PubMed and Google Scholar to identify peer-reviewed articles investigating NfL and GFAP as a biomarker in NMOSD. RESULTS: Our search identified 13 relevant studies. NfL consistently showed promise in distinguishing NMOSD patients from healthy individuals, although it had limited specificity in distinguishing NMOSD from other demyelinating diseases. NfL offered certain advantages over GFAP, notably its ability to predict disability worsening during attacks. In contrast, GFAP provided valuable insight, particularly in distinguishing NMOSD from multiple sclerosis and identifying clinical relapses. In addition, GFAP showed predictive potential for future attacks. Some studies even suggested that NfL may serve as an indicator of treatment response in NMOSD. CONCLUSIONS: NfL and GFAP hold promise as biomarkers for NMOSD, demonstrating their usefulness in distinguishing patients from healthy individuals, assessing disease severity, and possibly reflecting treatment response. However, it is important to recognize that NfL and GFAP may, at some point, have different roles.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Measurement device hacking-free mutual quantum identity authentication over a deployed optical fiber.

Quantum identity authentication serves as a crucial technology for secure quantum communication, but its security often faces challenges due to quantum hacking of measurement devices. This study introduces a measurement-device-independent mutual quantum identity authentication (MDI MQIA) scheme capable of ensuring secure user authentication, despite the use of measurement devices vulnerable to quantum hacking. To realize the MDI MQIA scheme, we proposed and applied a modified Bell state measurement based on linear optics, enabling the probabilistic measurement of all Bell states. Furthermore, the proposed experimental setup adopted a plug-and-play architecture, thus efficiently establishing the indistinguishability of two photons prepared by the communication members. Finally, we successfully performed a proof-of-principle experimental demonstration of the proposed scheme using a field-deployed fiber, achieving quantum bit error rates of less than 3%.

TCTP overexpression reverses age-associated telomere attrition by upregulating telomerase activity in mouse oocytes.

A prolonged time span between ovulation and fertilization can cause postovulatory aging of oocytes, which impairs oocyte quality and subsequent embryo development. Telomere attrition has long been considered as the primary hallmark of aging or the cause of age-associated diseases. However, the status of telomere and its regulation during postovulatory oocyte aging are poorly understood. Here we found that oocytes experience telomere shortening during postovulatory aging, although they have the capacity to maintain telomere length. However, translationally controlled tumor protein (TCTP) overexpression could reverse age-associated telomere shortening by upregulating telomerase activity in mouse oocytes. Telomere length in mature oocytes gradually decreased with postovulatory aging, which was associated with a marked reduction in TRF1 expression, decreased telomerase activity, and decreased homologous combination (HR)-based alternative lengthening of telomeres (ALT) with a concomitant increase in oxidative stress. Surprisingly, however, overexpression of TCTP led to a remarkable increase in telomere length during postovulatory aging. Notably, neither TRF1 nor BRCA1 level was altered by TCTP overexpression. Moreover, TCTP-mediated telomere lengthening was not blocked by HR inhibition. In striking contrast, telomerase activity, as well as TERT and TERC levels, increased after TCTP overexpression. Importantly, unlike the chromosome-wide distribution of endogenous TCTP, overexpressed TCTP was ectopically localized at telomeres, implying that TCTP overexpression is required to increase telomerase activity. Collectively, our results demonstrate that TCTP prevents telomere attrition during postovulatory aging by upregulating telomerase activity in mouse oocytes.

Pulmonary inflammation and cellular responses following exposure to benzalkonium chloride: Potential impact of disrupted pulmonary surfactant homeostasis.

Benzalkonium chloride (BKC) is a prototypical quaternary ammonium disinfectant. Previously, we suggested a no lethal dose level (0.005%) and an LD50 range (0.5-0.05%) of BKC following a single pharyngeal aspiration. Herein, we exposed BKC repeatedly by pharyngeal aspiration for 14 days (0.005 and 0.01%, female mice, total five times with interval of two days, 5 mice/group) and 28 days (0, 0.001, 0.005, and 0.01%, male and female mice, weekly, 16 mice/sex/group). Death following 14 days-repeated exposure did not occur. Meanwhile, chronic pathological lesions were observed in the lung tissues of mice exposed to BKC for 28 days. The total number of bronchial alveolar lavage cells increased, and pulmonary homeostasis of immunologic messenger molecules was disturbed. Following, we investigated BKC-induced cellular responses using human bronchial epithelial cells. The cytotoxicity increased rapidly with concentration. Lysosomal volume, NO production, and lipid peroxidation increased in BKC-treated cells, whereas intracellular ROS level decreased accompanying structural and functional damage of mitochondria. We also found that BKC affected the expression level of immune response, DNA damage, and amino acid biosynthesis-related molecules. More interestingly, lamellar body- and autophagosome-like structures were notably observed in cells exposed to BKC, and necrotic and apoptotic cell death were identified accompanying cell accumulation in the G2/M phase. Therefore, we suggest that repeated respiratory exposure of BKC causes pulmonary inflammation and lung tissue damage and that dead and damaged cells may contribute to the inflammatory response. In addition, the formation process of lamellar body-like structures may function as a key toxicity mechanism.

Finger Drop-Dominant Variant of Guillain-Barre Syndrome in a Patient With COVID-19: A Case Report.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that may trigger Guillain-Barre syndrome (GBS) in selected patients. We describe a case of GBS presenting as marked finger extensor weakness in a 73-year-old woman with COVID-19. Her clinical and electrophysiological findings were consistent with a diagnosis of acute motor axonal neuropathy subtype of GBS with prominent finger dropping. Treatment with intravenous immunoglobulin for 5 days completely resolved her finger extension weakness after 19 months, although other involved extremities recovered earlier at 3 months. This study highlights that COVID-19-associated GBS can present in various forms aside from the classic variant, even in patients without any COVID-19 symptoms. Therefore, it is important to always consider the diagnosis of GBS in patients with COVID-19.

Enhanced Spin Seebeck Thermopower in Pt/Holey MoS2/Y3Fe5O12 Hybrid Structure.

We first observed the spin-to-charge conversion due to both the inverse Rashba-Edelstein effect (IREE) and inverse spin-Hall effect in a holey multilayer molybdenum disulfide (MoS2) intermediate layer in a Pt/YIG structure via LSSE measurements under nonequilibrium magnetization. We found an enhancement of approximately 238%, 307%, and 290% in the longitudinal spin Seebeck effect (LSSE) voltage, spin-to-charge current, and thermoelectric (TE) power factor, respectively, compared with the monolayer MoS2 interlayer in a Pt/YIG structure. Such an enhancement in the LSSE performance of Pt/holey MoS2/YIG can be explained by the improvement of spin accumulation in the Pt layer by induced spin fluctuation as well as increased additional spin-to-charge conversion due to in-plane IREE. Our findings represent a significant achievement in the understanding of spin transport in atomically thin MoS2 interlayers and pave the way toward large-area TE energy-harvesting devices in two-dimensional transition metal dichalcogenide materials.

Newly Discovered Alleles of the Tomato Antiflorigen Gene SELF PRUNING Provide a Range of Plant Compactness and Yield.

In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato breeding for open field production. Heterozygous single flower truss (sft) mutants in the florigen SFT gene in the background of sp-classic provide a heterosis-like effect by delaying shoot termination, suggesting the subtle suppression of determinacy by genetic modification of the florigen-antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminated functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.

Detection of intracellular lamellar bodies as a screening marker for fibrotic lesions.

With the rapid increase in application of disinfectants worldwide as a method to block the spread of coronavirus, many new products are being introduced into the market without thorough verification of their impacts on human health and the environment. In the present study, we aimed to propose a screening marker for materials that can induce fibrotic lung disease using disinfectants, which had been demonstrated as causative materials of chronic inflammation and interstitial fibrosis. We first calculated the corresponding LC50 level based on results from cell viability test and exposed the LC50 level of disinfectants to human bronchial epithelial cells for 24 h. Formation of lamellar body-like structures, cleavage of the nuclear matrix, structural damage of mitochondria were found in the cytosol of the treated cells. We also dosed disinfectants by pharyngeal aspiration to mice to determine the LD0 level. The mice were sacrificed on Day 14 after a single dosing, and lamellar body-like structures were observed in the lung tissue of mice. Herein, we hypothesize that DNA damage and metabolic disturbance may play central roles in disinfectant-induced adverse health effects. Additionally, we propose that formation of lamellar bodies can be a screening marker for interstitial fibrosis.

Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response.

Due to the pandemic of coronavirus disease 2019, the use of disinfectants is rapidly increasing worldwide. Didecyldimethylammonium chloride (DDAC) is an EPA-registered disinfectant, it was also a component in humidifier disinfectants that had caused idiopathic pulmonary diseases in Korea. In this study, we identified the possible pulmonary toxic response and mechanism using human bronchial epithelial (BEAS-2B) cells and mice. First, cell viability decreased sharply at a 4 µg/mL of concentration. The volume of intracellular organelles and the ROS level reduced, leading to the formation of apoptotic bodies and an increase of the LDH release. Secretion of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and matrix metalloproteinase-1 also significantly increased. More importantly, lamellar body-like structures were formed in both the cells and mice exposed to DDAC, and the expression of both the indicator proteins for lamellar body (ABCA3 and Rab11a) and surfactant proteins (A, B, and D) was clearly enhanced. In addition, chronic fibrotic pulmonary lesions were notably observed in mice instilled twice (weekly) with DDAC (500 µg), ultimately resulting in death. Taken together, we suggest that disruption of pulmonary surfactant homeostasis may contribute to DDAC-induced cell death and subsequent pathophysiology and that the formation of lamellar body-like structures may play a role as the trigger. In addition, we propose that the cause of sudden death of mice exposed to DDAC should be clearly elucidated for the safe application of DDAC.

Analysis of the Position Recognition of the Bucket Tip According to the Motion Measurement Method of Excavator Boom, Stick and Bucket.

On modern construction sites, guidance and automation systems are increasingly applied to excavators. Recently, studies have been actively conducted to compare the estimation results of the bucket tip with the motion measurement method of the boom, stick, and bucket and the sensor selection. This study selected the method of measuring the cylinder length of boom, stick, and bucket, and the method of directly measuring the boom, arm, and bucket, which are commonly used in guidance and automation systems. A low-cost sensor that can be attached and detached to the excavator in modular form was selected to apply the above methods to commercial excavator. After the sensor selection, hardware and excavator simulation models for sensor measurements were constructed. Finally, the trajectory of the bucket tip was compared and analyzed through graphs and simulation results when the boom, stick, and bucket were independently rotated one by one, or together. The results gives a guideline on what kinds of sensors would be better in machine guidance or controlling an excavator according to given external environments.

Identification of Newly Emerging Influenza Viruses by Detecting the Virally Infected Cells Based on Surface Enhanced Raman Spectroscopy and Principal Component Analysis.

Rapid diagnosis and quarantine of influenza virus mutant-infected people is critical to contain the fatal viral infection spread because effective antiviral drugs are normally not available. Conventional methods, however, cannot be used for the diagnosis because these methods need predefined labels, likely also unavailable for just emerging viruses. Here, we propose label-free identification of cells infected with different influenza viruses based on surface-enhanced Raman spectroscopy (SERS) and principal component analysis (PCA). Viral envelope proteins that are displayed on the surface of cells after infection of influenza viruses were targeted for this identification. Cells that expressed the envelope proteins of A/WSN/33 H1N1 or A/California/04/2009 H1N1 influenza viruses produced distinct SERS signals. Cells that displayed combinations of the envelope proteins from these two viral variants, an indication of emergence of a new virus, also generated characteristic SERS patterns. However, the cell's own surface proteins often hindered the identification of virally infected cells by producing SERS peaks similar to viral ones. PCA of the obtained SERS patterns could effectively capture the virus-specific signal components from the jumbled SERS peaks. Our study demonstrates a potential of combination of SERS and PCA to identify newly emerging influenza viruses through sensing the cells infected with the viruses.

Photonic scheme of quantum phase estimation for quantum algorithms via cross-Kerr nonlinearities under decoherence effect.

Quantum phase estimation (QPE) is the key procedure in various quantum algorithms. The main aim of the QPE scheme is to estimate the phase of an unknown eigenvalue, corresponding to an eigenstate of an arbitrary unitary operation. The QPE scheme can be applied as a subroutine to design many quantum algorithms. In this paper, we propose the basic structure of a QPE scheme that could be applied in quantum algorithms, with feasibility by utilizing cross-Kerr nonlinearities (controlled-unitary gates) and linearly optical devices. Subsequently, we analyze the efficiency and the performance of the controlled-unitary gate. This gate consists of a controlled-path gate and a merging-path gate via cross-Kerr nonlinearities under the decoherence effect. Also shown in this paper is a method by which to enhance robustness against the decoherence effect to provide a reliable QPE scheme based on controlled-unitary gates.

Informationally symmetrical Bell state preparation and measurement.

Bell state measurement (BSM) plays crucial roles in photonic quantum information processing. The standard linear optical BSM is based on Hong-Ou-Mandel interference where two photons meet and interfere at a beamsplitter (BS). However, a generalized two-photon interference is not based on photon-photon interaction, but interference between two-photon probability amplitudes. Therefore, it might be possible to implement BSM without interfering photons at a BS. Here, we investigate a linear optical BSM scheme which does not require two photon overlapping at a BS. By unleashing the two photon coexistence condition, it can be symmetrically divided into two parties. The symmetrically dividable property suggests an informationally symmetrical BSM between remote parties without a third party. We also present that our BSM scheme can be used for Bell state preparation between remote parties without a third party. Since our BSM scheme can be easily extended to multiple photons, it can be useful for various quantum communication applications.

Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.

Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.