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Abstract In graphite, a moderate magnetic field confines electrons and holes into their lowest Landau levels. In the extreme quantum limit, two insulating states with a dome-like field dependence of the their critical temperatures are induced by the magnetic field. Here, we study the evolution of the first dome (below 60 T) under hydrostatic pressure up to 1.7 GPa. With increasing pressure, the field-temperature phase boundary shifts towards higher magnetic fields, yet the maximum critical temperature remains unchanged. According to our fermiology data, pressure amplifies the density and the in-plane effective cyclotron mass of hole-like and electron-like carriers. Thanks to this information, we verify the persistent relevance of the BCS relation between the critical temperature and the density of states in the weak-coupling boundary of the dome. In contrast, the strong-coupling summit of the dome does not show any detectable change with pressure. We argue that this is because the out-of-plane BCS coherence length approaches the interplane distance that shows little change with pressure. Thus, the BCS-BEC crossover is tunable by magnetic field and pressure, but with a locked summit.

Abstract Background This study explores the relationship between serum uric acid(UA) levels and depression. UA is the final product of purine metabolism in the human body, possessing certain physiological functions such as blood pressure regulation, antioxidation, DNA protection, and anti-aging, thereby drawing attention for its potential role in preventing and treating depression. Methods This cross-sectional study includes 32,424 participants aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2018, generating a nationally representative database. Depressive symptoms were assessed using the Patient Health Questionnaire-9. Serum uric acid concentration was measured using the uricase-peroxidase coupled method, and participants were divided into quartiles of serum uric acid concentration. Weighted data were calculated according to analysis guidelines. The association between serum uric acid and depressive symptoms was analyzed using weighted multivariable logistic regression models and restricted cubic spline regression analyses. Subgroup analyses were also performed. Results Among 32,424 participants, 3,421 were defined as having depressive symptoms. The crude prevalence of depressive symptoms was 10.5% (weighted prevalence: 9.086% [95% confidence interval: 9.032–9.139%]). Compared with the first quartile, individuals with higher UA levels had a decreased risk of depressive symptoms by 9% (OR: 0.910, 95% CI: 0.797–10.40), 14.6% (OR: 0.854, 95% CI: 0.741–0.983), and 20.5% (OR: 7795, 95% CI: 0.680–0.930), respectively. Further restricted cubic spline regression analysis revealed a nonlinear association between UA and depressive symptoms, with an inflection point of 319.72 µmol/L. Subgroup multivariable weighted logistic regression analysis found that the association between UA and the risk of depressive symptoms remained consistent across all subgroups, demonstrating high stability and reliability. Conclusion This study emphasizes a significant nonlinear negative correlation between serum uric acid and depressive symptoms. This suggests that proper control of serum uric acid levels may play a role in preventing and treating depression.

Abstract In recent years, significant improvement has been made in the management of non‐small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V‐Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two‐month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen‐activated extracellular signal‐regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E‐mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC.

Abstract Whenever the elastic energy of a solid depends on magnetic field, there is a magnetostrictive response. Field-linear magnetostriction implies piezomagnetism and vice versa. Here, we show that Mn3Sn, a non-collinear antiferromanget with Weyl nodes, hosts a large and almost perfectly linear magnetostriction even at room temperature. The longitudinal and transverse magnetostriction, with opposite signs and similar amplitude are restricted to the kagome planes and the out-of-plane response is negligibly small. By studying four different samples with different Mn:Sn ratios, we find a clear correlation between the linear magnetostriction, the spontaneous magnetization and the concentration of Sn vacancies. The recently reported piezomagnetic data fits in our picture. We show that linear magnetostriction and piezomagnetism are both driven by the field-induced in-plane twist of spins. A quantitative account of the experimental data requires the distortion of the spin texture by Sn vacancies. We find that the field-induced domain nucleation within the hysteresis loop corresponds to a phase transition. Within the hysteresis loop, a concomitant mesoscopic modulation of local strain and spin twist angles, leading to twisto-magnetic stripes, arises as a result of the competition between elastic and magnetic energies.

Abstract Objectives Pulmonary neuroendocrine neoplasms (NENs) are the most frequent cause of ectopic adrenocorticotropic hormone syndrome (EAS); lung infection is common in EAS. An imaging finding of infection in EAS patients can mimic NENs. This retrospective study investigated EAS-associated pulmonary imaging indicators. Methods Forty-five pulmonary NENs and 27 tumor-like infections from 59 EAS patients (45 NEN and 14 infection patients) were included. Clinical manifestations, CT features, 18F-FDG, or 68Ga-DOTATATE-PET/CT images and pathological results were collected. Results High-sensitivity C-reactive protein (p

Abstract Purpose To examine whether there is a significant difference in image quality between the deep learning reconstruction (DLR [AiCE, Advanced Intelligent Clear-IQ Engine]) and hybrid iterative reconstruction (HIR [AIDR 3D, adaptive iterative dose reduction three dimensional]) algorithms on the conventional enhanced and CE-boost (contrast-enhancement-boost) images of indirect computed tomography venography (CTV) of lower extremities. Materials and methods In this retrospective study, seventy patients who underwent CTV from June 2021 to October 2022 to assess deep vein thrombosis and varicose veins were included. Unenhanced and enhanced images were reconstructed for AIDR 3D and AiCE, AIDR 3D-boost and AiCE-boost images were obtained using subtraction software. Objective and subjective image qualities were assessed, and radiation doses were recorded. Results The CT values of the inferior vena cava (IVC), femoral vein ( FV), and popliteal vein (PV) in the CE-boost images were approximately 1.3 (1.31–1.36) times higher than in those of the enhanced images. There were no significant differences in mean CT values of IVC, FV, and PV between AIDR 3D and AiCE, AIDR 3D-boost and AiCE-boost images. Noise in AiCE, AiCE-boost images was significantly lower than in AIDR 3D and AIDR 3D-boost images ( P

Abstract The electrical outputs of single-layer antiferromagnetic memory devices relying on the anisotropic magnetoresistance effect are typically rather small at room temperature. Here we report a new type of antiferromagnetic memory based on the spin phase change in a Mn-Ir binary intermetallic thin film at a composition within the phase boundary between its collinear and noncollinear phases. Via a small piezoelectric strain, the spin structure of this composition-boundary metal is reversibly interconverted, leading to a large nonvolatile room-temperature resistance modulation that is two orders of magnitude greater than the anisotropic magnetoresistance effect for a metal, mimicking the well-established phase change memory from a quantum spin degree of freedom. In addition, this antiferromagnetic spin phase change memory exhibits remarkable time and temperature stabilities, and is robust in a magnetic field high up to 60 T.

This study explored the potential of ultrasonic-assisted three-phase partitioning (UTPP) to simultaneously extract lipids, proteins, and polysaccharides from Idesia polycarpa Maxim (IPM) cake meal, a significant byproduct of oil extraction. The impact of variables such as inorganic salt type, solid–liquid ratio, salt concentration, pH, ultrasonic time, temperature, and volume of dimethyl carbonate was examined. Based on the single-factor tests and response surface methodology (RSM), optimal conditions were identified as 30 % ammonium citrate, a 1:26 solid–liquid ratio, pH 3, 31 min of ultrasonic time, 30 °C temperature, and 15 mL of dimethyl carbonate. These conditions achieved extraction rates of 8.10 % for lipids, 5.03 % for proteins, and 10.03 % for polysaccharides, with recovery rates of 91.62 %, 83.08 %, and 93.95 % respectively. Chemical analysis showed the lipid fraction rich in linoleic acid, and the protein fraction high in glutamic acid, aspartate, and serine. The polysaccharide fraction, mainly RG-I pectin with a molecular weight of 226.58 kDa, exhibited strong thermal stability and inhibitory effects on α-glucosidase and glycation, suggesting potential for functional food and dietary supplement applications. This highlights UTPP as a sustainable method for effectively utilizing valuable compounds from IPM cake meal, outperforming traditional extraction techniques.

BackgroundGiven the high prevalence of fibrotic interstitial lung abnormalities (ILAs) post-COVID-19, this study aims to evaluate the effectiveness of quantitative CT features in predicting fibrotic ILAs at 3-month follow-up.MethodsThis retrospective study utilized cohorts from distinct clinical settings: the training dataset comprised individuals presenting at the fever clinic and emergency department, while the validation dataset included patients hospitalized with COVID-19 pneumonia. They were classified into fibrotic group and nonfibrotic group based on whether the fibrotic ILAs were present at follow-up. A U-Net-based AI tool was used for quantification of both pneumonia lesions and pulmonary blood volumes. Receiver operating characteristic (ROC) curve analysis and multivariate analysis were used to assess their predictive abilities for fibrotic ILAs.ResultsAmong the training dataset, 122 patients (mean age of 68 years ±16 [standard deviation], 73 men), 55.74% showed fibrotic ILAs at 3-month follow-up. The multivariate analysis identified the pneumonia volume [PV, odd ratio (OR) 3.28, 95% confidence interval (CI): 1.20–9.31, p = 0.02], consolidation volume (CV, OR 3.77, 95% CI: 1.37–10.75, p = 0.01), ground-glass opacity volume (GV, OR 3.38, 95% CI: 1.26–9.38, p = 0.02), pneumonia mass (PM, OR 3.58, 95% CI: 1.28–10.46, p = 0.02), and the CT score (OR 12.06, 95% CI: 3.15–58.89, p 0.05). And the area under the curve (AUC) values were PV (0.79), GV (0.78), PM (0.79), CV (0.80), and the CT score (0.77). The validation dataset, comprising 45 patients (mean age 67.29 ± 14.29 years, 25 males) with 57.78% showing fibrotic ILAs at follow-up, confirmed the predictive validity of these parameters with AUC values for PV (0.86), CV (0.90), GV (0.83), PM (0.88), and the CT score (0.85). Additionally, the percentage of blood volume in vessels

BackgroundPrevious studies have investigated the association between the haptoglobin rs72294371 polymorphism and coronary artery disease (CAD) risk, but the results are controversial and uncertain. Therefore, this study aimed to systematically review the literature on haptoglobin polymorphism and susceptibility to CAD.MethodsPubMed, Embase, Web of Science, Cochrane Library, and Wanfang databases were used to identify relevant studies from their inception to April 2024. The pooled odds ratio (OR) with corresponding 95% confidence interval (CI) were used to assess the strength of the association. An OR value greater than one suggested an increased risk; otherwise, it suggested a protective risk.ResultsA total of 15 studies comprising 8,632 individuals (2,988 cases and 5,644 controls) were included. In the current meta-analysis, a significant association between haptoglobin polymorphism and CAD was found under recessive model (OR:0.74, 95% CI:0.60–0.92), dominant model (OR: 0.82, 95% CI: 0.71–0.95), homozygote model (OR: 0.70, 95% CI: 0.53–0.92), and allelic genetic model (OR: 0.80, 95% CI: 0.69–0.94). In the analysis stratified by ethnicity, a statistically significant association was observed in Asians rather than Caucasian population.ConclusionThis meta-analysis indicates that haptoglobin polymorphism is associated with CAD susceptibility, especially in Asians.

This study aimed to evaluate the quality characteristics of Shui ethnic red sour soup, using Miao ethnic red sour soup as a reference. The physicochemical components, free amino acids, and aroma compounds of Miao and Shui ethnic red sour soups were analyzed and compared using national standard methods, amino acid analysis, and headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). The results showed that the contents of total acids, reducing sugars, fats, and proteins in Shui ethnic red sour soup were higher than those in Miao ethnic red sour soup. Nineteen free amino acids were detected in both types of red sour soup, and the content of savory amino acids in Shui ethnic red sour soup was twice that of Miao ethnic red sour soup. Proline and glutamic acid, with taste activity values (TAV) > 1, were identified as the key savory amino acids in both types of red sour soup. A total of 101 volatile compounds were detected in the red sour soups. Moreover, using orthogonal least squares-discriminant analysis (OPLS-DA) and variable importance in projection (VIP) selection, thirty-two key differential compounds, including hexadecanoic acid propyl ester, 4-ethyl-2-methoxyphenol, 5-cyclohexyl-2-pentanone, and sorbic acid, were identified in the red sour soups. Based on the relative odor activity value (ROAV), it was found that the sour taste was more pronounced in Miao ethnic red sour soup, while the fruity aroma was more prominent in Shui ethnic red sour soup. Both types of red sour soup contained salicyl methyl ether as the main contributor to the fatty aroma, but the volatile compounds responsible for the wine-like aroma differed. Ethanol was the main contributor in Miao ethnic red sour soup, while 4-ethylphenol was the main contributor in Shui ethnic red sour soup. In addition, sensory evaluation showed that Shui ethnic red sour soup received higher scores than Miao ethnic red sour soup. In conclusion, the Shui ethnic red sour soup exhibits superior quality and flavor, and has wider market development value.

Abstract Bioactive molecules in tick saliva are considered to be key to successful feeding and further the transmission of tick-borne pathogens. Problems such as pathogen transmission and animal weight loss result in tick infestation can cause tremendous economic losses to the livestock industry. Therefore, the development of a universal tick vaccine is urgently needed. In this paper, three serine protease inhibitor (serpin) proteins RMS-3, L7LRK7 and L7LTU1 were analyzed with bioinformatics methods. Subsequently the proteins were expressed and purified, and inoculated into Kunming mice for immune protection analysis. The amino acid sequence similarities between RMS-3, L7LRK7 and L7LTU1 were up to 90% in Rhipicephalus sanguineus. The recombinant RMS-3 + L7LRK7 + L7LTU1 showed anticoagulant reaction function and could inhibit the activity of CD4+ lymphocytes, when inoculated into Kunming mice. Additionally, After the immunized mice were challenged with Rhipicephalus sanguineus, the percentage of larvae and nymphs that were fully engorged dropped to 40.87% (P 0.05) in the RmS-3 + L7LRK7 immune group, 49.57% (P

Abstract With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-d-aspartate receptor encephalitis in PLWH.

Currently approved human epidermal growth factor receptor 2 (HER2)-targeted antibody therapies are largely derived from trastuzumab, including trastuzumab-chemotherapy combinations, fixed-dose trastuzumab-pertuzumab combinations, and trastuzumab antibody-drug conjugates. To expand the options, bispecific antibodies, which may better utilize the benefits of combination therapy, are being developed. Among them, biparatopic antibodies (bpAbs) have shown improved efficacy compared to monoclonal antibody (mAb) combinations in HER2-positive patients. BpAbs bind two independent epitopes on the same antigen, which allows fine-tuning of mechanisms of action, including enhancement of on-target specificity and induction of strong antigen clustering due to the unique binding mode. To fully utilize the potential of bpAbs for anti-HER2 drug development, it is crucial to consider formats that offer stability and high-yield production, along with a functional balance between the two epitopes. In this study, we rationally designed a bpAb, KJ015, that shares a common light chain with two Fab arms and exhibits functionally balanced high affinity for two HER2 non-overlapping epitopes. KJ015 demonstrated high-expression titers over 7 g/L and stable physicochemical properties at elevated concentrations, facilitating subcutaneous administration with hyaluronidase. Moreover, KJ015 maintained comparable antibody-dependent cytotoxicity, phagocytosis, and complement-dependent cytotoxicity with trastuzumab plus pertuzumab. It exhibited enhanced synergy when administered subcutaneously with hyaluronidase and anti-PD-1 mAb in a mouse tumor model, suggesting promising clinical prospects for this combination.

BackgroundAutophagy plays important roles in cancer progression and therapeutic resistance, and the autophagy underlying the tumor pathogenesis and further mechanisms of chemoresistance emergence remains unknown.MethodsIn this study, via the single-sample gene set enrichment analysis (ssGSEA) method, an autophagy 45-gene list was identified to evaluate samples’ autophagy activity, verified through six GEO datasets with a confirmed autophagy phenotype. It was further utilized to distinguish tumors into autophagy score-high and score-low subtypes, and analyze their transcriptome landscapes, including survival analysis, correlation analysis of autophagy- and resistance-related genes, biological functional enrichment, and immune- and hypoxia-related and genomic heterogeneity comparison, in TCGA pan-cancer datasets. Furthermore, we performed an analysis of autophagy status in breast cancer chemoresistance combined with multiple GEO datasets and in vitro experiments to validate the mechanisms of potential anticancer drugs for reversing chemoresistance, including CCK-8 cell viability assays, RT-qPCR, and immunofluorescence.ResultsThe 45-gene list was used to identify autophagy score-high and score-low subtypes and further analyze their multi-dimensional features. We demonstrated that cancer autophagy status correlated with significantly different prognoses, molecular alterations, biological process activations, immunocyte infiltrations, hypoxia statuses, and specific mutational processes. The autophagy score-low subtype displayed a more favorable prognosis compared with the score-high subtype, associated with their immune-activated features, manifested as high immunocyte infiltration, including high CD8+T, Tfh, Treg, NK cells, and tumor-associated macrophages M1/M2. The autophagy score-low subtype also showed a high hypoxia score, and hypoxic tumors showed a significantly differential prognosis in different autophagy statuses. Therefore, “double-edged” cell fates triggered by autophagy might be closely correlated with the immune microenvironment and hypoxia induction. Results demonstrated that dysregulated autophagy was involved in many cancers and their therapeutic resistance and that the autophagy was induced by the resistance-reversing drug response, in five breast cancer GEO datasets and validated by in vitro experiments. In vitro, dihydroartemisinin and artesunate could reverse breast cancer doxorubicin resistance, through inducing autophagy via upregulating LC3B and ATG7.ConclusionOur study provided a comprehensive landscape of the autophagy-related molecular and tumor microenvironment patterns for cancer progression and resistance, and highlighted the promising potential of drug-induced autophagy in the activation of drug sensitivity and reversal of resistance.

Age-related skeletal muscle weakness deteriorate the prognosis of underlying diseases. Previous studies revealed that crude polysaccharides of Helvella leucopus (HLP) exhibited immunomodulatory, anti-aging and antioxidant activities. We studied the effect of HLP on myogenic differentiation of mouse myoblasts (C2C12). Cellular immunofluorescence staining was used to observe the changes of C2C12 myotubes after different doses of HLP intervention. qRT-PCR was conducted to quantitatively analyze the mRNA expression levels of myogenesis, mitochondrial quality control and peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC1-α) after HLP treatment. Western blotting was conducted to quantitatively analyze the protein expression levels after HLP treatment. The increased differentiation of myoblasts and MyHC levels were found. It is worth noting that the expression of MFN2, Drp1 in mitochondrial dynamic of C2C12 cell-derived muscle fibers were observed to be increased. HLP stimulates myogenic differentiation in C2C12 cells which is associated with increased levels of genes involved in mitochondrial dynamics.

BackgroundThe significant impact of digital health emerged prominently during the COVID-19 pandemic. Despite this, there is a paucity of bibliometric analyses focusing on technologies within the field of digital health patents. Patents offer a wealth of insights into technologies, commercial prospects, and competitive landscapes, often undisclosed in other publications. Given the rapid evolution of the digital health industry, safeguarding algorithms, software, and advanced surgical devices through patent systems is imperative. The patent system simultaneously acts as a valuable repository of technological knowledge, accessible to researchers. This accessibility facilitates the enhancement of existing technologies and the advancement of medical equipment, ultimately contributing to public health improvement and meeting public demands. ObjectiveThe primary objective of this study is to gain a more profound understanding of technology hotspots and development trends within the field of digital health. MethodsUsing a bibliometric analysis methodology, we assessed the global technological output reflected in patents on digital health published between 2017 and 2021. Using Citespace5.1R8 and Excel 2016, we conducted bibliometric visualization and comparative analyses of key metrics, including national contributions, institutional affiliations, inventor profiles, and technology topics. ResultsA total of 15,763 digital health patents were identified as published between 2017 and 2021. The China National Intellectual Property Administration secured the top position with 7253 published patents, whereas Koninklijke Philips emerged as the leading institution with 329 patents. Notably, Assaf Govari emerged as the most prolific inventor. Technology hot spots encompassed categories such as “Medical Equipment and Information Systems,” “Image Analysis,” and “Electrical Diagnosis,” classified by Derwent Manual Code. A patent related to the technique of receiving and transmitting data through microchips garnered the highest citation, attributed to the patentee Covidien LP. ConclusionsThe trajectory of digital health patents has been growing since 2017, primarily propelled by China, the United States, and Japan. Applications in health interventions and enhancements in surgical devices represent the predominant scenarios for digital health technology. Algorithms emerged as the pivotal technologies protected by patents, whereas techniques related to data transfer, storage, and exchange in the digital health domain are anticipated to be focal points in forthcoming basic research.

Tumor metastasis occurs in hepatocellular carcinoma (HCC), leading to tumor progression and therapeutic failure. Anoikis is a matrix detachment-induced apoptosis, also known as detachment-induced cell death, and mechanistically prevents tumor cells from escaping their native extracellular matrix to metastasize to new organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat HCC. Several natural and synthetic products induce anoikis in HCC cells and in vivo models. Here, we first briefly summarize the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in HCC metastasis. Then we discuss the therapeutic potential of pharmacological induction of anoikis as a potential treatment against HCC. Finally, we discuss the key limitations of this therapeutic paradigm and propose possible strategies to overcome them. Cumulatively this review suggests that the pharmacological induction of anoikis can be used a promising therapeutic modality against HCC.

Conversion of solid waste tailings into building materials is an effective way to turn waste into resources as well as resolve the problems of their accumulation and pollution. Herein, in this paper, light-weight and high strength molybdenum tailings ceramsites (LHMCs) were prepared using molybdenum tailings as the main raw material supplemented with fly ash, sludge, steel slag and other solid wastes by egg-structure (three-layer structure) design and high-temperature sintering. The effects of raw material ratio, amount of carbon powder agent, sintering temperature, and sintering time on the properties of LHMCs were investigated, and the optimal preparation process was proposed to be preheating at 400 °C for 60 min and sintering at 1150 °C for 40 min. The results of the physicochemical properties, morphology, and component analysis of LHMCs show that the LHMCs with egg-structure including porous core, reinforced middle layer, and dense outer layer can significantly increase the strength of the ceramsites under the premise of ensuring the low density of the ceramsites. Meanwhile, the doping of molybdenum tailings improves the physical properties of the ceramsites and achieves the reuse of waste tailings. Importantly, the optimized LHMCs can meet the performance requirements of 900-grade ceramsites. This paper proposes a strategy for the preparation of tailings-doped light-weight and high-strength ceramic building materials, which provides a new idea for the recycling of solid waste.

A detailed assessment of flame–flame interaction and laminar flame evolution using multi-ignition sources is experimentally studied. To understand the flame interaction, the centrally ignited flame is measured and calculated for comparison with multi-ignition sources hydrogen–ammonia/flame. The location of the external ignition source, the delay time, the hydrogen blending, and the mixture equivalence ratio at an initial pressure of 0.1 MPa affect the propagation and morphology of the flame. It can be observed that the advancement of the pressure wave of the external flame causes deformation to the central flame front; This deformation occurs even before the interaction of the flames. The deformation can be decomposed into horizontal deformation, which decelerates the flame front as a result of the drag or accelerates due to the thrust of the flow field on the flame front. At the same time, vertical deformation is influenced by drag and thrust-lift forces. Therefore, the equivalent flame decelerates with time. This effect gives a nonsymmetric shape for expanding flame, and the shape changes from spherical to ellipsoidal, then a triaxial quasi-ellipsoid flame (scalene). The equivalent flame speed and laminar burning velocity are maximized near stoichiometry for all delay times and locations of the ignition source. As the delay time of the stoichiometric hydrogen ammonia/air increases, the equivalent laminar flame speed and laminar burning velocity monotonously decrease, as well as the time and location of the interaction. The equivalent flame speed and laminar burning velocity for ignition sources 1 and 2 decreases with delay time, and this becomes evident on the rich side. While employing a third ignition source increases with delay time since the drag force get eliminated from the horizontal axis. Furthermore, the hydrogen blending effect enhances and highlights these tendencies.

Abstract Background Glioblastoma (GBM) is the most common brain tumor with the worst prognosis. Temozolomide is the only first-line drug for GBM. Unfortunately, the resistance issue is a classic problem. Therefore, it is essential to develop new drugs to treat GBM. As an oncogene, Skp2 is involved in the pathogenesis of various cancers including GBM. In this study, we investigated the anticancer effect of AAA237 on human glioblastoma cells and its underlying mechanism. Methods CCK-8 assay was conducted to evaluate IC50 values of AAA237 at 48, and 72 h, respectively. The Cellular Thermal Shift Assay (CETSA) was employed to ascertain the status of Skp2 as an intrinsic target of AAA237 inside the cellular milieu. The EdU-DNA synthesis test, Soft-Agar assay and Matrigel assay were performed to check the suppressive effects of AAA237 on cell growth. To identify the migration and invasion ability of GBM cells, transwell assay was conducted. RT-qPCR and Western Blot were employed to verify the level of BNIP3. The mRFP-GFP-LC3 indicator system was utilized to assess alterations in autophagy flux and investigate the impact of AAA237 on the dynamic fusion process between autophagosomes and lysosomes. To investigate the effect of compound AAA237 on tumor growth in vivo, LN229 cells were injected into the brains of mice in an orthotopic model. Results AAA237 could inhibit the growth of GBM cells in vitro. AAA237 could bind to Skp2 and inhibit Skp2 expression and the degradation of p21 and p27. In a dose-dependent manner, AAA237 demonstrated the ability to inhibit colony formation, migration, and invasion of GBM cells. AAA237 treatment could upregulate BNIP3 as the hub gene and therefore induce BNIP3-dependent autophagy through the mTOR pathway whereas 3-MA can somewhat reverse this process. In vivo, the administration of AAA237 effectively suppressed the development of glioma tumors with no side effects. Conclusion Compound AAA237, a novel Skp2 inhibitor, inhibited colony formation, migration and invasion of GBM cells in a dose-dependent manner and time-dependent manner through upregulating BNIP3 as the hub gene and induced BNIP3-dependent autophagy through the mTOR pathway therefore it might be a viable therapeutic drug for the management of GBM. Graphical Abstract

Abstract Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.

Abstract Bulk bismuth has a complex Landau spectrum. The small effective masses and the large g-factors are anisotropic. The chemical potential drifts at high magnetic fields. Moreover, twin boundaries further complexify the interpretation of the data by producing extra anomalies in the extreme quantum limit. Here, we present a study of angle dependence of magnetoresistance up to 65 T in bismuth complemented with Nernst, ultrasound, and magneto-optic data. All observed anomalies can be explained in a single-particle picture of a sample consisting of two twinned crystals tilted by 108° and with two adjacent crystals keeping their own chemical potentials despite a shift between chemical potentials as large as 68 meV at 65 T. This implies an energy barrier between adjacent twinned crystals reminiscent of a metal- semiconductor Schottky barrier or a p-n junction. We argue that this barrier is built by accumulating charge carriers of opposite signs across a twin boundary.

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Paper-based cultural relics inevitably face a variety of diseases such as acidification, yellowing, and strength loss during long-term preservation, where weakly alkaline inorganic materials play an important role in their deacidification treatments. In this work, by simply adjusting the supersaturation of crystal growing solution without the use of any organic additives, one-dimensional (1D) and two-dimensional (2D) weakly alkaline materials—magnesium carbonate hydrates (MCHs)—were controllably synthesized. It is worth noting that the coatings of 1D/2D MCHs not only cause little change in chromatic aberration and water wettability, but also ensure their safety for alkali-sensitive pigments. Meanwhile, the deacidification, anti-aging, strength-enhancing, and flame-retardant effects of these materials have been tested on ancient book papers, all of which achieved good protective effects. In contrast, 1D MCH materials brought about significant enhancement in both mechanical strengths and flame-retardant effects, and the related effects were investigated. Based on this facile micromorphology control strategy, more low-dimensional nanomaterials are expected to be synthesized by design for the protection of paper-based relics, which will expand our knowledge on functional deacidification and protection mechanisms.

Lung cancer is the leading cause of global cancer-related deaths. Platinum-based chemotherapy is the first-line treatment for the most common type of lung cancer, i.e., non-small-cell lung cancer (NSCLC), but its therapeutic efficiency is limited by chemotherapeutic resistance. Therefore, it is vital to develop effective therapeutic modalities that bypass the common molecular mechanisms associated with chemotherapeutic resistance. Ferroptosis is a form of non-apoptotic regulated cell death characterized by iron-dependent lipid peroxidation (LPO). Ferroptosis is crucial for the proper therapeutic efficacy of lung cancer-associated chemotherapies. If targeted as a novel therapeutic mechanism, ferroptosis modulators present new opportunities for increasing the therapeutic efficacy of lung cancer chemotherapy. Emerging studies have revealed that the pharmacological induction of ferroptosis using natural compounds boosts the efficacy of chemotherapy in lung cancer or drug-resistant cancer. In this review, we first discuss chemotherapeutic resistance (or chemoresistance) in lung cancer and introduce the core mechanisms behind ferroptosis. Then, we comprehensively summarize the small-molecule compounds sourced from traditional medicines that may boost the anti-tumor activity of current chemotherapeutic agents and overcome chemotherapeutic resistance in NSCLC. Cumulatively, we suggest that traditional medicines with ferroptosis-related anticancer activity could serve as a starting point to overcome chemotherapeutic resistance in NSCLC by inducing ferroptosis, highlighting new potential therapeutic regimens used to overcome chemoresistance in NSCLC.

Rationale and objectives: The computed tomography (CT) score has been used to evaluate the severity of COVID-19 during the pandemic; however, most studies have overlooked the impact of infection duration on the CT score. This study aimed to determine the optimal cutoff CT score value for identifying severe/critical COVID-19 during different stages of infection and to construct corresponding predictive models using radiological characteristics and clinical factors. Materials and methods: This retrospective study collected consecutive baseline chest CT images of confirmed COVID-19 patients from a fever clinic at a tertiary referral hospital from November 28, 2022, to January 8, 2023. Cohorts were divided into three subcohorts according to the time interval from symptom onset to CT examination at the hospital: early phase (0–3 days), intermediate phase (4–7 days), and late phase (8–14 days). The binary endpoints were mild/moderate and severe/critical infection. The CT scores and qualitative CT features were manually evaluated. A logistic regression analysis was performed on the CT score as determined by a visual assessment to predict severe/critical infection. Receiver operating characteristic analysis was performed and the area under the curve (AUC) was calculated. The optimal cutoff value was determined by maximizing the Youden index in each subcohort. A radiology score and integrated models were then constructed by combining the qualitative CT features and clinical features, respectively, using multivariate logistic regression with stepwise elimination. Results: A total of 962 patients (aged, 61.7 ± 19.6 years; 490 men) were included; 179 (18.6%) were classified as severe/critical COVID-19, while 344 (35.8%) had a typical Radiological Society of North America (RSNA) COVID-19 appearance. The AUCs of the CT score models reached 0.91 (95% confidence interval (CI) 0.88–0.94), 0.82 (95% CI 0.76–0.87), and 0.83 (95% CI 0.77–0.89) during the early, intermediate, and late phases, respectively. The best cutoff values of the CT scores during each phase were 1.5, 4.5, and 5.5. The predictive accuracies associated with the time-dependent cutoff values reached 88% (vs.78%), 73% (vs. 63%), and 87% (vs. 57%), which were greater than those associated with universal cutoff value (all P

Afidopyropen has high activity against pests. However, it poses potential risks to the soil ecology after entering the environment. The toxicity of afidopyropen to earthworms (Eisenia fetida) was studied for the first time in this study. The results showed that afidopyropen had low level of acute toxicity to E. fetida. Under the stimulation of chronic toxicity, the increase of reactive oxygen species (ROS) level activated the antioxidant and detoxification system, which led to the increase of superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. Lipid peroxidation and DNA damage were characterized by the increase of malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) contents. Meanwhile, the functional genes SOD, CAT, GST, heat shock protein 70 (HSP70), transcriptionally controlled tumor protein (TCTP), and annetocin (ANN) played a synergistic role in antioxidant defense. However, the comprehensive toxicity of high concentration still increased on the 28th day. In addition, strong histopathological damage in the body wall and intestine was observed, accompanied by weight loss, which indicated that afidopyropen inhibited the growth of E. fetida. The molecular docking revealed that afidopyrene combined with the surface structure of SOD and GST proteins, which made SOD and GST become sensitive biomarkers reflecting the toxicity of afidopyropen to E. fetida. Summing up, afidopyropen destroys the homeostasis of E. fetida through chronic toxic. These results provide theoretical data for evaluating the environmental risk of afidopyropen to soil ecosystem.

The present work was to compare quality differences of the duck leg roasted with or without tinfoil paper wrapping using electric oven. The sensory characteristics, cooking loss, fatty acids, amino acids, and volatile flavor composition in the meat of the two roasted duck leg samples were analyzed. In comparison, the duck leg roasted without tinfoil paper wrapping had greater roasted aroma and cooking loss, while that with paper wrapping was more tender and had lower cooking loss. No matter with or without tinfoil paper wrapping, both fatty acid contents and amino acid contents in the meat were increased after roasting. The sample roasted without tinfoil paper wrapping had higher values in polyunsaturated fatty acids content to saturated fatty acids content (PUFA/SFA) and essential amino acid content to total amino acid content (EAA/TAA). Head-space solid phase microextraction and gas chromatography-mass spectrometry (HS-SPME/GC-MS) analysis identified in total 44 volatile compounds in the two samples while those like aldehydes, alcohols, ketones, etc. had greater amounts in the sample roasted without tinfoil paper wrapping. Orthogonal partial least squares discriminant analysis (OPLS-DA) suggested that hexadecanal, octanal, tetradecanal, (E,E)-2,4-decadienal, pentanal, hexanal, etc. (VIP>1) could be markers to differentiate volatile flavor composition of the two samples. Moreover, gas chromatography-olfactometry of aroma extract dilution analysis (AEDA/GC-O) identified 22 odor-active compounds (i.e. odorants) in the two samples with aldehydes being the highest number followed by sulfur-containing compounds and pyrazines. Overall, the odor-active compounds found by GC-O were similar in the two samples whereas they had different flavor dilution factors. Then aroma profile of the two samples was compared by radar charts based on the compounds of higher dilution factors representing the roasted duck leg odors. It suggested harmonious and more prominent roasted and fatty aromas pertaining to the sample without tinfoil paper wrapping，which agreed with the sensory analysis results.

Abstract Anaplasmosis is a highly prevalent tick-borne intracellular bacterial disease that affects various host species globally, particularly ruminants in tropical and subtropical regions. However, information regarding the distribution and epidemiology of anaplasmosis in small and large ruminants on Hainan Isalnd is limited. To address this knowledge gap, the present study aimed to assess the occurrence of Anaplasma spp. infections in goats (N = 731) and cattle (N = 176) blood samples using nested PCR and conventional PCR based assays. The results revealed an overall prevalence of 30.1% in goats and 14.8% in cattle. The infection rates of A. bovis, A. phagocytophilum, A. ovis and A. capra in goat samples were 22.7%, 13.8%, 2.0% and 3.4%, respectively, while the infection rates of A. bovis, A. phagocytophilum and A. marginale in cattle samples were 11.4%, 6.3% and 5.7%, respectively. A. bovis exhibited the highest prevalence among the Anaplasma spp. in both goat and cattle samples. In addition, the most frequent co-infection was the one with A. phagocytophilum and A. bovis. It was found that the age, sex and feeding habits of cattle and goats were considered to be important risk factors. Evaluation of the risk factor relating to the rearing system showed that the infection rate for the free-range goats and cattle was significantly higher when compared with stall-feeding system. This study represents one of the largest investigations on the distribution, prevalence, and risk factors associated with Anaplasma infection in ruminants on Hainan Island, highlighting a higher circulation of the infection in the region than previously anticipated. Further reasesrch is necessary to investigate tick vectors, reservoir animals, and the zoonotic potential of the Anaplasma spp. in this endemic region of Hainan Island.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1’s carcinogenic effects in ccRCC. Methods Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways. Results The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P

Abstract Background Breast cancer (BC) is the leading cause of morbidity and the second leading cause of death among female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER-positive, HER2+) currently, there are still no effective targeted drugs or treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it is urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, the effect of ERCC6L on the tumorigenesis and progression of breast cancer is unclear. Methods and results Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. An ERCC6L conditional knockout mouse model was first established in this study, and the results confirmed that ERCC6L was required for the development of the mammary gland and the tumorigenesis and progression of mammary gland cancers. In in vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L promoted cell proliferation, migration and invasion, while knockdown of ERCC6L caused the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G2/M checkpoint signalling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are closely related factors in mitosis and are involved in the malignant progression of breast cancer. Conclusions We first demonstrated that ERCC6L deficiency can significantly inhibit the occurrence and development of mammary gland tumors. ERCC6L was found to accelerate the cell cycle by regulating the p53/p21/CDK1/Cyclin B and PLK/CDC25C/CDK1/Cyclin B signalling pathways, thereby promoting the malignant progression of breast cancer cell lines. There was a direct interaction between KIF4A and ERCC6L, and both are closely associated with mitosis and contribute to growth and metastasis of breast tumor. To sum up, our results suggest that ERCC6L may be used as a promising target for the treatment of BC.

Eukaryotic phytoplankton play a major role in the circulation of material and energy in a lake’s ecosystem. The acquisition of information on the eukaryotic phytoplankton community is extremely significant for handling and regulating the ecosystems of lakes. In this study, samples were collected from the western half of Chaohu Lake in the summer and winter periods. Analyses revealed that the eukaryotic phytoplankton in this region comprised 70 genera, 34 orders, and 7 phyla. There were 61 genera, 29 orders, and 7 phyla in summer, and 25 genera, 14 orders, and 5 phyla in winter. The dominant genus was Chlamydomonas of Chlorophyta in summer. In contrast, the dominant genus was Mychonastes of Chlorophyta in winter. The diversity index analysis revealed that the eukaryotic phytoplankton community exhibited greater fluctuation in the summer than in the winter. Moreover, analysis of the physiochemical properties of the water samples showed considerable spatial and temporal differences in the water quality. This paper focusses primarily on analysing the influence of the physiochemical properties of water on the eukaryotic phytoplankton community. In particular, the effects of the major physicochemical properties of water on the community evolution of eukaryotic phytoplankton classes were evaluated using the redundancy analysis method. The findings demonstrated that total phosphorus (TP), PO4−-P, NH4+-N, and total nitrogen (TN) were the primary influencing factors in summer, whereas NO3−-N, DO, and water temperature (WT) were the major influencing factors in winter. Subsequently, the Mantel test revealed that the phylum level of the eukaryotic phytoplankton community was significantly correlated with WT, DO, NH4+-N, TN, TP, and Chlorophyll a. Variance partitioning analysis indicated that seasonal factors accounted for a large proportion of the variation in the eukaryotic phytoplankton community, reaching 48.4%. Subsequently, co-occurrence network analysis demonstrated that most families of eukaryotic phytoplankton were facilitated mutually, with the proportion of promotion being 94.1%. This study provides insight into the crucial factors that influence the phytoplankton communities and a reasonable control direction for the positive evolution of the eukaryotic phytoplankton community in the western half of Chaohu Lake.

PDR positioning is currently the core issue of autonomous positioning, there is a problem of high noise and interference in dynamic measurement using PDR (Pedestrian Dead Reckoning) MEMS (Micro-Electro-Mechanical System) device, which is often a low precision multi-source integration sensor. Two new models of improved spectral subtraction (ISS) and PDRS (PDR-Spectral subtraction) spectral subtraction are constructed in this paper according to the spectrum features of the periodic noise generated from personnel stepping in PDR positioning. It is proposed a two-stage noise reduction method of spectrum subtraction-Wiener filtering for obtaining the static magnetic sequence of personnel path and reducing the real-time noise in PDR positioning, which main mechanism is to use the step power spectrum as the background noise for primary noise reduction, secondary Wiener filtering noise reduction according to the correlation between the denoised signal and the reference signal. A self-made MEMS-based positioning device HBEQ-1 and a high-precision magnetometer FVM-400 were used to collect dynamic and static magnetic value from the test area, and a spectral subtraction-Wiener two-stage noise reduction test was carried out. The experimental results show that the improved ISS spectral subtraction and PDRS spectral subtraction are effective in denoising the dynamic magnetic measurement, but there is still a certain deviation between the peak value and the amplitude of the denoised signal. After secondary noise reduction by Wiener filtering, the signal morphology similarity of magnetic curve and the reference reached 0.7975, and the matched path values of the dynamic magnetic value reached around 12000–13000. It showed that the denoising effect is good and the waveform of denoised signal and the reference signal is similar, but there is spatial stretching of the overall magnetic sequence. It is shown that the spectral subtraction-Wiener noise reduction method cannot eliminate the inertial delay bias generated by personnel walking, the processing does not distort the magnetic signal, maintains spatial characteristics of the static magnetic sequence of personnel path, which is an excellent model for noise reduction of dynamic magnetic measurements in PDR positioning.

Abstract Background Dirofilariasis, the disease caused by Dirofilaria spp., and in particular by Dirofilaria immitis and Dirofilaria repens in canines, occurs frequently in canids and felids, and occasionally in humans, in temperate, sub-tropical and tropical regions globally. Although highly effective, safe and convenient preventive medicines have been available for the treatment of dirofilariasis for the past three decades, the disease remains a major veterinary and public health concern in endemic areas. The insect vectors, host-parasite relationships and interactions of Dirofilaria spp. have received little attention in China, and there is very little information in English regarding the prevalence of dirofilariasis in animals and humans in the country. The aim of this systematic review and meta-analysis is to evaluate the status of canine dirofilariasis in China based on the available literature in English and in Chinese. Methods We systematically searched five databases for epidemiologic studies on the prevalence of canine dirofilariasis in China and finally selected 42 studies eligible for inclusion in the systematic review and meta-analysis. The meta-analysis was performed using the random effects model in the meta package in R v4.2.1. Results The random effects model gave a pooled and weighted prevalence of Dirofilaria infection among dogs in China in the past 100 years of 13.8% (2896/51,313, 95% confidence interval 8.2–20.4%) with a high level of heterogeneity (I 2 = 99.5%). Conclusions Our analyses indicated that the prevalence of canine dirofilariasis in China has gradually declined, but that the range of Dirofilaria spp. has expanded. Older and outdoor dogs presented a higher rate of positive infection. The findings indicated that more attention should be paid to host factors for the effective control and management of this disease. Graphical Abstract

Abstract Divergent N6-methyladenosine (m6A) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by m6A regulators or m6A RNA methylation regulators, i.e., methyltransferases (“writers”), demethylases (“erasers”), and m6A-binding proteins (“readers”). Aberrant m6A modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant m6A regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of m6A regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that m6A regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of m6A regulators in cancer. The roles and mechanisms for epigenetic modification of m6A regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of m6A regulators.

Abstract Increased rates of ribosome biogenesis have been recognized as hallmarks of many cancers and are associated with poor prognosis. Using a CRISPR synergistic activation mediator (SAM) system library targeting 89 ribosomal proteins (RPs) to screen for the most oncogenic functional RPs in human esophageal squamous cell carcinoma (ESCC), we found that high expression of RPS15 correlates with malignant phenotype and poor prognosis of ESCC. Gain and loss of function models revealed that RPS15 promotes ESCC cell metastasis and proliferation, both in vitro and in vivo. Mechanistic investigations demonstrated that RPS15 interacts with the K homology domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which recognizes and directly binds the 3′-UTR of MKK6 and MAPK14 mRNA in an m6A-dependent manner, and promotes translation of core p38 MAPK pathway proteins. By combining targeted drug virtual screening and functional assays, we found that folic acid showed a therapeutic effect on ESCC by targeting RPS15, which was augmented by the combination with cisplatin. Inhibition of RPS15 by folic acid, IGF2BP1 ablation, or SB203580 treatment were able to suppress ESCC metastasis and proliferation via the p38 MAPK signaling pathway. Thus, RPS15 promotes ESCC progression via the p38 MAPK pathway and RPS15 inhibitors may serve as potential anti-ESCC drugs.

Abstract Gene behavior is governed by activity of other genes in an ecosystem as well as context-specific cues including cell type, microenvironment, and prior exposure to therapy. Here, we developed the Algorithm for Linking Activity Networks (ALAN) to compare gene behavior purely based on patient -omic data. The types of gene behaviors identifiable by ALAN include co-regulators of a signaling pathway, protein-protein interactions, or any set of genes that function similarly. ALAN identified direct protein-protein interactions in prostate cancer (AR, HOXB13, and FOXA1). We found differential and complex ALAN networks associated with the proto-oncogene MYC as prostate tumors develop and become metastatic, between different cancer types, and within cancer subtypes. We discovered that resistant genes in prostate cancer shared an ALAN ecosystem and activated similar oncogenic signaling pathways. Altogether, ALAN represents an informatics approach for developing gene signatures, identifying gene targets, and interpreting mechanisms of progression or therapy resistance.

Parkinson’s disease (PD) is characterized by microglia activation that leads to neuroinflammation. Heat shock transcription factor 1 (HSF1) is known to exert neuroprotective effects on neurodegenerative diseases. This study sought to analyse the role and mechanism of HSF1 in PD-induced neuroinflammation. The PD mouse models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animal behaviour capacities and neuronal damage were assessed via behavioural tests, tyrosine hydroxylase (TH) staining, and immunofluorescence. Levels of HSF1, miR-214-3p, nuclear factor of activated T cells 2 (NFATc2), and neuroinflammatory factors were detected via RT-qPCR, Western blotting, and ELISA.Binding relationships between HSF1 and miR-214-3p, miR-214-3p, and NFATc2 were tested via dual-luciferase or chromatin immunoprecipitation assays. Functional rescue experiments were designed to confirm the roles of miR-214-3p and NFATc2. HSF1 expression in brain tissues was downregulated upon MPTP treatment. HSF1 overexpression reduced motor deficits and loss of dopaminergic neurons, increased TH-positive neurons, and repressed neuroinflammation and micro-glia activation. Mechanically, HSF1 bound to the miR-214-3p promoter to increase its expression and inhibited NFATc2 transcription. miR-214-3p downregulation or NFATc2 overexpression reversed the inhibition of HSF1 overexpression on neuroinflammation and microglia activation. Overall, our findings unveiled the therapeutic role of HSF1 in PD-induced neuroinflammation and microglia activation via regulating miR-214-3p and NFATc2.

Abstract Breast carcinoma is the second largest cancer in the world among women. Early detection of breast cancer has been shown to increase the survival rate, thereby significantly increasing patients’ lifespan. Mammography, a noninvasive imaging tool with low cost, is widely used to diagnose breast disease at an early stage due to its high sensitivity. Although some public mammography datasets are useful, there is still a lack of open access datasets that expand beyond the white population as well as missing biopsy confirmation or with unknown molecular subtypes. To fill this gap, we build a database containing two online breast mammographies. The dataset named by Chinese Mammography Database (CMMD) contains 3712 mammographies involved 1775 patients, which is divided into two branches. The first dataset CMMD1 contains 1026 cases (2214 mammographies) with biopsy confirmed type of benign or malignant tumors. The second dataset CMMD2 includes 1498 mammographies for 749 patients with known molecular subtypes. Our database is constructed to enrich the diversity of mammography data and promote the development of relevant fields.

Abstract As one member of fatty acid binding proteins (FABPs), FABP5 makes a contribution in the occurrence and development of several tumor types, but existing analysis about FABP5 and FABP5-related molecular mechanism remains limited. Meanwhile, some tumor patients showed limited response rates to current immunotherapy, and more potential targets need to be explored for the improvement of immunotherapy. In this study, we made a pan-cancer analysis of FABP5 based on the clinical data from The Cancer Genome Atlas database for the first time. FABP5 overexpression was observed in many tumor types, and was statistically associated with poor prognosis of several tumor types. Additionally, we further explored FABP5-related miRNAs and corresponding lncRNAs. Then, miR-577-FABP5 regulatory network in kidney renal clear cell carcinoma as well as CD27-AS1/GUSBP11/SNHG16/TTC28-AS1-miR-22-3p-FABP5 competing endogenous RNA regulatory network in liver hepatocellular carcinoma were constructed. Meanwhile, Western Blot and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis were used to verify miR-22-3p-FABP5 relationship in LIHC cell lines. Moreover, the potential relationships of FABP5 with immune infiltration and six immune checkpoints (CD274, CTLA4, HAVCR2, LAG3, PDCD1 and TIGIT) were discovered. Our work not only deepens the understanding of FABP5’s functions in multiple tumors and supplements existing FABP5-related mechanisms, but also provides more possibilities for immunotherapy.

The application of ammonia (NH3) in combustion devices, such as internal combustion engines (ICEs), is expected to largely reduce the greenhouse gas (CO2) emission. NH3/H2 cofiring fuels in homogeneous charge compression ignition (HCCI) engines may provide a potential way to deal with zero carbon requirements. However, in HCCI engines, the ignition process needs to be moderated since the ignition is only controlled by the chemical kinetics of the fuel. Therefore, this study investigates the effects of temperature and composition stratification strategies on the auto-ignition characteristics of NH3/H2/air mixtures under HCCI engine operating conditions with direct numerical simulation (DNS). 12 cases with different stratification strategies have been set under turbulent conditions. The chemical kinetics of NH3/H2/air was verified with the laminar flame speeds and ignition delay times. Results show that the temperature stratification can reduce the peak value of heat release rate (HRR), advance the ignition time and extend the combustion duration. In this case, the chemical reaction front is dominated by the deflagration or flame propagation mode. However, in contrast, composition stratification shows very limited effect on the overall combustion process, which is similar to homogeneous ignition and denoted as the spontaneous ignition mode. When increasing the hydrogen content in the fuel, the ignition time is obviously advanced and the peak of HRR is slightly increased. Higher NO emission is also observed which is mainly due to the increase of O, H, and OH intermediates to enhance the fuel NO production. Temperature stratification degree can improve the ignition process under both negatively correlated or unrelated T-Φ fields. However, the improvement is more evident for unrelated T-Φ condition when increasing the stratification degree.

Although miR-5195-3p has been acknowledged for its tumor suppressor role in diverse cancer categories, its precise functions and mechanisms concerning melanoma have not been comprehensively elucidated. In this study, we employed quantitative reverse transcription PCR, Western blot analysis, and immunohistochemistry staining to investigate the expression patterns of miR-5195-3p and poly (rC) binding protein 2 (PCBP2) in melanoma tissues compared to adjacent tissues. Our findings revealed downregulation of miR-5195-3p and upregulation of PCBP2 in melanoma tissues. Through the implementation of a luciferase reporter assay, we successfully identified PCBP2 as a newly discovered target of miR-5195-3p in melanoma cells. Enforced expression of miR-5195-3p via mimics inhibited cell proliferation and migration in A375 and A2058 cells, as demonstrated by CCK-8 and transwell migration assays. In melanoma cells, reintroduction of PCBP2 partially reversed the inhibitory effects of miR-5195-3p overexpression. Treatment with LY294002, an inhibitor of the PI3K/AKT signaling pathway, also reversed the effects of PCBP2 in melanoma cells. Furthermore, our results suggest that miR-5195-3p inhibits the activation of the PI3K/AKT signaling pathway in melanoma by inhibiting PCBP2. In conclusion, our research has identified the miR-5195-3p targeting of the PCBP2-mediated PI3K/AKT signaling pathway as a potential therapeutic target for melanoma treatment.

Stoichiometric operation natural gas engine can achieve low emissions and high-power output by combining EGR and three-way catalytic converter. However, under high load conditions, engine performance will be deteriorated due to the knocking limits. The main methods to solve the knocking problems of spark ignition engines are shortening the flame propagation time and reducing the temperature and pressure rise of the end mixture. This paper firstly established a 3D model based on a natural gas engine, and then conducted the numerical simulations to investigate the effects of chamber geometry, hydrogen ratio and EGR ratio on engine knocking and combustion. The validation indicates a satisfied numerical results of chamber pressure and heat release rate. The turbine chamber exhibits relatively better swirl and tumble, thus achieving the highest turbulence intensity. HCNG fuel will increase the knocking tendency of the engine. In the meantime, the addition of hydrogen will also reduce the IMEP of the engine due to the low volume heat value of hydrogen. However, the addition of hydrogen may accelerate the combustion rate at the end of combustion to a certain extent. EGR can significantly reduce the knocking tendency of HCNG engine by reducing the combustion temperature in the cylinder. Compared with the case of 14% EGR rate, the ignition angle of 30% EGR case is advanced by 19 °CA, and the indicated thermal efficiency is increased by 2.06%.

Abstract Background The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non‐muscle‐invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette‐Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients. Methods A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non‐response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan–Meier method was used to compare recurrence‐free survival (RFS) and progression‐free survival (PFS) between the two groups. Results Multivariable logistic regression analysis revealed that high SIRI (p = 0.001), high MLR (p = 0.015), and high tumor pathological T stage (p = 0.015) were significantly correlated with non‐response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p