Methanol-involved heterogeneous transformation of ginsenoside Rb1 to rare ginsenosides using heteropolyacids embedded in mesoporous silica with HPLC-MS investigation.

Background: The biological activity and pharmacological effects of rare ginsenosides have been proven to be superior to those of the major ginsenosides, but they are rarely found in ginseng. Methods: Ginsenoside Rb1 was chemically transformed with the involvement of methanol molecules by a synthesized heterogeneous catalyst 12-HPW@MeSi, which was obtained by the immobilization of 12-phosphotungstic acid on a mesoporous silica framework. High-performance liquid chromatography coupled with mass spectrometry was used to identify the transformation products. Results: A total of 18 transformation products were obtained and identified. Methanol was found to be involved in the formation of 8 products formed by the addition of methanol molecules to the C-24 (25), C-20 (21) or C-20 (22) double bonds of the aglycone. The transformation pathways of ginsenoside Rb1 involved deglycosylation, addition, elimination, cycloaddition, and epimerization reactions. These pathways could be elucidated in terms of the stability of the generated carbenium ion. In addition, 12-HPW@MeSi was able to maintain a 60.5% conversion rate of Rb1 after 5 cycles. Conclusion: Tandem and high-resolution mass spectrometry analysis allowed rapid and accurate identification of the transformation products through the characteristic fragment ions and neutral loss. Rare ginsenosides with methoxyl groups grafted at the C-25 and C-20 positions were obtained for the first time by chemical transformation using the composite catalyst 12-HPW@MeSi, which also enabled cyclic heterogeneous transformation and facile centrifugal separation of ginsenosides. This work provides an efficient and recyclable strategy for the preparation of rare ginsenosides with the involvement of organic molecules.

EFFICACY OF INTRAVENOUS IMMUNOGLOBULIN ALONE ON CORONARY ARTERY LESION REDUCTION IN KAWASAKI DISEASE.

Background: Though Aspirin and intravenous immunoglobulin (IVIG) remain the standard treatments for Kawasaki Disease (KD) to minimize coronary artery damage, the duration and dosage of aspirin are inconsistent across hospitals. However, the lack of multi-center randomized trials prevents definitive answers to the impact of high-dose aspirin. Methods: This clinical trial was structured as a prospective, evaluator-blinded, multi-center randomized controlled trial with two parallel arms, aiming to assess the effectiveness of IVIG as a standalone primary therapy of KD in comparison to the combination of IVIG with high-dose aspirin therapy. KD patients were enrolled between September, 2016 and August, 2019. A final cohort of 134 patients were randomly assigned to the standard and test groups with 69 and 65 patients, respectively. The Standard group received IVIG (2 g/kg) along with aspirin (80-100 mg/kg/day) until fever subsided for 48 hours. The test group received IVIG (2 g/kg) alone. Following the initial treatment, both groups received a daily aspirin dose (3-5 mg/kg) for six weeks. The primary outcome measure was the occurrence of coronary artery lesions (CAL) at the 6-8 weeks mark. The secondary outcome is IVIG resistance. Results: The overall rate of CAL in test group decreased from 10.8% at diagnosis to 1.5% and 3.1% at 6 weeks and 6 months, respectively. The CAL rate of standard group declined from 13.0% to 2.9% and 1.4%, with no statistically significant difference (P>0.1) in the frequency of CAL between the two groups. Furthermore, no statistically significant differences were found for treatment (P>0.1) and prevention (P>0.1) effect between the two groups. Conclusions: This marks the first prospective multi-center randomized controlled trial comparing the standard treatment of KD using IVIG plus high-dose aspirin against IVIG alone. Our analysis indicates that addition of high-dose aspirin during initial IVIG treatment is neither statistically significant nor clinically meaningful for CAL reduction. Registration: URL: http://www.clinicaltrials.gov ; identifier: NCT02951234. What is New?: This study represents the first multi-center randomized controlled trial investigating the efficacy of high-dose aspirin or intravenous immunoglobulin (IVIG) during the acute stage of KD. This study assessed the impact of discontinuing high-dose aspirin (80-100 mg/kg/day) on the occurrence of CAL during the acute phase treatment of Kawasaki Disease.No significant differences were observed between high-dose aspirin plus IVIG treatment and IVIG alone treatment in terms of the frequency of abnormal coronary artery abnormalities. Additionally, our analysis revealed no statistically significant differences in either the treatment effect (the number of cases successfully treated) or prevention effect (the prevention of new cases) between these two treatments. What Are the Clinical Implications?: Comparison analysis indicated the non-inferiority between two groups with or without high-dose aspirin.Administering the standard 2 g/kg/day IVIG without high-dose aspirin (80-100 mg/kg/day) during the acute phase therapy for KD does not increase the risk of coronary artery lesions, which are a primary cause of morbidity and mortality in KD patients.Addition of high-dose aspirin during initial IVIG treatment is not statistically significant or clinically meaningful.

Generative Artificial Intelligence for Designing Multi-Scale Hydrogen Fuel Cell Catalyst Layer Nanostructures.

Multiscale design of catalyst layers (CLs) is important to advancing hydrogen electrochemical conversion devices toward commercialized deployment, which has nevertheless been greatly hampered by the complex interplay among multiscale CL components, high synthesis cost and vast design space. We lack rational design and optimization techniques that can accurately reflect the nanostructure-performance relationship and cost-effectively search the design space. Here, we fill this gap with a deep generative artificial intelligence (AI) framework, GLIDER, that integrates recent generative AI, data-driven surrogate techniques and collective intelligence to efficiently search the optimal CL nanostructures driven by their electrochemical performance. GLIDER achieves realistic multiscale CL digital generation by leveraging the dimensionality-reduction ability of quantized vector-variational autoencoder. The powerful generative capability of GLIDER allows the efficient search of the optimal design parameters for the Pt-carbon-ionomer nanostructures of CLs. We also demonstrate that GLIDER is transferable to other fuel cell electrode microstructure generation, e.g., fibrous gas diffusion layers and solid oxide fuel cell anode. GLIDER is of potential as a digital tool for the design and optimization of broad electrochemical energy devices.

Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses.

BACKGROUND: After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs. RESULTS: Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

Excess multi-cause mortality linked to influenza virus infection in China, 2012-2021: a population-based study.

Objectives: The aim of this study is to estimate the excess mortality burden of influenza virus infection in China from 2012 to 2021, with a concurrent analysis of its associated disease manifestations. Methods: Laboratory surveillance data on influenza, relevant population demographics, and mortality records, including cause of death data in China, spanning the years 2012 to 2021, were incorporated into a comprehensive analysis. A negative binomial regression model was utilized to calculate the excess mortality rate associated with influenza, taking into consideration factors such as year, subtype, and cause of death. Results: There was no evidence to indicate a correlation between malignant neoplasms and any subtype of influenza, despite the examination of the effect of influenza on the mortality burden of eight diseases. A total of 327,520 samples testing positive for influenza virus were isolated between 2012 and 2021, with a significant decrease in the positivity rate observed during the periods of 2012-2013 and 2019-2020. China experienced an average annual influenza-associated excess deaths of 201721.78 and an average annual excess mortality rate of 14.53 per 100,000 people during the research period. Among the causes of mortality that were examined, respiratory and circulatory diseases (R&C) accounted for the most significant proportion (58.50%). Fatalities attributed to respiratory and circulatory diseases exhibited discernible temporal patterns, whereas deaths attributable to other causes were dispersed over the course of the year. Conclusion: Theoretically, the contribution of these disease types to excess influenza-related fatalities can serve as a foundation for early warning and targeted influenza surveillance. Additionally, it is possible to assess the costs of prevention and control measures and the public health repercussions of epidemics with greater precision.

Biotransformation of Ginsenoside Rb1 to Ginsenoside Rd and 7 Rare Ginsenosides Using Irpex lacteus with HPLC-HRMS/MS Identification.

The biotransformation of ginsenosides using microorganisms represents a promising and ecofriendly approach for the production of rare ginsenosides. The present study reports on the biotransformation of ginsenoside Rb1 using the fungus Irpex lacteus, resulting in the production of ginsenoside Rd and seven rare ginsenosides with novel structures. Employing high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry, the identities of the transformation products were rapidly determined. Two sets of isomers with molecular weights of 980.56 and 962.55 were discovered among the seven rare ginsenosides, which were generated through the isomerization of the olefin chain in the protopanaxadiol (PPD)-type ginsenoside skeleton. Each isomer exhibited characteristic fragment ions and neutral loss patterns in their tandem mass spectra, providing evidence of their unique structures. Time-course experiments demonstrated that the transformation reaction reached equilibrium after 14 days, with Rb1 initially generating Rd and compound 5, followed by the formation of other rare ginsenosides. The biotransformation process catalyzed by I. lacteus was found to involve not only the typical deglycosylation reaction at the C-20 position but also hydroxylation at the C-22 and C-23 positions, as well as hydrogenation, transfer, and cyclization of the double bond at the C-24(25) position. These enzymatic capabilities extend to the structural modification of other PPD-type ginsenosides such as Rc and Rd, revealing the potential of I. lacteus for the production of a wider range of rare ginsenosides. The transformation activities observed in I. lacteus are unprecedented among fungal biotransformations of ginsenosides. This study highlights the application of a medicinal fungi-based biotransformation strategy for the generation of rare ginsenosides with enhanced structural diversity, thereby expanding the variety of bioactive compounds derived from ginseng.

Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma.

OBJECTIVE: Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown. DESIGN: The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment. RESULTS: FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+ T cells, resulting in the inhibition of CD8+ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment. CONCLUSION: Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.

MicroRNA-195-5p Attenuates Intracerebral-Hemorrhage-Induced Brain Damage by Inhibiting MMP-9/MMP-2 Expression.

Intracerebral hemorrhage (ICH) remains a devastating disease with high mortality, and there is a lack of effective strategies to improve functional outcomes. The primary injury of ICH is mechanical damage to brain tissue caused by the hematoma. Secondary injury, resulting from inflammation, red cell lysis, and thrombin production, presents a potential target for therapeutic intervention. Inflammation, crucial in secondary brain injury, involves both cellular and molecular components. MicroRNAs (miRNAs) are vital regulators of cell growth, differentiation, and apoptosis. Their deregulation may lead to diseases, and modulating miRNA expression has shown therapeutic potential, especially in cancer. Recent studies have implicated miRNAs in the pathogenesis of stroke, affecting endothelial dysfunction, neurovascular integrity, edema, apoptosis, inflammation, and extracellular matrix remodeling. Preclinical and human studies support the use of miRNA-directed gene modulation as a therapeutic strategy for ICH. Our study focused on the effects of miR-195 in ICH models. Neurological tests, including the corner turn and grip tests, indicated that miR-195 treatment led to improvements in motor function impairments caused by ICH. Furthermore, miR-195-5p significantly reduced brain edema in the ipsilateral hemisphere and restored blood-brain barrier (BBB) integrity, as shown by reduced Evans blue dye extravasation. These results suggest miR-195-5p's potential in attenuating ICH-induced apoptosis, possibly related to its influence on MMP-9 and MMP-2 expression, enzymes associated with secondary brain injury. The anti-apoptotic effects of miR-195-5p, demonstrated through TUNEL assays, further underscore its therapeutic promise in addressing the secondary brain injury and apoptosis associated with ICH. In conclusion, miR-195-5p demonstrates a significant neuroprotective effect against ICH-induced neural damage, brain edema, and BBB disruption, primarily through the downregulation of MMP-9 and MMP-2. Our findings indicate that miR-195-5p holds therapeutic potential in managing cerebral cell death following ICH.

Insurance Disparities in Quality of Care Among Patients With Head and Neck Cancer.

Importance: Significant insurance status disparities have been demonstrated in head and neck cancer (HNC) outcomes. The effects of insurance status on HNC outcomes may be explained by differential access to high-quality care. Objective: To evaluate the association of insurance status with the quality of the treating hospital and receipt of guideline-compliant care among patients with HNC. Design, Setting, and Participants: This retrospective cohort study of data from the California Cancer Registry dataset linked with discharge records and hospital characteristics from the California Department of Health Care Access and Information included adult patients with HNC diagnosed between January 1, 2010, and December 31, 2019. Data were analyzed from May 10, 2023, to March 25, 2024. Exposures: Insurance status: commercial, Medicare, Medicaid, uninsured, other, or unknown. Main Outcomes and Measures: Quality of the treating hospital (tertiles), receipt of National Comprehensive Cancer Network guideline-compliant care, and overall survival. Results: A total of 23 933 patients (mean [SD] age, 64.8 [12.3] years; 75.3% male) met the inclusion criteria. Treatment in top-tertile hospitals (hazard ratio, 0.87; 95% CI, 0.79-0.95) was associated with improved overall survival compared with treatment in bottom-tertile hospitals. Medicare (odds ratio [OR], 0.78; 95% CI, 0.73-0.84), Medicaid (OR, 0.60; 95% CI, 0.54-0.66), and uninsured (OR, 0.38; 95% CI, 0.29-0.49) status were associated with lower likelihood of treatment in high-quality hospitals compared with commercial insurance. Among patients with advanced disease, Medicaid (OR, 0.72; 95% CI, 0.62-0.83) and uninsured (OR, 0.64; 95% CI, 0.44-0.93) patients were less likely to receive dual-modality therapy. Among patients with surgically resected advanced disease, Medicaid coverage (OR, 0.73; 95% CI, 0.58-0.93) was associated with lower likelihood of receiving adjuvant radiotherapy. Conclusions and Relevance: This study found significant insurance disparities in quality of care among patients with HNC. These findings highlight the need for continued health insurance reform in the US to improve the quality of insurance coverage, in addition to expanding access to health insurance.

Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial.

Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms. Design, Setting, and Participants: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration. Interventions: Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days. Main Outcomes and Measures: Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline. Results: Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade. Conclusions and Relevance: The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC. Trial Registration: ClinicalTrials.gov Identifier: NCT05576662.

Advancing presurgical non-invasive molecular subgroup prediction in medulloblastoma using artificial intelligence and MRI signatures.

Global investigation of medulloblastoma has been hindered by the widespread inaccessibility of molecular subgroup testing and paucity of data. To bridge this gap, we established an international molecularly characterized database encompassing 934 medulloblastoma patients from thirteen centers across China and the United States. We demonstrate how image-based machine learning strategies have the potential to create an alternative pathway for non-invasive, presurgical, and low-cost molecular subgroup prediction in the clinical management of medulloblastoma. Our robust validation strategies-including cross-validation, external validation, and consecutive validation-demonstrate the model's efficacy as a generalizable molecular diagnosis classifier. The detailed analysis of MRI characteristics replenishes the understanding of medulloblastoma through a nuanced radiographic lens. Additionally, comparisons between East Asia and North America subsets highlight critical management implications. We made this comprehensive dataset, which includes MRI signatures, clinicopathological features, treatment variables, and survival data, publicly available to advance global medulloblastoma research.

Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease.

OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024.

Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.

Inhibitor of apoptosis stimulating protein of p53 protects against MPP+-induced neurotoxicity of dopaminergic neurons.

Inhibitor of apoptosis stimulating protein of p53 (iASPP) is related to the pathogenesis of several neurological disorders by affecting the oxidative stress and survival of neurons. However, whether iASPP has a role in Parkinson disease (PD) remains to be determined. This work explored the potential regulatory effect of iASPP in an in vitro model of PD based on 1-methyl-4-phenylpyridinium (MPP+)-evoked neurotoxicity of dopaminergic neurons in culture. MN9D neurons were treated with MPP+ at 200 µM in the culture media for 24 h to induce neurotoxicity. Overexpression and silencing of iASPP in neurons were achieved by infecting recombinant adenovirus expressing iASPP and sh-iASPP, respectively. Protein expression was examined by immunoblotting. MPP+-evoked neurotoxicity of dopaminergic neurons was determined by cell viability, TUNEL, and flow cytometric assays. The transcriptional activity of nuclear erythroid factor 2-like 2 (Nrf2) was assessed by luciferase reporter assay. Kelch-like ECH-associated protein 1 (Keap1)-knockout neurons were generated by lentiCRISPR/Cas9-Keap1 constructs. Expression levels of iASPP declined in MPP+-stimulated neurons. Overexpression of iASPP in neurons exhibited inhibitory effects on MPP+-evoked apoptosis, α-synuclein accumulation, and oxidative stress, while iASPP-deficient neurons were more sensitive to MPP+-induced neurotoxicity. Overexpression of iASPP led to an enhancing effect on Nrf2 activation in MPP+-stimulated neurons. Mechanism research revealed that iASPP may contribute to the activation of Nrf2 by competing with Nrf2 in binding with Keap1. Notably, the regulatory effect of iASPP on Nrf2 was diminished in Keap1-knockout neurons. The chemical inhibition of Nrf2 or knockdown of Nrf2 abrogated the protective effects of iASPP on MPP+-induced neurotoxicity. To conclude, iASPP protects dopaminergic neurons against MPP+-induced neurotoxicity through modulation of the Keap1/Nrf2 axis. Therefore, iASPP may play a crucial role in mediating the loss of dopaminergic neurons in PD, and targeting the iASPP-Nrf2 axis could be a promising strategy for treating PD.

Interplay among extracellular vesicles, cancer stemness and immune regulation in driving hepatocellular carcinoma progression.

The intricate interplay among extracellular vesicles, cancer stemness properties, and the immune system significantly impacts hepatocellular carcinoma (HCC) progression, treatment response, and patient prognosis. Extracellular vesicles (EVs), which are membrane-bound structures, play a pivotal role in conveying proteins, lipids, and nucleic acids between cells, thereby serving as essential mediators of intercellular communication. Since a lot of current research focuses on small extracellular vesicles (sEVs), with diameters ranging from 30 nm to 200 nm, this review emphasizes the role of sEVs in the context of interactions between HCC stemness-bearing cells and the immune cells. sEVs offer promising opportunities for the clinical application of innovative diagnostic and prognostic biomarkers in HCC. By specifically targeting sEVs, novel therapeutics aimed at cancer stemness can be developed. Ongoing investigations into the roles of sEVs in cancer stemness and immune regulation in HCC will broaden our understanding and ultimately pave the way for groundbreaking therapeutic interventions.

Regression models for average hazard.

Limitations of using the traditional Cox's hazard ratio for summarizing the magnitude of the treatment effect on time-to-event outcomes have been widely discussed, and alternative measures that do not have such limitations are gaining attention. One of the alternative methods recently proposed, in a simple 2-sample comparison setting, uses the average hazard with survival weight (AH), which can be interpreted as the general censoring-free person-time incidence rate on a given time window. In this paper, we propose a new regression analysis approach for the AH with a truncation time τ. We investigate 3 versions of AH regression analysis, assuming (1) independent censoring, (2) group-specific censoring, and (3) covariate-dependent censoring. The proposed AH regression methods are closely related to robust Poisson regression. While the new approach needs to require a truncation time τ explicitly, it can be more robust than Poisson regression in the presence of censoring. With the AH regression approach, one can summarize the between-group treatment difference in both absolute difference and relative terms, adjusting for covariates that are associated with the outcome. This property will increase the likelihood that the treatment effect magnitude is correctly interpreted. The AH regression approach can be a useful alternative to the traditional Cox's hazard ratio approach for estimating and reporting the magnitude of the treatment effect on time-to-event outcomes.

Microglial gp91phox-mediated neuroinflammation and ferroptosis contributes to learning and memory deficits in rotenone-treated mice.

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2, and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention.

Coal-based carbon nanosheets contained carbon microfibers modified with grown carbon nanotubes as efficient air electrode material for rechargeable zinc-air batteries.

Coal-based oxygen electrocatalysts hold immense promise for cost-effective applications in rechargeable Zn-air batteries (ZABs) and the value-added, clean utilization of traditional coal resources. Herein, an electrospun membrane electrode comprising coal-derived carbon nanosheets and directly grown carbon nanotubes (CNS/CMF@CNT) was successfully synthesized. The hierarchical porous structure of the electrode, composed of multiple components, significantly facilitates mass and ion transportation, resulting in exceptional electrochemical performance. Employing Fe as the catalyst for CNT growth, the CNS/CMF@CNT electrode exhibits a remarkable onset potential of 0.96 V and a half-wave potential of 0.87 V in the oxygen reduction reaction (ORR). In-situ surface-enhanced Raman spectroscopy reveals that hydroxyl radical desorption on the surface of CNS/CMF@CNT(Fe) is the rate-determining step of the ORR. Notably, the aqueous ZAB featuring the CNS/CMF@CNT(Fe) electrode achieved a peak power density of 216.0 mW cm-2 at a current density of 414 mA cm-2 and maintained a voltage efficiency of 65.1 % after 2000 charge/discharge cycles at 5 mA cm-2. Furthermore, the all-solid-state ZAB incorporating this electrode displayed an open-circuit voltage of 1.43 V, a peak power density of 70.1 mW cm-2 at a current density of 110 mA cm-2, and a voltage efficiency of 66.5 % after 150 charge/discharge cycles. The utilization of abundant coal as the raw material for electrode fabrication not only brings conceivable economic benefits in ZAB construction, but also commendably advances the effective application of traditional coal resources in a more sustainable manner.

Interpretable baseflow segmentation and prediction based on numerical experiments and deep learning.

Baseflow is a crucial water source in the inland river basins of high-cold mountainous region, playing a significant role in maintaining runoff stability. It is challenging to select the most suitable baseflow separation method in data-scarce high-cold mountainous region and to evaluate effects of climate factors and underlying surface changes on baseflow variability and seasonal distribution characteristics. Here we attempt to address how meteorological factors and underlying surface changes affect baseflow using the Grey Wolf Optimizer Digital Filter Method (GWO-DFM) for rapid baseflow separation and the Long Short-Term Memory (LSTM) neural network model for baseflow prediction, clarifying interpretability of the LSTM model in baseflow forecasting. The proposed method was successfully implemented using a 63-year time series (1958-2020) of flow data from the Tai Lan River (TLR) basin in the high-cold mountainous region, along with 21 years of ERA5-land meteorological data and MODIS data (2000-2020). The results indicate that: (1) GWO-DFM can rapidly identify the optimal filtering parameters. It employs the arithmetic average of three methods, namely Chapman, Chapman-Maxwell and Eckhardt filter, as the best baseflow separation approach for the TLR basin. Additionally, the baseflow significantly increases after the second mutation of the baseflow rate. (2) Baseflow sources are mainly influenced by precipitation infiltration, glacier frozen soil layers, and seasonal ponding. (3) Solar radiation, temperature, precipitation, and NDVI are the primary factors influencing baseflow changes, with Nash-Sutcliffe efficiency coefficients exceeding 0.78 in both the LSTM model training and prediction periods. (4) Changes in baseflow are most influenced by solar radiation, temperature, and NDVI. This study systematically analyzes the changes in baseflow and response mechanisms in high-cold mountainous region, contributing to the management of water resources in mountainous basins under changing environmental conditions.