Downregulation of the (pro)renin receptor alleviates ferroptosis-associated cardiac pathological changes via the NCOA 4-mediated ferritinophagy pathway in diabetic cardiomyopathy.

Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxidation, is involved in various cardiovascular diseases. (Pro)renin receptor (PRR) in performs as ligands in the autophagic process, and its function in diabetic cardiomyopathy (DCM) is not fully understood. We investigated whether PRR promotes ferroptosis through the nuclear receptor coactivator 4 (NCOA 4)-mediated ferritinophagy pathway and thus contributes to DCM. We first established a mouse model of DCM with downregulated and upregulated PRR expression and used a ferroptosis inhibitor. Myocardial inflammation and fibrosis levels were then measured, cardiac function and ferroptosis-related indices were assessed. In vitro, neonatal rat ventricular primary cardiomyocytes were cultured with high glucose and transfected with recombinant adenoviruses knocking down or overexpressing the PRR, along with a ferroptosis inhibitor and small interfering RNA for the ferritinophagy receptor, NCOA4. Ferroptosis levels were measured in vitro. The results showed that the knockdown of PRR not only alleviated cardiomyocyte ferroptosis in vivo but also mitigated the HG-induced ferroptosis in vitro. Moreover, administration of Fer-1 can inhibit HG-induced ferroptosis. NCOA4 knockdown blocked the effect of PRR on ferroptosis and improved cell survival. Our result indicated that inhibition of PRR and NCOA4 expression provides a new therapeutic strategy for the treatment of DCM. The effect of PRR on the pathological process of DCM in mice may be in promoting cardiomyocyte ferroptosis through the NCOA 4-mediated ferritinophagy pathway.

Reduction of Oxidative Stress and Excitotoxicity by Mesenchymal Stem Cell Biomimetic Co-Delivery System for Cerebral Ischemia-Reperfusion Injury Treatment.

A cerebral ischemia-reperfusion injury is ensued by an intricate interplay between various pathological processes including excitotoxicity, oxidative stress, inflammation, and apoptosis. For a long time, drug intervention policies targeting a single signaling pathway have failed to achieve the anticipated clinical efficacy in the intricate and dynamic inflammatory environment of the brain. Moreover, inadequate targeted drug delivery remains a significant challenge in cerebral ischemia-reperfusion injury therapy. In this study, a multifunctional nanoplatform (designated as PB-006@MSC) is developed using ZL006-loaded Prussian blue nanoparticles (PBNPs) camouflaged by a mesenchymal stem cell (MSC) membrane (MSCm). ZL006 is a neuroprotectant. It can be loaded efficiently into the free radical scavenger PBNP through mesoporous adsorption. This can simultaneously modulate multiple targets and pathways. MSCm biomimetics can reduce the nanoparticle immunogenicity, efficiently enhance their homing capability to the cerebral ischemic penumbra, and realize active-targeting therapy for ischemic stroke. In animal experiments, PB-006@MSC integrated reactive oxygen species (ROS) scavenging and neuroprotection. Thereby, it selectively targeted the cerebral ischemic penumbra (about fourfold higher accumulation at 24 h than in the non-targeted group), demonstrated a remarkable therapeutic efficacy in reducing the volume of cerebral infarction (from 37.1% to 2.3%), protected the neurogenic functions, and ameliorated the mortality.

Vernalization promotes bolting in sugar beet by inhibiting the transcriptional repressors of BvGI.

Sugar beet (Beta vulgaris L.), a biennial sugar crop, contributes about 16% of the world's sugar production. The transition from vegetative growth, during which sugar accumulated in beet, to reproductive growth, during which sugar exhausted in beet, is determined by vernalization and photoperiod. GIGANTEA (GI) is a key photoperiodic flowering gene that is induced by vernalization in sugar beet. To identify the upstream regulatory factors of BvGI, candidate transcription factors (TF) that were co-expressed with BvGI and could bind to the BvGI promoter were screened based on weighted gene co-expression network analysis (WGCNA) and TF binding site prediction. Subsequently, their transcriptional regulatory role on the BvGI was validated through subcellular localization, dual-luciferase assays and yeast transformation tests. A total of 7,586 differentially expressed genes were identified after vernalization and divided into 18 co-expression modules by WGCNA, of which one (MEcyan) and two (MEdarkorange2 and MEmidnightblue) modules were positively and negatively correlated with the expression of BvGI, respectively. TF binding site predictions using PlantTFDB enabled the screening of BvLHY, BvTCP4 and BvCRF4 as candidate TFs that negatively regulated the expression of BvGI by affecting its transcription. Subcellular localization showed that BvLHY, BvTCP4 and BvCRF4 were localized to the nucleus. The results of dual-luciferase assays and yeast transformation tests showed that the relative luciferase activity and expression of HIS3 was reduced in the BvLHY, BvTCP4 and BvCRF4 transformants, which suggested that the three TFs inhibited the BvGI promoter. In addition, real-time quantitative reverse transcription PCR showed that BvLHY and BvTCP4 exhibited rhythmic expression characteristics similar to that of BvGI, while BvCRF4 did not. Our results revealed that vernalization crosstalked with the photoperiod pathway to initiate bolting in sugar beet by inhibiting the transcriptional repressors of BvGI.

Prediction of Pre-Loading Relaxation of Bolt Structure of Complex Equipment under Tangential Cyclic Load.

Bolts have the advantages of simple installation and easy removal. They are widely applied in aerospace and high-speed railway traffic. However, the loosening of bolts under mixed loads can lead to nonlinear decreases in pre-loading. This affects the safety performance of the structure and may lead to catastrophic consequences. Existing techniques cannot be used to monitor the bolt performance status in time. This has caused significant problems with the safety and reliability of equipment. In order to study the relaxation law of bolt pre-loading, this paper carries out an experimental analysis for 8.8-grade hexagonal bolts and calibrates the torque coefficient. We also studied different loading waveforms, nickel steel plate surface roughnesses, tangential displacement frequencies, four different strengths and bolt head contact areas of the bolt, the initial pre-loading, and the effects of tangential cyclic displacement on pre-loading relaxation. This was done in order to accurately predict the degree of bolt pre-loading loosening under external loads. The laws are described using the allometric model function and the nine-stage polynomial function. The least squares method is used to identify the parameters in the function. The results show that bolts with a smooth surface of the connected structure nickel steel flat plate, high-frequency working conditions, half-sine wave, and a high-strength have better anti-loosening properties. Taking 5-10 cycles of cyclic loading as a boundary, the pre-loading relaxation is divided into two stages. The first stage is a stage of rapid decrease in bolt pre-loading, and the second stage is the slow decrease process. The performance prediction study shows that the allometric model function is the worst fitted, at 71.7% for the small displacement condition. Other than that, the allometric model function and the nine-stage polynomial function can predict more than 85.5% and 90.4%, which require the use of least squares to identify two and ten unknown parameters, respectively. The complexity of the two is different, but both can by better indicators than the pre-loading relaxation law under specific conditions. It helps to improve the monitoring of bolt loosening and the system use cycle, and it can provide theoretical support for complex equipment working for a long time.

Competitive electrochemical aptasensor for high sensitivity detection of liver cancer marker GP73 based on rGO-Fc-PANi nanocomposites.

Golgi protein 73 (GP73) is a novel tumor marker in the early diagnosis and prognosis of hepatocellular carcinoma (HCC). Herein, a competitive electrochemical aptasensor for detecting GP73 was constructed using reduced graphene oxide-ferrocene-polyaniline nanocomposite (rGO-Fc-PANi) as the biosensing platform. The rGO-Fc-PANi had larger specific surface area, excellent conductivity and outstanding electroactive performance, which served as nanocarrier for GP73 aptamer (GP73Apt) binding and as redox nanoprobe for record electrical signal. Then, a complementary chain (cDNA) was fixed to the electrode by hybridization with GP73Apt. When GP73 was present, a competitive process happened among cDNA, GP73Apt and GP73, formed the GP73-GP73Apt stable chemical structure and made cDNA detach from the sensing electrode, resulting in enhancement of electrical signal. The difference in the corresponding peak current before and after the competition can be used to indicate the quantitative of GP73. Under optimal conditions, the DPV current response showed a good log-linear relationship with GP73 concentrations (0.001 âˆ¼ 100.0 ng/mL) with a detection limit of 0.15 pg/mL (S/N = 3). It was successfully used for GP73 detection in human serum with RSDs ranging from 1.08 % to 6.96 %. Therefore, the aptasensor could provide an innovative technology platform and hold a great potential in clinical application.

Insights into the removal of antibiotics from livestock and aquaculture wastewater by algae-bacteria symbiosis systems.

With the burgeoning growth of the livestock and aquaculture industries, antibiotic residues in treated wastewater have become a serious ecological threat. Traditional biological wastewater treatment technologies-while effective for removing conventional pollutants, such as organic carbon, ammonia and phosphate-struggle to eliminate emerging contaminants, notably antibiotics. Recently, the use of microalgae has emerged as a sustainable and promising approach for the removal of antibiotics due to their non-target status, rapid growth and carbon recovery capabilities. This review aims to analyse the current state of antibiotic removal from wastewater using algae-bacteria symbiosis systems and provide valuable recommendations for the development of livestock/aquaculture wastewater treatment technologies. It (1) summarises the biological removal mechanisms of typical antibiotics, including bioadsorption, bioaccumulation, biodegradation and co-metabolism; (2) discusses the roles of intracellular regulation, involving extracellular polymeric substances, pigments, antioxidant enzyme systems, signalling molecules and metabolic pathways; (3) analyses the role of treatment facilities in facilitating algae-bacteria symbiosis, such as sequencing batch reactors, stabilisation ponds, membrane bioreactors and bioelectrochemical systems; and (4) provides insights into bottlenecks and potential solutions. This review offers valuable information on the mechanisms and strategies involved in the removal of antibiotics from livestock/aquaculture wastewater through the symbiosis of microalgae and bacteria.

The Role of Liquid-Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases.

It is widely accepted that living organisms form highly dynamic membrane-less organelles (MLOS) with various functions through phase separation, and the indispensable role that phase separation plays in the mechanisms of normal physiological functions and pathogenesis is gradually becoming clearer. Pathological aggregates, regarded as hallmarks of neurodegenerative diseases, have been revealed to be closely related to aberrant phase separation. Specific proteins are assembled into condensates and transform into insoluble inclusions through aberrant phase separation, contributing to the development of diseases. In this review, we present an overview of the progress of phase separation research, involving its biological mechanisms and the status of research in neurodegenerative diseases, focusing on five main disease-specific proteins, tau, TDP-43, FUS, α-Syn and HTT, and how exactly these proteins reside within dynamic liquid-like compartments and thus turn into solid deposits. Further studies will yield new perspectives for understanding the aggregation mechanisms and potential therapeutic strategies, and future research directions are anticipated.

Parent-adolescent conflict and problematic internet use among Chinese adolescents: the mediating role of depression and the moderating role of school climate.

BACKGROUND: Problematic Internet use (PIU) may lead adolescents to physical, emotional, social, or functional impairment due to the risky, excessive, or impulsive internet use manner. How do the experiences of adolescents influence them using the internet in a problematic manner? The answer to this question is the key to preventing and intervening PIU of adolescents. To address this question, we focus on the interactions among family (parent-adolescent conflict), school (school climate), and individual factors (PIU, depression), exploring the influence factors of PIU. METHODS: A moderated mediation model was constructed to explore the relationship between variables. Using a two-wave longitudinal design with a six-month interval between timepoints, this study collected data from 801 Chinese adolescents (411 boys, Mage = 14.68) by questionnaires. Path analysis was employed to test the model and participants' age, sex and baseline were controlled. RESULTS: Parent-adolescent conflict at Time 1 (T1) was positively related to PIU at Time 2 (T2) in adolescents. Depression at T2 mediated the relationship between parent-adolescent conflict at T1 and PIU at T2. School climate at T2 significantly moderated the mediation effect of depression on the relationship between parent-adolescent conflict at T1 and PIU at T2. Specifically, positive school climate could significantly weaken the negative effect of depression on PIU for adolescents with low level of depression. CONCLUSIONS: The present study reveals that parent-adolescent conflict leads to PIU in adolescents through depression whilst the school climate moderates the impacts of depression on PIU. This adds further evidence regarding the significance of systematically and consistently incorporating family and school in the alleviating of problem behaviors displayed by teens.

The effect of duration between sessions on microperimetric biofeedback training in patients with maculopathies.

Aim of this study was to explore the optimal training interval and times of microperimetric biofeedback training (MBFT) in maculopathies. Twenty-nine patients with maculopathies were divided into two groups: daily training (Group A) or alternate daily training (Group B). Both groups underwent 15 MBFT sessions. We compared the BCVA, reading speed, and fixation stability at baseline, after 5, 10, 15 sessions. After 15 sessions of MBFT, all visual parameters in both groups improved. There was a significant increase in BCVA after 5 sessions in both groups (P=0.016, and P<0.001 respectively), but Group A showed further improvement after 10 sessions (P<0.001). Regarding reading speed, Group A showed significant improvement from baseline after 15 sessions(P=0.020), Group B improved significantly after 5 sessions (P=0.047) and continued to improve after 10 sessions (P=0.030). Additionally, P1 and LgBCEA of Group A significantly improved after 10 sessions (P=0.001, and P=0.001 respectively), while Group B significantly improved after 5 sessions (P=0.002, and P<0.001 respectively). There was no significant difference in visual outcomes between the two groups (P>0.05) except LgBCEA (P=0.046) after 15 sessions. We concluded that the both MBFT frequencies are effective at improving vision and quality of life in patients with maculopathies. The alternate daily training group showed less time-dependent of improvement in all parameters and a greater benefit in fixation stability. Ten sessions are the optimal number of treatment sessions for alternate daily training.

Association of healthy lifestyle with self-reported sleep disordered breathing: A cross-sectional study.

Some healthy lifestyle components have been linked with sleep disordered breathing (SDB), yet little is known about the relationship between comprehensive lifestyle factors and SDB. This study aimed to examine the healthy lifestyle with SDB in community-dwelling adults. We conducted a cross-sectional analysis of the Suzhou Food Consumption and Health Survey in China between 2018 and 2020. The healthy lifestyle index (HLI) was created by combining smoking, alcohol drinking, diet, physical activity, and body mass index (BMI). Its association with SDB was assessed by multiple logistic regression analysis. Subgroup analysis and sensitivity analysis were conducted to assess the robustness of our results. The final analysis included 3788 participants (2859 without SDB and 929 with SDB). In multivariable-adjusted analyses, non-smoking (OR: 0.58, 95 % CI: 0.47-0.71), non-drinking (OR: 0.55, 95 % CI: 0.45-0.68), healthy diet (OR: 0.79, 95 % CI: 0.65-0.95), and healthy BMI (OR: 0.72, 95 % CI: 0.6-0.86) were associated with SDB. Compared with participants with HLI score of 0-1, participants with HLI score of 2, 3, 4, and 5 had OR of 0.68 (95 % CI: 0.51-0.91), 0.49 (95 % CI: 0.37-0.64), 0.29 (95 % CI: 0.21-0.38), and 0.22 (95 % CI: 0.15-0.33), respectively, after adjustment for confounding factors (P-trend<0.001). An inverse dose-response relationship between HLI and SDB was also observed. The association was similar in subgroups stratified by sex, marital status, diabetes and dyslipidemia. A higher score of HLI was associated with reduced odds of SDB in Chinese adults. Our findings suggest the potential of addressing five modifiable lifestyle factors for the prevention of SDB.

Role of CRH in colitis and colitis-associated cancer: a combinative result of central and peripheral effects?

Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.

A dual-signal output electrochemical aptasensor for glypican-3 ultrasensitive detection based on reduced graphene oxide-cuprous oxide nanozyme catalytic amplification strategy.

Glypican-3 (GPC3) is an essential reference target for hepatocellular carcinoma detection, follow-up and prediction. Herein, a dual-signal electrochemical aptasensor based on reduced graphene oxide-cuprous oxide (RGO-Cu2O) nanozyme was developed for GPC3 detection. The RGO-Cu2O nanoenzyme displayed excellent electron transport effect, large specific surface area and outstanding peroxidase-like ability. The differential pulse voltammetry (DPV) signal of Cu2O oxidation fraction and the chronoamperometry (i-t) signal of H2O2 decomposition catalyzed by RGO-Cu2O nanozyme were used as dual-signal detection. Under optimal conditions, the log-linear response ranges were 0.1 to 500.0 ng/mL with the limit of detection 0.064 ng/mL for DPV technique, and 0.1-50.0 ng/mL for i-t technique (detection limit of 0.0177 ng/mL). The electrochemical aptasensor has remarkably analytical performance with wide response range, low detection limit, excellent repeatability and specificity, good recovery in human serum samples. The two output signals of one sample achieve self-calibration of the results, effectively avoiding the occurrence of possible leakage and misdiagnosis of a single detection signal, suggesting that it will be a promising method in the early biomarker detection.

Micro-environment triple-responsive hyaluronic acid hydrogel dressings to promote antibacterial activity, collagen deposition, and angiogenesis for diabetic wound healing.

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.

[Biological characteristics and osteogenic differentiation of magnesium-doped nanoporous titanium coating].

PURPOSE: Bioactive magnesium ions were successfully incorporated into the nanoporous titanium base coating by micro-arc oxidation(MAO), and its physical properties and osteogenic effects were explored. METHODS: Non-magnesium-containing and magnesium-containing titanium porous titanium coatings(MAO, MAO-mg) were prepared by changing the composition of MAO electrolyte and controlling the doping of magnesium in porous titanium coatings. The samples were characterized by scanning electron microscope (SEM), roughness, contact angle and energy dispersive X-ray spectrometer (EDS). Mg2+ release ability of magnesium-doped nanoporous titanium coatings was determined by inductively coupled plasma/optical emission spectrometer(ICP-OES). The structure of the cytoskeleton was determined by live/dead double staining, CCK-8 detection of material proliferation-toxicity, and staining of ß-actin using FITC-phalloidin. The effects of the coating on osteogenic differentiation in vitro were determined by alizarin red (ARS), alkaline phosphatase (ALP) staining and real-time polymerase chain reaction (qRT-PCR). SPSS 25.0 software package was used for statistical analysis. RESULTS: The MAO electrolyte with magnesium ions did not change the surface characteristics of the porous titanium coating. Each group prepared by MAO had similar microporous structure(P＞0.05). There was no significant difference in surface roughness and contact angle between MAO treatment group (MAO, MAO-mg)(P＞0.05), but significantly higher than that of Ti group (P＜0.05). With the passage of cell culture time, MAO-mg group promoted cell proliferation (P＜0.05). MAO-mg group was significantly higher than other groups in ALP and ARS staining. The expression of Runx2 mRNA (P＜0.05), ALP(P＜0.05) and osteocalcin OCN(P＜0.05) in MAO-mg group was significantly higher than that in Ti and MAO groups. CONCLUSIONS: MAO successfully prepared magnesium-containing nanoporous titanium coating, and showed a significant role in promoting osteogenic differentiation.

Cascade-EC Network: Recognition of Gastrointestinal Multiple Lesions Based on EfficientNet and CA_stm_Retinanet.

Capsule endoscopy (CE) is non-invasive and painless during gastrointestinal examination. However, capsule endoscopy can increase the workload of image reviewing for clinicians, making it prone to missed and misdiagnosed diagnoses. Current researches primarily concentrated on binary classifiers, multiple classifiers targeting fewer than four abnormality types and detectors within a specific segment of the digestive tract, and segmenters for a single type of anomaly. Due to intra-class variations, the task of creating a unified scheme for detecting multiple gastrointestinal diseases is particularly challenging. A cascade neural network designed in this study, Cascade-EC, can automatically identify and localize four types of gastrointestinal lesions in CE images: angiectasis, bleeding, erosion, and polyp. Cascade-EC consists of EfficientNet for image classification and CA_stm_Retinanet for lesion detection and location. As the first layer of Cascade-EC, the EfficientNet network classifies CE images. CA_stm_Retinanet, as the second layer, performs the target detection and location task on the classified image. CA_stm_Retinanet adopts the general architecture of Retinanet. Its feature extraction module is the CA_stm_Backbone from the stack of CA_stm Block. CA_stm Block adopts the split-transform-merge strategy and introduces the coordinate attention. The dataset in this study is from Shanghai East Hospital, collected by PillCam SB3 and AnKon capsule endoscopes, which contains a total of 7936 images of 317 patients from the years 2017 to 2021. In the testing set, the average precision of Cascade-EC in the multi-lesions classification task was 94.55%, the average recall was 90.60%, and the average F1 score was 92.26%. The mean mAP@ 0.5 of Cascade-EC for detecting the four types of diseases is 85.88%. The experimental results show that compared with a single target detection network, Cascade-EC has better performance and can effectively assist clinicians to classify and detect multiple lesions in CE images.

Aberrant METTL14 gene expression contributes to malignant transformation of benzene-exposed myeloid cells.

Benzene is a known contributor to human leukaemia through its toxic effects on bone marrow cells, and epigenetic modification is believed to be a potential mechanism underlying benzene pathogenesis. However, the specific roles of N6-methyladenosine (m6A), a newly discovered RNA post-transcriptional modification, in benzene-induced hematotoxicity remain unclear. In this study, we identified self-renewing malignant proliferating cells in the bone marrow of benzene-exposed mice through in vivo bone marrow transplantation experiments and Competitive Repopulation Assay. Subsequent analysis using whole transcriptome sequencing and RNA m6A methylation sequencing revealed a significant upregulation of RNA m6A modification levels in the benzene-exposed group. Moreover, RNA methyltransferase METTL14, known as a pivotal player in m6A modification, was found to be aberrantly overexpressed in Lin-Sca-1+c-Kit+ (LSK) cells of benzene-exposed mice. Further analysis based on the GEO database showed a positive correlation between the expression of METTL14, mTOR, and GFI and benzene exposure dose. In vitro cellular experiments, employing experiments such as western blot, q-PCR, m6A RIP, and CLIP, validated the regulatory role of METTL14 on mTOR and GFI1. Mechanistically, continuous damage inflicted by benzene exposure on bone marrow cells led to the overexpression of METTL14 in LSK cells, which, in turn, increased m6A modification on the target genes' (mTOR and GFI1) RNA. This upregulation of target gene expression activated signalling pathways such as mTOR-AKT, ultimately resulting in malignant proliferation of bone marrow cells. In conclusion, this study offers insights into potential early targets for benzene-induced haematologic malignant diseases and provides novel perspectives for more targeted preventive and therapeutic strategies.

Mitigation of myocardial ischemia/reperfusion-induced chronic heart failure via Shexiang Baoxin Pill-mediated regulation of the S1PR1 signaling pathway.

BACKGROUND: Well-defined and effective pharmacological interventions for clinical management of myocardial ischemia/reperfusion (MI/R) injury are currently unavailable. Shexiang Baoxin Pill (SBP), a traditional Chinese medicine Previous research on SBP has been confined to single-target treatments for MI/R injury, lacking a comprehensive examination of various aspects of MI/R injury and a thorough exploration of its underlying mechanisms. PURPOSE: This study aimed to investigate the therapeutic potential of SBP for MI/R injury and its preventive effects on consequent chronic heart failure (CHF). Furthermore, we elucidated the specific mechanisms involved, contributing valuable insights into the potential pharmacological interventions for the clinical treatment of MI/R injury. METHODS: We conducted a comprehensive identification of SBP components using high-performance liquid chromatography. Subsequently, we performed a network pharmacology analysis based on the identification results, elucidating the key genes influenced by SBP. Thereafter, through bioinformatics analysis of the key genes and validation through mRNA and protein assays, we ultimately determined the centralized upstream targets. Lastly, we conducted in vitro experiments using myocardial and endothelial cells to elucidate and validate potential underlying mechanisms. RESULTS: SBP can effectively mitigate cell apoptosis, oxidative stress, and inflammation, as well as promote vascular regeneration following MI/R, resulting in improved cardiac function and reduced CHF risk. Mechanistically, SBP treatment upregulates sphingosine-1-phosphate receptor 1 (S1PR1) expression and activates the S1PR1 signaling pathway, thereby regulating the expression of key molecules, including phosphorylated Protein Kinase B (AKT), phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, vascular endothelial growth factor A, tumor necrosis factor-α, and p53. CONCLUSION: This study elucidated the protective role of SBP in MI/R injury and its potential to reduce the risk of CHF. Furthermore, by integrating downstream effector proteins affected by SBP, this research identified the upstream effector protein S1PR1, enhancing our understanding of the pharmacological characteristics and mechanisms of action of SBP. The significance of this study lies in providing compelling evidence for the use of SBP as a traditional Chinese medicine for MI/R injury and consequent CHF prevention.

Tumoral C2 Regulates the Tumor Microenvironment by Increasing the Ratio of M1/M2 Macrophages and Tertiary Lymphoid Structures to Improve Prognosis in Melanoma.

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.

Statistical detection of selfish mining in proof-of-work blockchain systems.

The core of many cryptocurrencies is the decentralised validation network operating on proof-of-work technology. In these systems, validation is done by so-called miners who can digitally sign blocks once they solve a computationally-hard problem. Conventional wisdom generally considers this protocol as secure and stable as miners are incentivised to follow the behaviour of the majority. However, whether some strategic mining behaviours occur in practice is still a major concern. In this paper we target this question by focusing on a security threat: a selfish mining attack in which malicious miners deviate from protocol by not immediately revealing their newly mined blocks. We propose a statistical test to analyse each miner's behaviour in five popular cryptocurrencies: Bitcoin, Litecoin, Monacoin, Ethereum and Bitcoin Cash. Our method is based on the realisation that selfish mining behaviour will cause identifiable anomalies in the statistics of miner's successive blocks discovery. Secondly, we apply heuristics-based address clustering to improve the detectability of this kind of behaviour. We find a marked presence of abnormal miners in Monacoin and Bitcoin Cash, and, to a lesser extent, in Ethereum. Finally, we extend our method to detect coordinated selfish mining attacks, finding mining cartels in Monacoin where miners might secretly share information about newly mined blocks in advance. Our analysis contributes to the research on security in cryptocurrency systems by providing the first empirical evidence that the aforementioned strategic mining behaviours do take place in practice.