Investigation on the interaction mechanism during co-combustion of sewage sludge and coal slime: The effect of coal slime type and pretreatment method.

Co-combustion of sewage sludge (SS) and coal slime (CS) is the preferred method for mitigating their environmental impact and increasing their added value. However, the interaction mechanism between SS and CS during the co-combustion process has not yet developed a unified understanding. This work aims to obtain the effect of CS types on SS-CS co-combustion and reveal the interaction mechanism between SS and CS based on the influence of pretreatment methods on the interaction. The results showed that during co-combustion, SS reduced the ignition and burnout temperatures, and CS with high fixed carbon content (e.g., XCS) improved the comprehensive combustion characteristics. Principal component analysis showed that the effect of CS on co-combustion was more significant. The interaction between SS and CS mainly occurred within 100-700 °C, in which inhibition and synergism coexisted. The large differences in the interactions before and after de-volatilization and pickling treatments revealed that the volatiles and ash in SS were the main interaction factors. The analysis of the interaction mechanisms showed that the free radicals and heat released from the SS volatiles combustion accelerated the weight loss of CS, but the formation of tars from its incomplete combustion may inhibit the decomposition of CS. The interaction in the fixed carbon combustion stage was mainly caused by SS ash, which can catalyze the combustion of CS fixed carbon, but for the high ash CS (e.g., QCS), the combustion of fixed carbon was hindered by the addition of SS ash higher than 10 %. The final manifestation (synergy or inhibition) of SS and CS interactions was the result of the competitive balance of the above interactive behaviors. This work provides a more comprehensive understanding of the interaction between SS and CS during co-combustion.

A Fully Biodegradable Spherical Nucleic Acid Nanoplatform for Self-codelivery of Doxorubicin and miR122 for Innate and Adaptive Immunity Activation.

Facile construction of a fully biodegradable spherical nucleic acid (SNA) nanoplatform is highly desirable for clinical translations but remains rarely explored. We developed herein the first polycarbonate-based biodegradable SNA nanoplatform for self-codelivery of a chemotherapeutic drug, doxorubicin (DOX), and a human liver-specific miR122 for synergistic chemo-gene therapy of hepatocellular carcinoma (HCC). Ring-opening polymerization (ROP) of a carbonate monomer leads to a well-defined polycarbonate backbone for subsequent DOX conjugation to the pendant side chains via acidic pH-cleavage Schiff base links and miR122 incorporation to the chain termini via click coupling, affording an amphiphilic polycarbonate-DOX-miR122 conjugate, PBis-Mpa30-DOX-miR122 that can self-assemble into stabilized SNA. Besides the desired biodegradability, another notable merit of this nanoplatform is the use of miR122 not only for gene therapy but also for enhanced innate immune response. Together with the ICD-triggering effect of DOX, PBis-Mpa30-DOX-miR122 SNA-mediated DOX and miR122 codelivery leads to synergistic immunogenicity enhancement, resulting in tumor growth inhibition value (TGI) of 98.1% significantly higher than those of the groups treated with only drug or gene in a Hepa1-6-tumor-bearing mice model. Overall, this study develops a useful strategy toward biodegradable SNA construction, and presents a drug and gene-based self-codelivery SNA with synergistic immunogenicity enhancement for efficient HCC therapy. STATEMENT OF SIGNIFICANCE: Facile construction of a fully biodegradable SNA nanoplatform is useful for in vivo applications but remains relatively unexplored likely due to the synthetic challenge. We report herein construction of a polycarbonate-based SNA nanoplatform for co-delivering a chemotherapeutic drug, DOX, and a human liver-specific miR-122 for synergistic HCC treatment. In addition to the desired biodegradability properties, this SNA nanoplatform integrates DOX-triggered ICD and miR-122-enhanced innate immunity for simultaneously activating adaptive and innate immunities, which leads to potent antitumor efficiency with a TGI value of 98.1% in a Hepa1-6-tumor-bearing mice model.

Effects of different oxidants on the behaviour of microplastic hetero-aggregates.

Microplastic hetero-aggregates are stable forms of microplastics in the aqueous environment. However, when disinfecting water containing microplastic hetero-aggregates, the response of them in water to different oxidizing agents and the effect on water quality have not been reported. Our results showed that Ca(ClO)2, K2S2O8, and sodium percarbonate (SPC) treatment could lead to the disaggregation of microplastic hetero-aggregates as well as a rise in cell membrane permeability, which caused a large amount of organic matter to be released. When the amount of oxidant dosing is insufficient, the oxidant cannot completely degrade the released organic matter, resulting in DOC, DTN, DTP and other indicators being higher than before oxidation, thus causing secondary pollution of the water body. In comparison, K2FeO4 can purify the water body stably without destroying the microplastic hetero-aggregates, but it only weakly inhibits the toxic cyanobacteria Microcystis and Pseudanabaena, which may cause cyanobacterial bloom as well as algal toxin and odorant contamination in practical application. Compared with the other oxidizers, K2S2O8 provides better inhibition of toxic cyanobacteria and has better ecological safety. Therefore, when treating microplastic-containing water bodies, we should consider both water purification and ecological safety, and select appropriate oxidant types and dosages to optimize the water treatment.

Assessment of the Conformation Stability and Glycosylation Heterogeneity of Lactoferrin by Native Mass Spectrometry.

Lactoferrin (LTF) has diverse biological activities and is widely used in functional foods and active additives. Nevertheless, evaluating the proteoform heterogeneity, conformational stability, and activity of LTF remains challenging during its production and storage processes. In this study, we describe the implementation of native mass spectrometry (nMS), glycoproteomics, and an antimicrobial activity assay to assess the quality of LTF. We systematically characterize the purity, glycosylation heterogeneity, conformation, and thermal stability of LTF samples from different sources and transient high-temperature treatments by using nMS and glycoproteomics. Meanwhile, the nMS peak intensity and antimicrobial activity of LTF samples after heat treatment decreased significantly, and the two values were positively correlated. The nMS results provide essential molecular insights into the conformational stability and glycosylation heterogeneity of different LTF samples. Our results underscore the great potential of nMS for LTF quality control and activity evaluation in industrial production.

Mobile genetic elements mediate the cross-media transmission of antibiotic resistance genes from pig farms and their risks.

Manure composting in traditional small-scale pig farms leads to the migration and diffusion of antibiotics and antibiotics resistance genes (ARGs) along the chain of transmission to the surrounding environment, increasing the risk of environmental resistance. Understanding the transmission patterns, driving factors, and health risks of ARGs on small-scale pig farms is important for effective control of ARGs transmission. This study was conducted on a small pig farm and its surrounding environment. The cross-media transmission of ARGs and their risks in the farming habitat were investigated using Metagenomic annotation and qPCR quantitative detection. The results indicate that ARGs in farms spread with manure pile-soil-channel sediment-mudflat sediment. Pig farm manure contributed 22.49 % of the mudflat sediment ARGs. Mobile genetic elements mediate the spread of ARGs across different media. Among them, tnpA and IS26 have the highest degree. Transmission of high-risk ARGs sul1 and tetM resulted in a 50 % and 116 % increase in host risk for sediment, respectively. This study provides a basis for farm manure management and control of the ARGs spread.

Clinical characteristics of patients with migraine accompanied by tremor. / åå¤´ç—›ä¼´å‘éœ‡é¢¤æ‚£è€ çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Migraine and tremor share some genetic mutation sites, and clinical studies have also confirmed their correlation. This study aims to explore the clinical and electrophysiological characteristics of migraine patients with concomitant tremor, and to analyze the relevant influential factors of tremor occurrence. METHODS: We retrospectively analyzed the clinical data of 217 migraine patients who visited the Third Affiliated Hospital of Qiqihar Medical University from June 2022 to October 2023. The Clinical Rating Scale for Tremor (CRST), Numerical Rating Scale (NRS), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) were respectively used to assess the tremor symptoms, degree of headache, anxiety, and depression of patients. All patients underwent routine head MR scanning and electromyography examination, and were divided into a migraine with tremor group and a migraine without tremor group based on the electromyogram examination. RESULTS: The migraine with tremor group and the migraine without tremor group were included 52 patients (23.96%) and 165 patients (76.04%), respectively. Compared with the migraine without tremor group, the migraine with tremor group had a longer course and duration of headache, higher frequency of headache attacks, higher NRS score, GAD-7 score, and PHQ-9 score, and fewer weekly physical exercises. The differences were statistically significant (all P<0.05). There were no statistically significant differences in the presence or absence of prodromal headache and white matter hyperintensities (WMHs) between the 2 groups (both P>0.05). The evaluation results of the CRST showed that out of 217 migraine patients, 39 patients (17.97%) were accompanied by tremors. The electromyographic results showed that all 52 migraine patients with tremors had upper limb tremors, including 28 migraine patients with postural tremors and 24 migraine patients with static tremors. Compared with the migraine patients with static tremors, the migraine patients with postural tremors had lower average frequency, peak frequency, and headache onset frequency (all P<0.05). Multiple linear regression analysis showed that frequency of physical exercise, duration of illness, frequency of headache attacks, NRS score, GAD-7 score, and PHQ-9 score were risk factors for migraine patients with concomitant tremors (all P<0.05). CONCLUSIONS: Patients with migraine mainly experience upper limb postural tremors. Reduced physical exercise, long course of disease, long duration of headache, frequent headache attacks, severe headache, anxiety, and depression are risk factors for migraine patients with concomitant tremors.

In Vivo Tissue Distribution of Polystyrene or Mixed Polymer Microspheres and Metabolomic Analysis after Oral Exposure in Mice.

BACKGROUND: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. OBJECTIVES: This study aims to investigate the impacts of polymer microspheres on tissue metabolism in mice by assessing the microspheres ability to translocate across the gut barrier and enter into systemic circulation. Specifically, we wanted to examine microsphere accumulation in different organ systems, identify concentration-dependent metabolic changes, and evaluate the effects of mixed microsphere exposures on health outcomes. METHODS: To investigate the impact of ingested microspheres on target metabolic pathways, mice were exposed to either polystyrene (5µm) microspheres or a mixture of polymer microspheres consisting of polystyrene (5µm), polyethylene (1-4µm), and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid) (5µm). Exposures were performed twice a week for 4 weeks at a concentration of either 0, 2, or 4mg/week via oral gastric gavage. Tissues were collected to examine microsphere ingress and changes in metabolites. RESULTS: In mice that ingested microspheres, we detected polystyrene microspheres in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolic differences that occurred in the colon, liver, and brain, which showed differential responses that were dependent on concentration and type of microsphere exposure. DISCUSSION: This study uses a mouse model to provide critical insight into the potential health implications of the pervasive issue of plastic pollution. These findings demonstrate that orally consumed polystyrene or mixed polymer microspheres can accumulate in tissues such as the brain, liver, and kidney. Furthermore, this study highlights concentration-dependent and polymer type-specific metabolic changes in the colon, liver, and brain after plastic microsphere exposure. These results underline the mobility within and between biological tissues of MPs after exposure and emphasize the importance of understanding their metabolic impact. https://doi.org/10.1289/EHP13435.

SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms.

Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.

Facial adult female acne in China: An analysis based on artificial intelligence over one million.

BACKGROUND: To further clarify the acne profile of Chinese adult women, we included 1,156,703 adult women. An artificial intelligence algorithm was used to analyze images taken by high-resolution mobile phones to further explore acne levels in Chinese adult women. METHOD: In this study, we assessed the severity of acne by evaluating patients' selfies through a smartphone application. Furthermore, we gathered basic user information through a questionnaire, including details such as age, gender, skin sensitivity, and dietary habits. RESULTS: This study showed a gradual decrease in acne severity from the age of 25 years. A trough was reached between the ages of 40 and 44, followed by a gradual increase in acne severity. In terms of skin problems and acne severity, we have found that oily skin, hypersensitive skin, frequent makeup application and unhealthy dietary habits can affect the severity of acne. For environment and acne severity, we observed that developed city levels, cold seasons and high altitude and strong radiation affect acne severity in adult women. For the results of the AI analyses, the severity of blackheads, pores, dark circles and skin roughness were positively associated with acne severity in adult women. CONCLUSIONS: AI analysis of high-res phone images in Chinese adult women reveals acne severity trends. Severity decreases after 25, hits a low at 40-44, then gradually rises. Skin type, sensitivity, makeup, diet, urbanization, seasons, altitude, and radiation impact acne. Blackheads, pores, dark circles, and skin roughness are linked to acne severity. These findings inform personalized skincare and public health strategies for adult women.

A Multifunctional CaII-EuIII Heterometallic Organic Framework with Sensing and Selective Adsorption in Water.

With increasing global industrialization, it is urgent and challenging to develop multifunctional species for detection and adsorption in the environment. For this purpose, a novel anionic heterometallic organic framework, [(CH3)2NH2][CaEu(CAM)2(H2O)2]·4H2O·4DMF (CaEuCAM), is hydrothermally synthesized based on chelidamic acid (H3CAM). Single crystal analysis shows that CaEuCAM features two different oxygen-rich channels along the c-axis in which one CAM3- bridges two sextuple-coordinated Ca2+ and two octuple-coordinated Eu3+ with a µ4-η1: η1: η1: η1: η1: η1 new chelating and bridging mode. The characteristic bright red emission and superior hydrostability of CaEuCAM under harsh acidic and basic conditions benefit it by acting as a highly sensitive sensor for Fe3+ and 3-nitrophenol (3-NP) with extremely low LODs through remarkable quenching. The combination of experiments and theoretical calculations for sensing mechanisms shows that the competitive absorption and interaction are responsible for Fe3+-induced selective emission quenching, while that for 3-NP is the result of the synergism of host-guest chemistry and the inner filter effect. Meanwhile, the assimilation of negative charge plus channels renders CaEuCAM a highly selective adsorbent for methylene blue (MB) due to a synergy of electrostatic affinity, ion-dipole interaction, and size matching. Of note is the reusability of CaEuCAM toward Fe3+/3-NP sensing and MB adsorption besides its fast response. These findings could be very useful in guiding the development of multifunctional Ln-MOFs for sensing and adsorption applications in water media.

Short-Term Changes in Weight, Body Composition, and Metabolic Biomarkers After Laparoscopic Sleeve Gastrectomy in Patients with Obesity: A Comparative Prospective Study.

PURPOSE: To investigate the changes in weight, body composition, and metabolic biomarkers in patients with obesity after laparoscopic sleeve gastrectomy (LSG) and compare those changes between patients with and without metabolic syndrome (MS). MATERIALS AND METHODS: This retrospective longitudinal study included 76 patients who underwent LSG, among whom 32 had complete 1-year postoperative body composition and metabolic biomarkers. Body composition was measured by quantitative CT. Weight changes were compared between the MS and non-MS groups at 1-, 3-, 6-, and 12-month post-LSG in all patients; changes in body compositions and metabolic biomarkers from one day pre-LSG to 12-month post-LSG were also compared in those 32 patients. RESULTS: MS occurred in 46% (35/76) of all patients and 44% (14/32) of patients with complete follow-up data. Excess weight loss was lower in the MS group than that in the non-MS group at 1-, 3-, 6-, and 12-month post-LSG; the 12-month difference was significant (MS vs. non-MS: 0.91 ± 0.22 vs. 1.07 ± 0.42, P = 0.04). The greatest rate of visceral fat area (VFA) change occurred 12-month post-LSG in both the non-MS [0.62(0.55,0.7)] and MS [0.6(0.51,0.63)] groups. The most significant reduction in ectopic fat occurred in liver fat (LF) [non-MS, 0.45(0.22,0.58); MS, 0.39(0.23,0.58)]. CONCLUSION: LGS significantly improves weight, body composition, and metabolic biomarkers in populations with obesity, regardless of whether they have MS. Among the body composition, VFA and LF were the most significantly improved body composition measurements.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Unveiling the regulatory mechanisms of nodules development and quality formation in Panax notoginseng using multi-omics and MALDI-MSI.

INTRODUCTION: Renowned for its role in traditional Chinese medicine, Panax notoginseng exhibits healing properties including bidirectional regulatory effects on hematological system diseases. However, the presence of nodular structures near the top of the main root, known as nail heads, may impact the quality of the plant's valuable roots. OBJECTIVES: In this paper, we aim to systematically analyze nail heads to identify their potential correlation with P. notoginseng quality. Additionally, we will investigate the molecular mechanisms behind nail head development. METHODS: Morphological characteristics and anatomical features were analyzed to determine the biological properties of nail heads. Active component analysis and MALDI mass spectrometry imaging (MALDI-MSI) were performed to determine the correlation between nail heads and P. notoginseng quality. Phytohormone quantitation, MALDI-MSI, RNA-seq, and Arabidopsis transformation were conducted to elucidate the mechanisms of nail head formation. Finally, protein-nucleic acid and protein-protein interactions were investigated to construct a transcriptional regulatory network of nodule development and quality formation. RESULTS: Our analyses have revealed that nail heads originate from an undeveloped lateral root. The content of ginsenosides was found to be positively associated with the amount of nail heads. Ginsenoside Rb1 specifically accumulated in the cortex of nail heads, while IAA, tZR and JAs also showed highest accumulation in the nodule. RNA-seq analysis identified PnIAA14 and PnCYP735A1 as inhibitors of lateral root development. PnMYB31 and PnMYB78 were found to form binary complexes with PnbHLH31 to synergistically regulate the expression of PnIAA14, PnCYP735A1, PnSS, and PnFPS. CONCLUSION: Our study details the major biological properties of nodular structures in P. notoginseng and outlines their impact on the quality of the herb. It was also determined that PnMYB31- and PnMYB78-PnbHLH31 regulate phytohormones and ginsenosides accumulation, further affecting plant development and quality. This research provides insights for quality evaluation and clinical applications of P. notoginseng.

Quantification of the aromatase inhibitor letrozole and its carbinol metabolite in mouse plasma by UHPLC-MS/MS.

A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 µL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.

The association between PM2.5 components and blood pressure changes in late pregnancy: A combined analysis of traditional and machine learning models.

BACKGROUND: PM2.5 is a harmful mixture of various chemical components that pose a challenge in determining their individual and combined health effects due to multicollinearity issues with traditional linear regression models. This study aimed to develop an analytical methodology combining traditional and novel machine learning models to evaluate PM2.5's combined effects on blood pressure (BP) and identify the most toxic components. METHODS: We measured late-pregnancy BP of 1138 women from the Heshan cohort while simultaneously analyzing 31 PM2.5 components. We utilized multiple linear regression modeling to establish the relationship between PM2.5 components and late-pregnancy BP and applied Random Forest (RF) and generalized Weighted Quantile Sum (gWQS) regression to identify the most toxic components contributing to elevated BP and to quantitatively evaluate the cumulative effect of the PM2.5 component mixtures. RESULTS: The results revealed that 16 PM2.5 components, such as EC, OC, Ti, Fe, Mn, Cu, Cd, Mg, K, Pb, Se, Na+, K+, Cl-, NO3-, and F-, contributed to elevated systolic blood pressure (SBP), while 26 components, including two carbon components (EC, OC), fourteen metallics (Ti, Fe, Mn, Cr, Mo, Co, Cu, Zn, Cd, Na, Mg, Al, K, Pb), one metalloid (Se), and nine water-soluble ions (Na+, K+, Mg2+, Ca2+, NH4+, Cl-, NO3-, SO42-, F-), contributed to elevated diastolic blood pressure (DBP). Mn and Cr were the most toxic components for elevated SBP and DBP, respectively, as analyzed by RF and gWQS models and verified against each other. Exposure to PM2.5 component mixtures increased SBP by 1.04 mmHg (95% CI: 0.33-1.76) and DBP by 1.13 mmHg (95% CI: 0.47-1.78). CONCLUSIONS: Our study highlights the effectiveness of combining traditional and novel models as an analytical strategy to quantify the health effects of PM2.5 constituent mixtures.

Label-free and portable detection of HIV-DNA by a handheld luminometer.

BACKGROUND: The human immunodeficiency virus (HIV) remains a major worldwide health problem. Nowadays, many methods have been developed for quantitative detecting human immunodeficiency virus DNA (HIV-DNA), such as fluorescence and colorimetry. However, these methods still have the disadvantages of being expensive and requiring professional technicians. Early diagnosis of pathogens is increasingly dependent on portable instruments and simple point-of-care testing (POCT). Therefore, it is meaningful and necessary to develop portable and cheap methods for detecting disease markers. RESULTS: In this work, a label-free chemiluminescence (CL) method was developed for detecting HIV-DNA via a handheld luminometer. To achieve label-free target detection, the CL catalyst, G-triplex-hemin DNAzyme (G3-hemin DNAzyme), was in-situ assembled in the presence of HIV-DNA. For improving sensitivity, HIV-DNA induced the cyclic strand displacement reaction (SDR), which can form three G3-hemin DNAzymes in one cycle. So, the chemiluminescence reaction between luminol and H2O2 was highly effectively catalyzed, and the CL intensity was linearly related with the concentration of HIV-DNA in the range of 0.05-10 nM with a detection limit of 29.0 pM. Due to the high specificity of hairpin DNA, single-base mismatch can be discriminated, which ensured the specific detection of HIV-DNA. SIGNIFICANCE: In-situ formation of G3-hemin DNAzyme led to label-free and selective detection without complex synthesis and functionalization. Therefore, it offers a cheap, selective, sensitive and portable method for detecting disease-related genes, which is promising for POCT of clinical diagnosis in resource-limited settings.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis.

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

[Mechanism of traditional Chinese medicine in regulating NLRP3 inflammasomes to alleviate renal interstitial fibrosis in diabetic nephropathy: a review].

Diabetic nephropathy(DN), a progressive chronic kidney disease(CKD) induced by diabetes mellitus, is the main cause of end-stage renal disease. Renal interstitial fibrosis(RIF) is an irreversible factor in the progression and deterioration of the renal function in DN. Chronic inflammation has become a key link in the pathogenesis of DN-RIF. The NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome is an important inflammatory regulator regulated by a variety of signals. It promotes the production of pro-inflammatory cytokines and induces renal inflammatory cell infiltration to participate in the process of renal fibrosis, demonstrating a complex mechanism of action. In view of the important role of NLRP3 inflammasomes in the prevention and treatment of DN-RIF, a large number of experimental studies have demonstrated that traditional Chinese medicine(TCM) can reduce the inflammation by regulating the pathways involving NLRP3 inflammasome, thereby slowing down the progression of DN-RIF and improving the renal function. This paper reviews the relationship between NLRP3 inflammasomes and DN-RIF, and the research progress in the mechanism of TCM intervention in NLRP3 inflammasomes to alleviate DN-RIF, aiming to provide new ideas for the targeted treatment of DN-RIF.

Downregulation of ABLIM3 confers to the metastasis of neuroblastoma via regulating the cell adhesion molecules pathway.

Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.

Pegbelfermin for reducing transaminase levels in patients with non-alcoholic steatohepatitis: a dose-response meta-analysis of randomized controlled trials.

Background: The efficacy of Pegbelfermin (PGBF) in treating non-alcoholic steatohepatitis (NASH) remains controversial. Therefore, we conducted a dose-response meta-analysis to explore the effect and pattern of PGBF at different dosages and treatment durations on transaminase reduction in NASH patients. Methods: We conducted searches on PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, and supplemented the search with gray literature and manual searches. Randomized controlled trials (RCTs) evaluating the efficacy of PGBF in NASH patients were included. Risk of bias was assessed by Cochrane Risk of Bias Tool 2.0. We used random-effects models, generalized least squares regression, constrained maximum likelihood, and restricted cubic splines to explore the dose-response relationship. Egger's linear regression was employed to assess publication bias. The study is registered with PROSPERO, CRD42023448024. Results: Four RCT studies from the period 2018-2023, involving 546 participants, were included. No participants discontinued PGBF treatment due to adverse events. High-dose PGBF treatment significantly reduced transaminase levels in NASH patients compared to the low-dose group (ALT %: MD = 14.94, 95% CI = 2.11-27.77; AST %: MD = 9.05, 95% CI = 3.17-14.92). Longer treatment duration further decreased transaminase levels (ALT%: MD = 8.81, 95% CI = 4.07-13.56; AST%: MD = 6.72, 95% CI = 2.62-10.81). Egger's test did not reveal significant publication bias (p > 0.05). Further investigation indicated a ceiling effect of PGBF dosage on transaminase reduction at 30 mg/week, and NASH patients experienced a rebound in transaminase levels after 28 weeks of continuous treatment. Conclusion: There is a positive correlation between PGBF dosage and transaminase reduction within a certain range, showing an overall non-linear dose-response relationship. This finding provides guidance for the clinical application of PGBF. Clinicians should be mindful of the dosage ceiling at 30 mg/week and monitor changes in transaminase levels after 28 weeks for timely adjustments in PGBF dosage. Systematic review registration: PROSPERO, CRD42023448024. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=448024.