Melatonin ameliorates multiorgan injuries induced by severe acute pancreatitis in mice by regulating the Nrf2 signaling pathway.

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.

Reversible encephalitis-like episodes in fragile X-associated tremor/ataxia syndrome: a case report.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

Intelligent cholinergic white matter pathways algorithm based on U-net reflects cognitive impairment in patients with silent cerebrovascular disease.

BACKGROUND AND OBJECTIVE: The injury of the cholinergic white matter pathway underlies cognition decline in patients with silent cerebrovascular disease (SCD) with white matter hyperintensities (WMH) of vascular origin. However, the evaluation of the cholinergic white matter pathway is complex with poor consistency. We established an intelligent algorithm to evaluate WMH in the cholinergic pathway. METHODS: Patients with SCD with WMH of vascular origin were enrolled. The Cholinergic Pathways Hyperintensities Scale (CHIPS) was used to measure cholinergic white matter pathway impairment. The intelligent algorithm used a deep learning model based on convolutional neural networks to achieve WMH segmentation and CHIPS scoring. The diagnostic value of the intelligent algorithm for moderate-to-severe cholinergic pathway injury was calculated. The correlation between the WMH in the cholinergic pathway and cognitive function was analysed. RESULTS: A number of 464 patients with SCD were enrolled in internal training and test set. The algorithm was validated using data from an external cohort comprising 100 patients with SCD. The sensitivity, specificity and area under the curve of the intelligent algorithm to assess moderate and severe cholinergic white matter pathway injury were 91.7%, 87.3%, 0.903 (95% CI 0.861 to 0.952) and 86.5%, 81.3%, 0.868 (95% CI 0.819 to 0.921) for the internal test set and external validation set. for the. The general cognitive function, execution function and attention showed significant differences among the three groups of different CHIPS score (all p<0.05). DISCUSSION: We have established the first intelligent algorithm to evaluate the cholinergic white matter pathway with good accuracy compared with the gold standard. It helps more easily assess the cognitive function in patients with SCD.

Murine skeletal muscle satellite cells isolation and preliminary study on regulation in immune microenvironment during nurse cells formation of Trichinella spiralis infection.

As an intracellular parasitic nematode, Trichinella spiralis (T. spiralis) can induce the formation of nurse cells (NC) in host muscles and keep it to survive within the NC for an extended period. The formation of NC is similar to muscle cell injury and repair which lead to the arrest of satellite cells in the G2/M phase and build a suitable parasitic environment for the muscle larvae of T. spiralis. However, the molecular mechanisms involved in skeletal muscle repair through skeletal muscle satellite cells (SMSC) and the host immune response during T. spiralis infection have not been fully elucidated. In this study, histopathological examination revealed that the severity of damage increased as the infection progressed in the soleus muscle. SMSCs were isolated from BALB/c mice infected with T. spiralis at 4, 21 and 35 days post-infection (dpi). The immunological characteristics of these cells were analyzed by real-time PCR and flow cytometry (FCM). FCM analysis revealed a notable increase in the expression of B7 homolog 1 (B7-H1) in SMSCs following T. spiralis infection, while conversely, the expression of inducible costimulatory ligand (ICOSL) significantly decreased. Furthermore, real-time PCR results showed that toll like receptor 3 (TLR3) expression in SMSCs of the infected mice was upregulated at 21 dpi. The expression levels of three subtypes (PPARα, PPARß and PPARγ) of peroxisome proliferator-activated receptors (PPARs) also increased in the cells. This study highlights the immunological regulation significance of SMSCs host during T. spiralis infection and suggests that SMSCs actively participant in the local immune response to T. spiralis by regulating the interaction between the parasite and the host.

Case Report: Thrombus aspiration and in situ thrombolysis via a Guidezilla guide extension catheter in a patient with high-risk pulmonary embolism.

Standard catheter-directed thrombolysis (CDT) and thrombus aspiration are considered potentially promising approaches for reopening the embolism-related pulmonary artery in patients with pulmonary embolism (PE) with high thrombotic burden and deteriorating hemodynamics, especially in those for whom systemic thrombolysis is contraindicated or has failed. However, the constrained accessibility of dedicated catheters has impeded the potential benefits of standard CDT in developing countries. The Guidezilla guide extension catheter (GEC) with a larger diameter and extended length is widely used in challenging coronary anatomy. Nevertheless, there have been few reports on the application of the Guidezilla GEC as a novel option for patients with massive PE when dedicated catheters and surgical thrombectomy are not available. In this case report, we demonstrated that thrombus aspiration and in situ thrombolysis through the Guidezilla GEC are applicable to patients with PE in whom systemic thrombolysis is contraindicated, resulting in successful reperfusion and positive clinical outcomes.

[Spatial Distribution Characteristics of PM2.5 and O3 in Beijing-Tianjin-Hebei Region Based on Time Series Decomposition].

Notably, clear spatial differences occur in the distribution of air pollution among cities in the Beijing-Tianjin-Hebei (BTH) Region. Clarifying the concentration distribution of PM2.5 and O3 at different time scales is helpful to formulate scientific and effective pollution prevention and control measures. Here, the concentrations of PM2.5 and O3 were decomposed using a seasonal-trend decomposition procedure based on the loess (STL) method; their long-term, seasonal, and short-term components were obtained; and their temporal and spatial distribution characteristics were studied. The results showed that the decrease in PM2.5 concentration in the BTH Region from 2017 to 2021 was higher than that of O3. There was a positive correlation between PM2.5 and O3 concentrations in spring and summer and a negative correlation in autumn and winter. The short-term component and seasonal component had the greatest contribution to PM2.5 and O3 concentrations, respectively. There were two principal components in the seasonal and short-term components of PM2.5 and the long-term and short-term components of O3, corresponding to the central and southern part of Hebei Province and the northern part of the BTH Region. Sub-regional distribution of PM2.5 and O3 in the BTH Region at different time scales were found. Compared with that in the original series, the long-term component could better reflect the evolution trend of PM2.5 and O3 concentrations, and the standard deviation (SD) of the seasonal component and short-term component could be used to measure the fluctuation in PM2.5 and O3 concentrations in various cities. The SD of the seasonal and short-term components of the PM2.5 concentration in every city in front of Taihang Mountain was higher, and the SD of the short-term component of the O3 concentration in Tangshan was the highest.

[Source and Cause Analysis of High Concentration of Inorganic Aerosol During Two Typical Pollution Processes in Winter over Tianjin].

Inorganic aerosol is the main component of haze days in winter over Tianjin. In this study, two typical high concentrations of secondary inorganic aerosol (SIA) processes, defined as CASE1 and CASE2, were selected during polluted days in January 2020 over Tianjin, and the effects of meteorological factors, regional transport, and chemical processes were comprehensively investigated combined with observations and numerical models (WRF-NAQPMS). The average SIA concentrations in CASE1 and CASE2 were 76.8 µg·m-3 and 66.0 µg·m-3, respectively, and the nitrate concentration was higher than that of sulfate and ammonium, which were typical nitrate-dominated pollution processes. Meteorological conditions played a role in inorganic aerosol formation. The temperature of approximately -6-0℃ and 2-4℃ and the relative humidity of 50%-60% and 80%-100% would be suitable conditions for the high SIA concentration (>80 µg·m-3) in CASE1, whereas the temperature of approximately 2-4℃ and the relative humidity of 60%-70% would be suitable in CASE2. The average contribution rates of external sources to SIA in the CASE1 and CASE2 processes were 62.3% and 22.1%, which were regional transport-dominant processes and local emission-dominant processes, respectively. The contribution of the local emission of CASE1 to nitrate and sulfate was 16.2 µg·m-3 and 8.2 µg·m-3, respectively, higher than that of external sources (31.7 µg·m-3 and 8.8 µg·m-3). the local contribution of CASE2 to nitrate and sulfate was 29.3 µg·m-3 and 25.1 µg·m-3, respectively, whereas the contribution from external sources was 8.1 µg·m-3 and 9.4 µg·m-3, respectively. The quantitative result indicated that local formation and regional transport resulted in higher nitrate concentration than sulfate in CASE1, in contrast to only local sources in CASE2. The gas phase reaction was the main source of inorganic aerosol formation, contributing 48.9% and 57.8% in CASE1 and CASE2, respectively, whereas the heterogeneous reactions were also important processes, with contribution rates of 48.1% and 42.2% to SIA. The effect of aqueous phase reaction was negligible.

Promiscuous Oxidosqualene Cyclases from Neoalsomitra integrifoliola Catalyzing the Formation of Tetracyclic, Pentacyclic, and Heterocyclic Triterpenes.

Six oxidosqualene cyclases (NiOSC1-NiOSC6) from Neoalsomitra integrifoliola were characterized for the biosynthesis of diverse triterpene scaffolds, including tetracyclic and pentacyclic triterpenes from the 2,3-oxidosqualene (1) and oxacyclic triterpenes from the 2,3:22,23-dioxidosqualene (2). NiOSC1 showed high efficiency in the production of naturally rare (20R)-epimers of oxacyclic triterpenes. Mutagenesis results revealed that the NiOSC1-F731G mutant significantly increased the yields of (20R)-epimers compared to the wild type. Homology modeling and molecular docking elucidated the origin of the (20R)-configuration in the epoxide addition step.

Effects of exogenous riboflavin or cytochrome addition on the cathodic reduction of Cr(VI) in microbial fuel cell with Shewanella putrefaciens.

Bioreduction of Cr(VI) is recognized as a cost-effective and environmentally friendly method, attracting widespread interest. However, the slow rate of Cr(VI) bioreduction remains a practical challenge. Additionally, the direct removal efficiency of microbes for high concentrations of Cr(VI) is not ideal due to the toxicity. Therefore, this study investigated the effects of exogenous riboflavin or cytochrome on the cathodic reduction of Cr(VI) in microbial fuel cells. The results demonstrated that the exogenous riboflavin or cytochrome effectively improved the voltage output of the cells, with riboflavin increasing the voltage by 52.08%. Within the first 24 h, the Cr(VI) removal ratio in the normal, cytochrome, and riboflavin groups was 14.3%, 29.3%, and 53.8%, respectively. And the final removal ratio was 55.1%, 69.1%, and 98.0%, respectively. These results showed different enhancement effects of riboflavin and cytochrome on Cr(VI) removal. The analysis of riboflavin and cytochrome contents revealed that the additions did not have a significant impact on the autocrine riboflavin of S. putrefaciens, but affected the autocrine cytochrome. SEM, XPS, and FTIR results confirmed the presence of reduced Cr(III) on the cathode, which formed precipitate and adhered to the cathode surface. The EDS analysis showed that the amount of Cr on the cathode in normal, cytochrome, and riboflavin groups was 4.71%, 6.37%, 7.56%, respectively, which was consistent with the voltage and Cr(VI) removal data. These findings demonstrated the significant enhancement of exogenous riboflavin or cytochrome on Cr(VI) reduction, thereby providing data reference for the future bio-assisted remediation of Cr(VI) pollution.

Aging increases the particulate- and leachate-induced toxicity of tire wear particles to microalgae.

The toxic effects of tire wear particles (TWPs) on organisms have attracted widespread concerns over the past decade. However, the underlying toxicity mechanism of TWPs, especially aged TWPs to marine microalgae remains poorly understood. This study investigated the physiological and metabolic responses of Phaeodactylum tricornutum to different concentrations of TWPs (Experiment 1), virgin and differently aged TWPs (Experiment 2) as well as their leachates and leached particles (Experiment 3). Results demonstrated that TWPs promoted the growth of microalgae at low concentrations (0.6 and 3 mg L-1) and inhibited their growth at high concentrations (15 and 75 mg L-1). Moreover, aged TWPs induced more profound physiological effects on microalgae than virgin TWPs, including inhibiting microalgae growth, decreasing the content of Chla, promoting photosynthetic efficiency, and causing oxidative damage to algal cells. Untargeted metabolomics analysis confirmed that aged TWPs induced more pronounced metabolic changes than virgin TWPs. This study represented the first to demonstrate that both particulate- and leachate-induced toxicity of TWPs was increased after aging processes, which was confirmed by the changes in the surface morphology of TWPs and enhanced release of additives. Through the significant correlations between the additives and the microalgal metabolites, key additives responsible for the shift of microalgal metabolites were identified. These results broaden the understanding of the toxicity mechanism of aged TWPs to microalgae at the physiological and metabolic levels and appeal for considering the effects of long-term aging on TWP toxicity in risk assessment of TWPs.

Pregnancy and neonatal outcomes in 25 pregnant women diagnosed with new-onset acute myeloid leukemia during pregnancy.

PURPOSE: The aim was to analyze the pregnancy and neonatal outcomes of pregnant women with new- onset acute myeloid leukemia (AML) diagnosed during pregnancy. METHODS: In this retrospective study 25 pregnant women who were diagnosed with new-onset AML during pregnancy from January 2010 to January 2021 were enrolled. RESULTS: A total of 4, 13 and 8 pregnant women with new-onset AML were diagnosed during the first, second, and third trimesters, respectively. Twelve of the 25 pregnant women underwent therapeutic abortion and 13 gave birth (9 preterm and 4 full-term newborns). The gestational age at initial clinical manifestations (13.4 ± 3.7 vs. 27.7 ± 5.6 weeks, P < 0.01) and diagnosis (16.9 ± 4.4 vs. 29.7 ± 5.5 weeks, P < 0.01) was lower in the pregnant women who underwent therapeutic abortion than in those who gave birth. Eighty-four percent (21/25) of the pregnant women with new-onset AML during pregnancy survived and were in remission and all the newborns were born alive. Three of the 13 newborns were exposed to chemotherapy, but no congenital malformations were observed. Eight newborns were admitted to the neonatal intensive care unit (NICU), and all recovered. The complete blood counts and biochemical examinations of the 8 newborns were normal. CONCLUSIONS: New-onset AML during an earlier stage of pregnancy may increase the risk of poor pregnancy outcomes. The neonatal outcomes of pregnant women with new-onset AML during pregnancy are good with proper treatment.

Influence of microplastics on the availability of antibiotics in soils.

Microplastics (MPs) and antibiotics, as two major types of emerging pollutants, inevitably coexist in the soil environment due to agricultural film residue, sewage irrigation and sludge application. However, the impact of MPs on antibiotic availability in soils with varying characteristics has not been extensively studied. Therefore, in this study, an interference experiment was conducted using three types of MPs (polyethylene (PE), polyvinyl chloride (PVC) and polypropylene (PP)) in red soil, paddy soil and cinnamon soil. The available antibiotics in soils were evaluated using diffusive gradients in thin-films (DGT). Results showed that MPs had a significant impact on the amount of antibiotics adsorbed on soil solid (Cs) by providing additional binding sites or altering soil characteristics (e.g., pH and dissolved organic carbon). The most significant effects on Cs were observed in cinnamon soil, and the Cs values were dependent on concentration of MPs. The available antibiotics, as measured by DGT significantly decreased after the addition of MPs. This decrease was influenced by the soil characteristics. However, the concentration of antibiotics in soil solutions (Cd) was only slightly impacted by MPs. Therefore, the influence of MPs on the migration of antibiotics was reflected by their impact on the soil/water partition coefficient (Kd), while the resupply ability (R) from the soil solid phase was less influential. Moreover, the dosage of MPs had a significant effect on the availability of antibiotics in CS by promoting the adsorption of antibiotics on the solid phase, while in RS and PS, the soil properties played a dominate role in the changes in antibiotic availability after MP addition. These results indicate that the impact of MPs on available antibiotics mainly depends on soil properties. In addition, DGT measurement is more sensitive than soil solution to investigate the effects of coexisting pollutants on the behavior of antibiotics in soil.

Chinese herbal medicine Ginkgo biloba L. preparations for ischemic stroke: An overview of systematic reviews and meta-analyses.

BACKGROUND: Ginkgo biloba L. preparations (GBLPs) are a class of Chinese herbal medicine used in the adjuvant treatment of ischemic stroke (IS). Recently, several systematic reviews (SRs) and meta-analyses (MAs) of GBLPs for IS have been published. OBJECTIVE: This overview aims to assess the quality of related SRs and MAs. SEARCH STRATEGY: PubMed, Embase, Cochrane Library, Web of Science, Chinese Biological Medicine, China National Knowledge Infrastructure, Wanfang, and Chinese Science and Technology Journals databases were searched from their inception to December 31, 2022. INCLUSION CRITERIA: SRs and MAs of randomized controlled trials (RCTs) that explored the efficacy of GBLPs for patients with IS were included. DATA EXTRACTION AND ANALYSIS: Two independent reviewers extracted data and assessed the methodological quality, risk of bias (ROB), reporting quality, and credibility of evidence of the included SRs and MAs using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), Risk of Bias in Systematic Reviews (ROBIS), the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. Additionally, descriptive analysis and data synthesis were conducted. RESULTS: Twenty-nine SRs/MAs involving 119 outcomes were included in this review. The overall methodological quality of all SRs/MAs was critically low based on AMSTAR 2, and 28 had a high ROB based on the ROBIS. According to the PRISMA statement, the reporting items of the included SRs/MAs are relatively complete. The results based on GRADE showed that of the 119 outcomes, 8 were rated as moderate quality, 24 as low quality, and 87 as very low quality. Based on the data synthesis, GBLPs used in conjunction with conventional treatment were superior to conventional treatment alone for decreasing neurological function scores. CONCLUSION: GBLPs can be considered a beneficial supplemental therapy for IS. However, because of the low quality of the existing evidence, high-quality RCTs and SRs/MAs are warranted to further evaluate the benefits of GBLPs for treating IS. Please cite this article as: Meng TT, You YP, Li M, Guo JB, Song XB, Ding JY, Xie XL, Li AQ, Li SJ, Yin XJ, Wang P, Wang Z, Wang BL, He QY. Chinese herbal medicine Ginkgo biloba L. preparations for ischemic stroke: An overview of systematic reviews and meta-analyses. J Integr Med. 2024;22(2): 163-179.

Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.

Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.

Diagnostic value of serum COMP and ADAMTS7 for intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is a major cause of morbidity and disability. Our study aimed to investigate the potential of cartilage oligomeric matrix protein (COMP) and ADAMTS7 (A disintegrin and metalloproteinases with thrombospondin motifs 7) as biomarkers for IVDD together with their functional relationship. METHODS: IVD tissues and peripheral blood samples were collected from IVDD rabbit models over 1-4 weeks. Tissues and blood samples were also collected from clinical patients those were stratified into four equal groups according to Pfirrmann IVDD grading (I-V) with baseline data collected for each participant. COMP and ADAMTS7 expression were analyzed and biomarker characteristics were assessed using linear regression and receiver operating curve (ROC) analyses. RESULTS: COMP and ADAMTS7 expression increased in tissues and serum during IVDD progression. Serum COMP (sCOMP) and serum ADAMTS7 (sADAMTS7) levels increased in a time-dependent manner following IVD damage in the rabbit model while significant positive correlations were detected between sCOMP and sADAMTS7 and Pfirrmann grade in human subjects. ROC analysis showed that combining sCOMP and sADAMTS7 assay results produced an improved diagnostic measure for IVDD compared to individual sCOMP or sADAMTS7 tests. In vitro assays conducted on human cell isolates revealed that COMP prevented extracellular matrix degradation and antagonized ADAMTS7 expression although this protective role was uncoupled under microenvironmental conditions mimicking IVDD. CONCLUSIONS: Increases in circulating COMP and ADAMTS7 correlate with IVDD progression and may play regulatory roles. Assays for sCOMP and/or sADAMTS7 levels can discriminate between healthy subjects and IVDD patients, warranting further clinical assessment.

Strong suppression of silver nanoparticles on antibiotic resistome in anammox process.

This study comprehensively deciphered the effect of silver nanoparticles (AgNPs) on anammox flocculent sludge, including nitrogen removal performance, microbial community structure, functional enzyme abundance, antibiotic resistance gene (ARGs) dissemination, and horizontal gene transfer (HGT) mechanisms. After long-term exposure to 0-2.5 mg/L AgNPs for 200 cycles, anammox performance significantly decreased (P < 0.05), while the relative abundances of dominant Ca. Kuenenia and anammox-related enzymes (hzsA, nirK) increased compared to the control (P < 0.05). For antibiotic resistome, ARG abundance hardly changed with 0-0.5 mg/L AgNPs but decreased by approximately 90% with 1.5-2.5 mg/L AgNPs. More importantly, AgNPs effectively inhibited MGE-mediated HGT of ARGs. Additionally, structural equation model (SEM) disclosed the underlying relationship between AgNPs, the antibiotic resistome, and the microbial community. Overall, AgNPs suppressed the anammox-driven nitrogen cycle, regulated the microbial community, and prevented the spread of ARGs in anammox flocs. This study provides a theoretical baseline for an advanced understanding of the ecological roles of nanoparticles and resistance elements in engineered ecosystems.

Sludge dewaterability improvement with microbial fuel cell powered electro-Fenton system (MFCⓠEFs): Performance and mechanisms.

Throughout the entire process of sludge treatment and disposal, it is crucial to explore stable and efficient techniques to improve sludge dewaterability, which can facilitate subsequent resource utilization and space and cost savings. Traditional Fenton oxidation has been widely researched to enhance the performance of sludge dewaterability, which was limited by the additional energy input and the instabilities of Fe2+ and H2O2. To reduce the consumption of energy and chemicals and further break the rate-limiting step of the iron cycle, a novel and feasible method that constructed microbial fuel cell powered electro-Fenton systems (MFCⓅEFs) with ferrite and biochar electrode (MgFe2O4@BC/CF) was successfully demonstrated. The MFCⓅEFs with MgFe2O4@BC/CF electrode achieved specific resistance filtration and sludge cake water content of 2.52 × 1012 m/kg and 66.54 %. Cellular structure and extracellular polymeric substances (EPS) were disrupted, releasing partially bound water and destroying hydrophilic structures to facilitate sludge flocs aggregation, which was attributed to the oxidation of hydroxyl radicals. The consistent electron supply supplied by MFCⓅEFs and catalytically active sites on the surface of the multifunctional functional group electrode was responsible for producing more hydroxyl radicals and possessing a better oxidizing ability. The study provided an innovative process for sludge dewaterability improvement with high efficiency and low energy consumption, which presented new insights into the green treatment of sludge.

Layer-polarized ferromagnetism in rhombohedral multilayer graphene.

Flat-band systems with strongly correlated electrons can exhibit a variety of phenomena, such as correlated insulating and topological states, unconventional superconductivity, and ferromagnetism. Rhombohedral multilayer graphene has recently emerged as a promising platform for investigating exotic quantum states due to its hosting of topologically protected surface flat bands at low energy, which have a layer-dependent energy dispersion. However, the complex relationship between the surface flat bands and the highly dispersive high-energy bands makes it difficult to study correlated surface states. In this study, we introduce moiré superlattices as a method to isolate the surface flat bands of rhombohedral multilayer graphene. The observed pronounced screening effects in the moiré potential-modulated rhombohedral multilayer graphene indicate that the two surface states are electronically decoupled. The flat bands that are isolated promote correlated surface states in areas that are distant from the charge neutrality points. Notably, we observe tunable layer-polarized ferromagnetism, which is evidenced by a hysteretic anomalous Hall effect. This is achieved by polarizing the surface states with finite displacement fields.

Alisol B regulates AMPK/mTOR/SREBPs via directly targeting VDAC1 to alleviate hyperlipidemia.

BACKGROUND: The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma, has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. PURPOSE: To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. STUDY DESIGN: HepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro. METHODS: Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1). RESULTS: ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. CONCLUSION: Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.

Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).