Metabolomics and proteomics reveal the inhibitory effect of Lactobacillus crispatus on cervical cancer.

Cervical cancer remains a significant global health issue due to its high morbidity and mortality rates. Recently, Lactobacillus crispatus has been recognized for its crucial role in maintaining cervical health. While some studies have explored the use of L. crispatus to mitigate cervical cancer, the underlying mechanisms remain largely unknown. In this study, we employed non-targeted proteomics and metabolomics to investigate how L. crispatus affects the growth of cervical cancer cells (SiHa) and normal cervical cells (Ect1/E6E7). Our findings indicated that the inhibitory effect of L. crispatus on SiHa cells was associated with various biological processes, notably the ferroptosis pathway. Specifically, L. crispatus was found to regulate the expression of proteins such as HMOX1, SLC39A14, VDAC2, ACSL4, and LPCAT3 by SiHa cells, which are closely related to ferroptosis. Additionally, it activated the tricarboxylic acid (TCA) cycle in SiHa cells, leading to increased levels of reactive oxygen species (ROS) and lipid peroxides (LPO). These results revealed the therapeutic potential of L. crispatus in targeting the ferroptosis pathway for cervical cancer treatment, opening new avenues for research and therapy in cervical cancer.

Intermediate bands and p-orbital tuning of the band structure of BiFeO3 for photovoltaic application.

BiFeO3 is a lead-free inorganic ferroelectric material that holds promise for photovoltaic applications. However, its larger band gap poses a challenge for efficient sunlight absorption, limiting its efficiency in such applications. In this work, nitrogen, which has lower electronegativity compared to oxygen, was selected to tune the band gap of BiFeO3. It was discovered that the band gap of BiFeO3-xNx (x = 0.125, 0.25, 0.375, and 0.5) was reduced from the original value of 3.1 eV for the parent phase to 1.45-1.77 eV, which originated from the intermediate bands caused by the stronger interaction between Fe 3d and N 2p and the valence band maximum shifted towards higher energy levels caused by the introduction of N 2p. In particular, the band gaps of 1.45 and 1.49 eV for BiFeO2.75N0.25 and BiFeO2.625N0.375, respectively, were closer to the optimal band gap of approximately 1.4 eV for photovoltaic materials. Accompanied with the reduction in the band gap, the optical absorption coefficient of N-substituted BiFeO3 in the visible range was evidently increased. Noticeably, N-substituted BiFeO3 showed good ferroelectricity with a decreased band gap and increased optical absorption. The presented results thus demonstrate that N substitution is a promising way to improve the ferroelectric photovoltaic properties of BiFeO3.

Diagnosis and Biomarker Screening of Endometrial Cancer Enabled by a Versatile Exosome Metabolic Fingerprint Platform.

Exosomes have emerged as a revolutionary tool for liquid biopsy (LB), as they carry specific cargo from cells. Profiling the metabolites of exosomes is crucial for cancer diagnosis and biomarker discovery. Herein, we propose a versatile platform for exosomal metabolite assay of endometrial cancer (EC). The platform is based on a nanostructured composite material comprising gold nanoparticle-coated magnetic COF with aptamer modification (Fe3O4@COF@Au-Apt). The unique design and novel synthesis strategy of Fe3O4@COF@Au-Apt provide the material with a large specific surface area, enabling the efficient and specific isolation of exosomes. The exosomes captured Fe3O4@COF@Au-Apt can be directly used as the laser desorption/ionization mass spectrometry (LDI-MS) matrix for rapid exosomal metabolic patterns. By integrating these functionalities into a single platform, the analytical process is simplified, eliminating the need for additional elution steps and minimizing potential sample loss, resulting in large-scale exosomal metabolic fingerprints. Combining with machine learning algorithms on the metabolic patterns, accurate discrimination between endometrial patients (EGs) and benign controls (CGs) was achieved, and the area under the receiver operating characteristic curve of the blind test cohort was 0.924. Confusion matrix analysis of important metabolic fingerprint features further demonstrates the high accuracy of the proposed approach toward EC diagnosis, with an overall accuracy of 94.1%. Moreover, four metabolites, namely, hydroxychalcone, l-acetylcarnitine, elaidic acid, and glutathione, have been identified as potential biomarkers of EC. These results highlight the great value of the integrated exosome metabolic fingerprint platform in facilitating low-cost and high-throughput characterization of exosomal metabolites for cancer diagnosis and biomarker discovery.

Identifying high-risk groups for deep vein thrombosis after primary total knee arthroplasty using preoperative Caprini scores and D-dimer levels.

BACKGROUND: Caprini score and D-dimer are well-recognized markers in deep vein thrombosis (DVT) assessment. However, their utility in guiding post-arthroplasty DVT risk is hampered by susceptibility to various post-operative factors, limiting their effectiveness as reminders. Conversely, these markers exhibit greater stability in the pre-operative setting. Despite this, research on the pre-operative predictive value of Caprini score and D-dimer for DVT following primary total knee arthroplasty (TKA) remains scarce. METHODS: In a retrospective study, we analyzed data from patients who underwent primary TKA, between August 2015 and December 2022. Upon admission, Caprini scores were assessed, and comprehensive blood panels were obtained from fasting blood samples. For all patients, lower limb vascular Doppler ultrasonography was performed pre-operatively to exclude those with pre-existing DVT, and all patients underwent DVT examination again post-operatively. RESULTS: Our study included 2,873 patients, averaging 67.98 ± 7.54years, including 676 men and 2,197 women. In this study, 303 (10.55%) patients developed postoperative DVT, and 57 (1.98%) cases presented with lower limb symptoms. DVT incidence in patients with pre-operative Caprini scores of 1-2 (6.50%), 3 (10.28%), and ≥ 4 (18.05%) showed significant differences (P < 0.05). DVT rates were 14.80% in patients with pre-operative D-dimer levels of ≥ 1 mg/L, higher than the 8.98% in those with levels of < 0.5 mg/L, and 10.61% in those with levels 0.5-1 mg/L (P < 0.05). In patients with Caprini scores of 1-2 and D-dimer levels ≤ 0.5 mg/L, the occurrence rate of postoperative DVT was only 5.84%. For patients with Caprini scores ≥ 4 and D-dimer levels ≥ 1.0 mg/L, the postoperative DVT occurrence rate soared to 24.81%, with the OR(odds ratio) was 4.744 compared to the former group. CONCLUSION: Patients with preoperative higher Caprini scores and D-dimer are more likely to develop DVT after TKA. Additionally, those with a preoperative Caprini score ≥ 4 and D-dimer level ≥ 1.0 mg/L have a significantly increased risk (24.81%) of developing DVT, identifying them as a high-risk group for DVT following TKA. These findings hold significant value for DVT risk stratification in primary TKA patients and the formulation of preoperative interventions to mitigate the risk of DVT.

Coexistence of ferroelectricity and antiferroelectricity in 2D van der Waals multiferroic.

Multiferroic materials have been intensively pursued to achieve the mutual control of electric and magnetic properties. The breakthrough progress in 2D magnets and ferroelectrics encourages the exploration of low-dimensional multiferroics, which holds the promise of understanding inscrutable magnetoelectric coupling and inventing advanced spintronic devices. However, confirming ferroelectricity with optical techniques is challenging in 2D materials, particularly in conjunction with antiferromagnetic orders in single- and few-layer multiferroics. Here, we report the discovery of 2D vdW multiferroic with out-of-plane ferroelectric polarization in trilayer NiI2 device, as revealed by scanning reflective magnetic circular dichroism microscopy and ferroelectric hysteresis loops. The evolution between ferroelectric and antiferroelectric phases has been unambiguously observed. Moreover, the magnetoelectric interaction is directly probed by magnetic control of the multiferroic domain switching. This work opens up opportunities for exploring multiferroic orders and multiferroic physics at the limit of single or few atomic layers, and for creating advanced magnetoelectronic devices.

Boosting Acidic Hydrogen Evolution Kinetics Induced by Weak Strain Effect in PdPt Alloy for Proton Exchange Membrane Water Electrolyzers.

Strain engineering is an effective strategy for manipulating the electronic structure of active sites and altering the binding strength toward adsorbates during the hydrogen evolution reaction (HER). However, the effects of weak and strong strain engineering on the HER catalytic activity have not been fully explored. Herein, the core-shell PdPt alloys with two-layer Pt shells (PdPt2L) and multi-layer Pt shells (PdPtML) is constructed, which exhibit distinct lattice strains. Notably, PdPt2L with weak strain effect just requires a low overpotential of 18 mV to reach 10 mA cm-2 for the HER and shows the superior long-term stability for 510 h with negligible activity degradation in 0.5 M H2SO4. The intrinsic activity of PdPt2L is 6.2 and 24.5 times higher than that of PdPtML and commercial Pt/C, respectively. Furthermore, PdPt2L||IrO2 exhibits superior activity over Pt/C||IrO2 in proton exchange membrane water electrolyzers and maintains stable operation for 100 h at large current density of 500 mA cm-2. In situ/operando measurements verify that PdPt2L exhibits lower apparent activation energy and accelerated ad-/desorption kinetics, benefiting from the weak strain effect. Density functional theory calculations also reveal that PdPt2L displays weaker H* adsorption energy compared to PdPtML, favoring for H* desorption and promoting H2 generation.

Nanoscale Multipatterning Zn,Co-ZIF@FeOOH for Eradication of Multidrug-Resistant Bacteria and Antibacterial Treatment of Wounds.

The rising incidence of infections caused by multidrug-resistant bacteria highlights the urgent need for innovative bacterial eradication strategies. Metal ions, such as Zn2+ and Co2+, have bactericidal effects by disrupting bacterial cell membranes and interfering with essential cellular processes. This has led to increased attention toward metal-organic frameworks (MOFs) as potential nonantibiotic bactericidal agents. However, the uniform and enhanced localized release of bactericidal metal ions remains a challenge. Herein, we introduce a nanoscale multipatterned Zn,Co-ZIF@FeOOH, featuring a multipod-like morphology with spiky corners, and dual-bactericidal metal ions. Compared to pure Zn,Co-ZIF, the multipod-like morphology of Zn,Co-ZIF@FeOOH exhibits enhanced adhesion toward bacterial surfaces via topological and multiple interactions of electrostatic interaction, significantly increasing the local release of Zn2+ and Co2+. Additionally, the spiky corners of the spindle-shaped FeOOH nanorods physically penetrate bacterial membranes, causing damage and further enhancing adhesion to bacteria. Nine Gram-negative and one Gram-positive bacteria were selected for in vitro test. Notably, the nanoscale multipatterned Zn,Co-ZIF@FeOOH exhibited high bactericidal efficacy against various multidrug-resistant bacteria, including extended-spectrum ß-lactamase-producing (ESBL+) bacteria and carbapenem-resistant bacteria, performing well in both acidic and neutral environments. The wound healing activity of Zn,Co-ZIF@FeOOH was further demonstrated using female Balb/c mouse models infected with bacteria, where the materials show robust antibacterial efficacy and commendable biocompatibility. This study showcases the assembly of metal oxide/MOF composites for nanoscale multipatterning, aims at synergistic bacterial eradication and offers insights into developing nanomaterial-based strategies against multidrug-resistant bacteria.

Nomograms for predicting short-term mortality in acute-on-chronic liver disease caused by the combination of hepatitis B virus and alcohol.

This study aimed to identify predictive factors for the prognosis of acute-on-chronic liver disease (AoCLD) due to both hepatitis B virus (HBV) and alcohol and to develop prognostic models to improve treatment management. AoCLD patients with HBV and alcohol as etiological factors were selected from two multicenter prospective cohorts (NCT02457637,NCT03641872) and included in separate training and validation cohorts (n = 180 and n = 148). In the training cohort, the CATCH-LIFE A nomogram (based on age, bilirubin, international normalized ratio, serum sodium, and hepatic encephalopathy score) and CATCH-LIFE B nomogram (based on age, bilirubin, international normalized ratio, serum albumin, white blood cell, platelet count, and hepatic encephalopathy score) had discriminatory ability for predicting 28-day (c-indexes of 0.910 and 0.899) and 90-day mortality (c-indexes of 0.878 and 0.887, respectively). The area under the curve values for 28-day and 90-day mortality prediction by the CATCH-LIFE A nomogram were 0.922 (95% CI : 0.874, 0.971) and 0.905 (0.856, 0.956), respectively, while those for the CATCH-LIFE B nomogram were 0.916(0.861,0.972) and 0.915 (0.866,0.964), respectively. Similar performance results were observed in the validation cohort. Optimal cut-off scores for each nomogram could be used for patient stratification in high- and low-risk groups, and the high-risk groups showed shorter survival times than the low-risk groups in both the training and validation cohorts. Two nomograms constructed from the first short-term follow-up data from patients with AoCLD due to combined HBV infection and alcohol exposure showed good predictive performance for 28-day and 90-day mortality and might be used to guide clinical management.

A Rapid Head Organ Localization System Based on Clinically Realistic Images: A 3D Two Step Progressive Registration Method with CVH Anatomical Knowledge Mapping.

Rapid localization of ROI (Region of Interest) for tomographic medical images (TMIs) is an important foundation for efficient image reading, computer-aided education, and well-informed rights of patients. However, due to the multimodality of clinical TMIs, the complexity of anatomy, and the deformation of organs caused by diseases, it is difficult to have a universal and low-cost method for ROI organ localization. This article focuses on actual concerns of TMIs from medical students, engineers, interdisciplinary researchers, and patients, exploring a universal registration method between the clinical CT/MRI dataset and CVH (Chinese Visible Human) to locate the organ ROI in a low-cost and lightweight way. The proposed method is called Two-step Progressive Registration (TSPR), where the first registration adopts "eye-nose triangle" features to determine the spatial orientation, and the second registration adopts the circular contour to determine the spatial scale, ultimately achieving CVH anatomical knowledge automated mapping. Through experimentation with representative clinical TMIs, the registration results are capable of labeling the ROI in the images well and can adapt to the deformation problem of ROI, as well as local extremum problems that are prone to occur in inter-subject registration. Unlike the ideal requirements for TMIs' data quality in laboratory research, TSPR has good adaptability to incomplete and non-thin-layer quality in real clinical data in a low-cost and lightweight way. This helps medical students, engineers, and interdisciplinary researchers independently browse images, receive computer-aided education, and provide patients with better access to well-informed services, highlighting the potential of digital public health and medical education.

Identification and functional validation of P450 genes associated with pyrethroid resistance in the malaria vector Anopheles sinensis (Diptera Culicidae).

Cytochrome P450 monooxygenases (P450s), a multifunctional protein superfamily, are one of three major classes of detoxification enzymes. However, the diversity and functions of P450 genes from pyrethroid-resistant populations of Anopheles sinensis have not been fully explored. In this study, P450 genes associated with pyrethroid resistance were systematically screened using RNA-seq in three field pyrethroid-resistant populations (AH-FR, CQ-FR, YN-FR) and one laboratory resistant strain (WX-LR) at developmental stages, tissues, and post blood-meal in comparison to the laboratory susceptible strain (WX-LS) in An. sinensis. Importantly, the expression of significantly upregulated P450s was verified using RT-qPCR, and the function of selected P450s in pyrethroid detoxification was determined with RNA interference using four laboratory pyrethroid-resistant strains (WX-LR, AH-LR, CQ-LR, YN-LR). Sixteen P450 genes were significantly upregulated in at least one field-resistant population, and 44 were significantly upregulated in different developmental stages, tissues or post blood-meal. A total of 19 P450s were selected to verify their association with pyrethroid resistance, and four of them (AsCYP6P3v1, AsCYP6P3v2, AsCYP9J10, and AsCYP9K1) demonstrated significant upregulation in laboratory pyrethroid-resistant strains using RT-qPCR. Knockdown of these four genes all significantly reduced pyrethroid resistance and increased the mortality by 57.19% (AsCYP6P3v1 and AsCYP6P3v2 knockdown group), 38.39% (AsCYP9K1 knockdown group) and 48.87% (AsCYP9J10 knockdown group) in An. sinensis by RNAi, which determined the pyrethroid detoxification function of these four genes. This study revealed the diversity of P450 genes and provided functional evidence for four P450s in pyrethroid detoxification in An. sinensis for the first time, which increases our understanding of the pyrethroid resistance mechanism, and is of potential value for pyrethroid resistance detection and surveillance.

Screening of promising molecules against potential drug targets in Yersinia pestis by integrative pan and subtractive genomics, docking and simulation approach.

This study focuses on Yersinia pestis, the bacterium responsible for plague, which posed a severe threat to public health in history. Despite the availability of antibiotics treatment, the emergence of antibiotic resistance in this pathogen has increased challenges of controlling the infections and plague outbreaks. The development of new drug targets and therapies is urgently needed. This research aims to identify novel protein targets from 28 Y. pestis strains by the integrative pan-genomic and subtractive genomics approach. Additionally, it seeks to screen out potential safe and effective alternative therapies against these targets via high-throughput virtual screening. Targets should lack homology to human, gut microbiota, and known human 'anti-targets', while should exhibit essentiality for pathogen's survival and virulence, druggability, antibiotic resistance, and broad spectrum across multiple pathogenic bacteria. We identified two promising targets: the aminotransferase class I/class II domain-containing protein and 3-oxoacyl-[acyl-carrier-protein] synthase 2. These proteins were modeled using AlphaFold2, validated through several structural analyses, and were subjected to molecular docking and ADMET analysis. Molecular dynamics simulations determined the stability of the ligand-target complexes, providing potential therapeutic options against Y. pestis.

Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling.

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

Longitudinal trajectories of blood glucose and 30-day mortality in patients with diabetes mellitus combined with acute myocardial infarction: A retrospective cohort analysis of the MIMIC database.

BACKGROUND: Although blood glucose changes have been suggested to be a potential better target for clinical control than baseline blood glucose levels, the association of blood glucose changes with the prognosis in acute myocardial infarction (AMI) patients with diabetes mellitus (DM) is unclear. Herein, this study aimed to investigate association of short-term longitudinal trajectory of blood glucose with 30-day mortality in this population. METHODS: Data of AMI patients with DM were extracted from the Medical Information Mart for Intensive Care (MIMIC) database in 2003-2019 in this retrospective cohort study. The latent growth mixture modeling (LGMM) model was utilized to classify the 24-hour longitudinal trajectory of blood glucose of the patients. Kaplan-Meier (KM) curve was drawn to show 30-day mortality risk in patients with different trajectory classes. Univariate and multivariate Cox regression analyses were employed to explore the association of longitudinal trajectory of blood glucose within 24 hours after the ICU admission with 30-day mortality. Also, subgroups analysis of age, gender, and AMI types was performed. The evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 1,523 eligible patients, 227 (14.9%) died within 30 days. We identified 4 longitudinal trajectories of blood glucose, including class 1 (a low initial average blood glucose level with steady trend within 24 hours), class 2 (a high initial average blood glucose with gently decreased trend), class 3 (the highest initial average blood glucose with rapidly decreased trend) and class 4 (a high initial average blood glucose level with the trend that increased at first and then decreased). After adjusting for covariates, an average blood glucose level of ≥200 mg/dL was linked to higher risk of 30-day mortality, comparing to that of <140 mg/dL (HR = 1.80, 95%CI: 1.23-2.63). Comparing to patients whose longitudinal trajectory of blood glucose conformed to class 1, those with class 2 (HR = 2.52, 95%CI: 1.79-3.53) or class 4 (HR = 3.53, 95%CI: 2.07-6.03) seemed to have higher risk of 30-day mortality. Additionally, these associations were also significant in aged ≥60 years old, female, male, NSTEMI, and STEMI subgroups (all P<0.05). CONCLUSION: A low level of average blood glucose at the ICU admission or reducing blood glucose to a normal level quickly with adequate measures in 24 hours after ICU admission may be beneficial for AMI patients with DM to reduce the risk of 30-day mortality. These findings may provide some information for further exploration on appropriate range of blood glucose changes in clinical practice.

Development of a core outcome set of clinical research on the integration of traditional Chinese and Western medicine for spinal metastases: a study protocol.

BACKGROUND: In recent years, the incidence of spinal metastasis (SM) has been increasing steadily. In response to this serious public health problem, researchers have made progress by using the integration of traditional Chinese and Western medicine. However, considerable heterogeneity in the definition and measurement of outcomes across clinical research studies, along with the lack of uniform measurement standards for study data, makes it difficult for researchers to compare different treatments. Therefore, it is crucial to accurately evaluate clinical research on the integration of traditional Chinese and Western medicine for SM. METHODS: This study protocol outlines a comprehensive research programme based on the Core Outcome Set Standards Protocol Items. The study consists of four phases: a literature review, semistructured interviews, a two-round modified Delphi survey, a consensus meeting. Phase 1 involves a comprehensive literature review to extract outcomes used in current clinical studies of integrated traditional Chinese and Western medicine or Western medicine for the treatment of SM. A semistructured interview format will be used to survey patients and caregivers in phase 2 to collect suggestions from the patient perspective. Phase 3 involves a two-round modified Delphi survey to complete a prioritisation evaluation of outcomes to generate a candidate list for core outcome set (COS). Finally, phase 4 involves a face-to-face consensus meeting to review and establish the COS. ETHICS AND DISSEMINATION: Conducted in response to the current dilemma of SM, the study was endorsed by the Spine Oncology Group of the Orthopaedic Surgeons Branch of the Chinese Physicians' Association. It will be developed and reported through a rigorous process, with the results of the study to be published in a peer-reviewed journal.Registration: COMET Registry: COMET 2938; https://www.comet-initiative.org/Studies/Details/2938.

Simultaneously Flame Retarding and Toughening of Epoxy Resin Composites Based on Two-Dimensional Polyhedral Oligomeric Silsesquioxane/Polyoxometalate Supramolecular Nanocrystals with Ultralow Loading.

For industrial practical applications, it is difficult to simultaneously endow epoxy resin (EP) composites with superior flame retardancy, smoke suppression, toughness, and low-dielectric constants. Herein, unique polyhedral oligomeric silsesquioxane/polyoxometalate (POM(Mo)-POSS(ibu-Li)) nanosheets were synthesized via a simple one-pot method using laboratory-made lithium-containing hepta-isobutyl-POSS (ibu-Li-POSS) and the low-cost industrial chromogenic agent H3PMo12O40 as raw materials. The incorporation of 2 wt % POM(Mo)-POSS(ibu-Li) nanoflakes into EP significantly enhanced the compatibility between nanoadditives and the EP matrix. Compared with EP, the flexural and impact strengths increased by 36.2 and 78.2%, respectively. Therefore, POM(Mo)-POSS(ibu-Li) has significant advantages in enhancing the toughness of EP compared with existing flame retardants. The dielectric constant and loss were apparently reduced to meet the increasing requirements of EP-type electronic packaging materials and components. Notably, the synthesized POM(Mo)-POSS(ibu-Li) contained various flame-retardant and smoke-suppression elements such as P, Mo, and Si. The ultralow loading (2 wt %) of POM(Mo)-POSS(ibu-Li) significantly reduced the peak heat release rate, peak of smoke production rate, and CO production rate by 43.9, 40.6, and 65.8%, respectively. Meanwhile, the value of LOI increased directly from 24.0% for EP to 30.2% and passed the V-0 rating in the UL-94 test. However, incorporating 5 wt % POSS derivatives into EP alone to ensure that the prepared composites pass the V-0 rating of the UL-94 test has always been an extraordinarily difficult problem. Therefore, the dilemmas of poor dielectric properties, inherent flammability, and brittleness of EP were completely overcome through the successful application of POM(Mo)-POSS(ibu-Li) supramolecular nanosheets.

A tumor-promotional molecular axis CircMAPKBP1/miR-17-3p/TGFß2 activates autophagy pathway to drive tongue squamous cell carcinoma cisplatin chemoresistance.

Platinum-based chemotherapy is the first-line treatment for tongue squamous cell carcinoma (TSCC), but most patients rapidly develop resistance. Circular RNAs (circRNAs) are a class of critical regulators in the pathogenesis of several tumors, but their role in cisplatin resistance in TSCC has not been fully elucidated. Here we found that circMAPKBP1 was enriched in cisplatin resistant TSCC cells and was closely associated with enhanced autophagic activity. Functionally, silencing circMAPKBP1 significantly restored the chemosensitivity of cisplatin-resistant TSCC cells both in vitro and in vivo by suppressing autophagy. Mechanistically, circMAPKBP1 enhanced cisplatin sensitivity through the miR-17-3p/TGFß2 axis by activating autophagy pathway. Data from clinical studies revealed that high expression of circMAPKBP1 and TGFß2 was closely linked to a poor outcome in TSCC patients. We thus concluded that circMAPKBP1 is a tumor promoting factor and confers cisplatin sensitivity by activating the miR-17-3p/TGFß2 axis-mediated autophagy. We propose that circMAPKBP1 may be a potential therapeutic target for TSCC.

Exploring the Frontier of Wheat Rust Resistance: Latest Approaches, Mechanisms, and Novel Insights.

Wheat rusts, including leaf, stripe, and stem rust, have been a threat to global food security due to their devastating impact on wheat yields. In recent years, significant strides have been made in understanding wheat rusts, focusing on disease spread mechanisms, the discovery of new host resistance genes, and the molecular basis of rust pathogenesis. This review summarizes the latest approaches and studies in wheat rust research that provide a comprehensive understanding of disease mechanisms and new insights into control strategies. Recent advances in genetic resistance using modern genomics techniques, as well as molecular mechanisms of rust pathogenesis and host resistance, are discussed. In addition, innovative management strategies, including the use of fungicides and biological control agents, are reviewed, highlighting their role in combating wheat rust. This review also emphasizes the impact of climate change on rust epidemiology and underscores the importance of developing resistant wheat varieties along with adaptive management practices. Finally, gaps in knowledge are identified and suggestions for future research are made. This review aims to inform researchers, agronomists, and policy makers, and to contribute to the development of more effective and sustainable wheat rust control strategies.

Integrative proteomic and metabolomic elucidation of cardiomyopathy with in vivo and in vitro models and clinical samples.

Cardiomyopathy is a prevalent cardiovascular disease that affects individuals of all ages and can lead to life-threatening heart failure. Despite its variety in types, each with distinct characteristics and causes, our understanding of cardiomyopathy at a systematic biology level remains incomplete. Mass spectrometry-based techniques have emerged as powerful tools, providing a comprehensive view of the molecular landscape and aiding in the discovery of biomarkers and elucidation of mechanisms. This review highlights the significant potential of integrating proteomic and metabolomic approaches with specialized databases to identify biomarkers and therapeutic targets across different types of cardiomyopathies. In vivo and in vitro models, such as genetically modified mice, patient-derived or induced pluripotent stem cells, and organ chips, are invaluable in exploring the pathophysiological complexities of this disease. By integrating omics approaches with these sophisticated modeling systems, our comprehension of the molecular underpinnings of cardiomyopathy can be greatly enhanced, facilitating the development of diagnostic markers and therapeutic strategies. Among the promising therapeutic targets are those involved in extracellular matrix remodeling, sarcomere damage, and metabolic remodeling. These targets hold the potential to advance precision therapy in cardiomyopathy, offering hope for more effective treatments tailored to the specific molecular profiles of patients.

Npc1 deficiency impairs microglia function via TREM2-mTOR signaling in Niemann-Pick disease type C.

Niemann-Pick disease Type C (NPC) is a neurodegenerative disease mainly caused by the mutation in NPC1 gene, leading to massive accumulation of unesterified cholesterol in the late endosome/lysosome of cells. Impaired phenotype of microglia is a hallmark in Npc1 mutant mice (Npc1-/- mice). However, the mechanism of Npc1 in regulating microglial function is still unclear. Here, we showed that the reactive microglia in the neonatal Npc1-/- mice indicated by the increased lysosome protein CD68 and phagocytic activity were associated with disrupted TREM2-mTOR signaling in microglia. Furthermore, in Npc1-deficient BV2 cells, genetic deletion of Trem2 partially restored microglial function, probably via restored mTOR signaling. Taken together, our findings indicated that loss of Npc1 in microglia caused changes of their morphologies and the impairment of lysosomal function, which were linked to the TREM2-mTOR signaling pathway.

Acidity-Responsive Fe-PDA@CaCO3 Nanoparticles for Photothermal-Enhanced Calcium-Overload- and Reactive-Oxygen-Species-Mediated Tumor Therapy.

Calcium-overload-mediated tumor therapy has received considerable interest in oncology. However, its efficacy has been proven to be inadequate due to insufficient calcium ion concentration at the tumor site coupled with challenges in facilitating efficient calcium uptake by tumors, leading to unsatisfactory therapeutic outcomes. In the present study, calcium carbonate nanoshell mineralized ferric polydopamine nanoparticles (Fe-PDA@CaCO3 NPs) were prepared for achieving Ca2+-overload-mediated tumor therapy. Upon entering the tumor site, the pH-responsive CaCO3 layer, acting as a "Ca2+ storage pool", rapidly degraded and released high quantities of free Ca2+ within the weakly acidic environment. The Fe-PDA core, with its excellent photothermal conversion properties, could significantly increase the temperature upon exposure to near-infrared (NIR) light irradiation, thereby activating the TRPV1 channel and leading to a large influx of released Ca2+ into the cytoplasm. Furthermore, the exposed Fe-PDA core could react with the tumor-overexpressed hydrogen peroxide (H2O2) to efficiently produce hydroxyl radicals (•OH), significantly increasing intracellular reactive oxygen species (ROS) levels and thus inhibiting the activity of the Ca2+ efflux pump, resulting in a high intracellular Ca2+ concentration. Ultimately, the increase in calcium/ROS levels could disrupt mitochondrial homeostasis and activate the apoptosis pathway. The current work presents a promising approach for tumor therapy using photothermal-enhanced calcium-overload-mediated ion interference therapy and chemodynamic therapy.