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Abstract Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.

BackgroundThe clinical phenotypes of 16p13.11 microduplication syndrome have been extensively reported in previous studies, mostly about adults and children, with limited information available on fetal cases. This study aims to explore the genotype-phenotype correlation of fetuses with 16p13.11 microduplication syndrome and analyze the characteristics of prenatal diagnosis indications and provide clinical information for prenatal and postnatal genetic counseling.MethodsWe conducted a retrospective analysis of 3,451 pregnant women who underwent invasive prenatal diagnosis for SNP array between January 2018 and December 2022 at the Jinan Maternal and Child Health Hospital. Descriptive statistical analysis was performed on the prenatal diagnosis indications, pedigree analysis, pregnancy outcomes and postnatal follow-up of 15 fetuses with 16p13.11 microduplication syndrome.ResultsSNP array revealed that 15 fetuses had duplications in the 16p13.11 region with varying prenatal diagnosis indications. Among the cases, 6/15 exhibited ultrasound abnormalities, 5/15 had abnormal chromosomal copy number variations as indicated by non-invasive prenatal testing (NIPT), one case involved advanced maternal age, and 3/15 had other abnormalities. 16p13.11 microduplication syndrome was closely related to ultrasound abnormalities, especially structural abnormalities and soft marker anomalies (abnormal ultrasonic soft indicators), while the indication of NIPT could improve the detection rate of copy number variations (CNVs) in this region. Only 7/15 fetuses underwent pedigree verification, with one case of de novo 16p13.11 microduplication, and the others inherited from one parent. Pregnancy was terminated in 2/15 cases and the outcome of one case is unknown due to loss to follow-up. Among the remaining cases, only one case exhibited a ventricular septal defect, while another presented with omphalocele. No other obvious abnormalities were reported postnatally.ConclusionThe prenatal phenotypes of fetuses with 16p13.11 microduplication were highly associated with ultrasound abnormalities but lacked specificity. Comprehensive genetic tracing, outcome analysis, and follow-up are essential for providing accurate prenatal and postnatal genetic counseling.

Stroke is a primary cause of noncommunicable disease-related death and disability worldwide. The most common form, ischemic stroke, is increasing in incidence resulting in a significant burden on patients and society. Urgent action is thus needed to address preventable risk factors and improve treatment methods. This review examines emerging technologies used in the management of ischemic stroke, including neuroimaging, regenerative medicine, biology, and nanomedicine, highlighting their benefits, clinical applications, and limitations. Additionally, we suggest strategies for technological development for the prevention, diagnosis, and treatment of ischemic stroke.

Abstract Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-Cre ERT2 ;Mettl3 fl/+ mice with Mettl3 fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.

Quantifying the vertical distribution of leaf chlorophyll content (LCC) is integral for a comprehensive understanding of the physiological status and function of winter wheat crops, having significant implications for crop management and yield optimization. In this study, we investigated the vertical LCC trait of winter wheat during two consecutive field growth seasons using proximal multispectral imaging measurements to evaluate vertical variations of LCC within winter wheat canopies. The results revealed the non-uniform vertical LCC distribution varied across the entire growth season. The effects of nitrogen fertilization rate on LCC among vertical layers increased gradually from upper to lower layers of canopy. To enhance LCC prediction accuracy, this study proposes a deep transfer learning network model for leaf trait estimation (LeafTNet). It integrates the advantages of physical radiative transfer simulations with deep neural network through transfer learning. The results demonstrate that the LeafTNet achieved remarkable predictive performance and strong robustness. Furthermore, the proposed method exhibits superior estimation accuracy compared to empirical statistical method and traditional machine learning method. This study highlights the performance of LeafTNet in accurately and efficiently quantifying LCC from proximal multispectral data, which provide technical support for the estimation of the vertical distribution of leaf traits and improve crop management.

Serine/arginine-rich splicing factor 7 (SRSF7), a known splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we find that the gene expression of SRSF7 is positively correlated with glioblastoma (GBM) cell-specific m6A methylation. We then indicate that SRSF7 is a novel m6A regulator, which specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration, through recruiting the methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of GBM cells largely dependent on the presence of the m6A methyltransferase. The two m6A sites on the mRNA for PDZ-binding kinase (PBK) are regulated by SRSF7 and partially mediate the effects of SRSF7 in GBM cells through recognition by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Together, our discovery reveals a novel role of SRSF7 in regulating m6A and validates the presence and functional importance of temporal- and spatial-specific regulation of m6A mediated by RNA-binding proteins (RBPs).

Introduction: Diabetic retinopathy (DR) represents a major cause of adult blindness, and early discovery has led to significant increase in the number of patients with DR. The drugs currently used for treatment, such as ranibizumab, mainly focus on the middle and late periods of DR, and thus do not meet the clinical need. Here, the potential mechanisms by which compound Danshen Dripping Pills (CDDP) might protect against early DR were investigated.Methods: Db/db mice were used to establish a DR model. The initial weights and HbA1c levels of the mice were monitored, and retinal pathology was assessed by hematoxylin-eosin (HE) staining. The vascular permeability of the retina and thickness of each retinal layer were measured, and electroretinogram were performed together with fundus fluorescein angiography and optical coherence tomography. The levels of inflammatory factors were examined in retinal tissue, as well as those of intercellular adhesion molecule 1 (ICAM-1), IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the serum using ELISA. Immunohistochemistry was used to evaluate levels of vascular endothelial growth factor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bclassociated X protein (Bax). Retinal cell injury and apoptosis were examined by TdT-mediated dUTP Nick End Labeling (TUNEL) assays.Results: The data showed that CDDP significantly improved cellular disarrangement. Imaging data indicated that CDDP could reduce vascular permeability and the amplitude of oscillatory potentials (OPs), and restore the thickness of the ganglion cell layer. Moreover, CDDP reduced the expression levels of inflammatory factors in both the retina and serum.Conclusion: These findings strongly suggest that CDDP prevents early DR through vascular and neuroprotection.

ABSTRACTObjective To analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML).Methods A total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L.Results The application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes.Conclusions G/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.

Abstract Porcine epidemic diarrhoea (PED) caused by porcine epidemic diarrhoea virus (PEDV) has led to significant economic losses in the swine industry worldwide. Histone Cluster 2, H2BE (HIST2H2BE), the main protein component in chromatin, has been proposed to play a key role in apoptosis. However, the relationship between H2BE and PEDV remains unclear. In this study, H2BE was shown to bind and interact with PEDV nonstructural protein 9 (Nsp9) via immunoprecipitation-mass spectrometry (IP-MS). Next, we verified the interaction of Nsp9 with H2BE by immunoprecipitation and immunofluorescence. H2BE colocalized with Nsp9 in the cytoplasm and nuclei. PEDV Nsp9 upregulated the expression of H2BE by inhibiting the expression of IRX1. We demonstrated that overexpression of H2BE significantly promoted PEDV replication, whereas knockdown of H2BE by small interfering RNA (siRNA) inhibited PEDV replication. Overexpression of H2BE led to significantly inhibited GRP78 expression, phosphorylated PERK (p-PERK), phosphorylated eIF2 (p-eIF2), phosphorylated IRE1 (p-IRE1), and phosphorylated JNK (p-JNK); negatively regulated CHOP and Bax expression and caspase-9 and caspase-3 cleavage; and promoted Bcl-2 production. Knocking down H2BE exerted the opposite effects. Furthermore, we found that after deletion of amino acids 1–28, H2BE did not promote PEDV replication. In conclusion, these studies revealed the mechanism by which H2BE is associated with ER stress-mediated apoptosis to regulate PEDV replication. Nsp9 upregulates H2BE. H2BE plays a role in inhibiting apoptosis and thus facilitating viral replication, which depends on the N-terminal region of H2BE (amino acids 1–28). These findings provide a reference for host–PEDV interactions and offer the possibility for developing strategies for PEDV decontamination and prevention.

More than 700 million confirmed cases of Coronavirus Disease-2019 (COVID-19) have been reported globally, and 10–60% of patients are expected to exhibit “post-COVID-19 symptoms,” which will continue to affect human life and health. In the absence of safer, more specific drugs, current multiple immunotherapies have failed to achieve satisfactory efficacy. Ginseng, a traditional Chinese medicine, is often used as an immunomodulator and has been used in COVID-19 treatment as a tonic to increase blood oxygen saturation. Ginsenosides are the main active components of ginseng. In this review, we summarize the multiple ways in which ginsenosides affect post-COVID-19 symptoms, including inhibition of lipopolysaccharide, tumor necrosis factor signaling, modulation of chemokine receptors and inflammasome activation, induction of macrophage polarization, effects on Toll-like receptors, nuclear factor kappa-B, the mitogen-activated protein kinase pathway, lymphocytes, intestinal flora, and epigenetic regulation. Ginsenosides affect virus-mediated tissue damage, local or systemic inflammation, immune modulation, and other links, thus alleviating respiratory and pulmonary symptoms, reducing the cardiac burden, protecting the nervous system, and providing new ideas for the rehabilitation of patients with post-COVID-19 symptoms. Furthermore, we analyzed its role in strengthening body resistance to eliminate pathogenic factors from the perspective of ginseng-epidemic disease and highlighted the challenges in clinical applications. However, the benefit of ginsenosides in modulating organismal imbalance post-COVID-19 needs to be further evaluated to better validate the pharmacological mechanisms associated with their traditional efficacy and to determine their role in individualized therapy.

Abstract Background Mitochondrial autophagy maintains mitochondrial function and cellular homeostasis and plays a critical role in the pathological process of cerebral ischemia/reperfusion injury (CIRI). Whether Gypenoside XVII (GP17) has regulatory effects on mitochondrial autophagy against CIRI remains unclear. The purpose of this study was to investigate the pharmacodynamic effects and mechanisms of GP17 on mitochondrial autophagy after CIRI. Methods A rat middle cerebral artery occlusion/reperfusion (MCAO/R) model was used to assess the effects of GP17 against CIRI and to explore the underlying mechanisms. An oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was used to verify the ameliorative effects on mitochondrial damage and to probe the autophagy pathways involved in combating neural injuries. Results The in vivo results showed that GP17 significantly improved mitochondrial metabolic functions and suppressed cerebral ischemic injury, possibly via the autophagy pathway. Further research revealed that GP17 maintains moderate activation of autophagy under ischemic and OGD conditions, producing neuroprotective effects against CIRI, and that the regulation of mitochondrial autophagy is associated with crosstalk between the SIRT1-FOXO3A and Hif1a-BNIP3 signalling pathway that is partially eliminated by the specific inhibitors AGK-7 and 2-ME. Conclusion Overall, this work offers new insights into the mechanisms by which GP17 protects against CIRI and highlights the potential of therapy with Notoginseng leaf triterpene compounds as a novel clinical strategy in humans.

Numerous viruses manipulate host factors for viral production. We demonstrated that human enterovirus A71 (EVA71), a primary causative agent for hand, foot, and mouth disease (HFMD), increased the level of the DNA damage response (DDR) marker γ-H2AX. DDR is primarily mediated by the ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), or DNA-dependent protein kinase (DNA-PK) pathways. Upregulation of γ-H2AX by EVA71 was dependent on the ATR but not the ATM or DNA-PK pathway. As a nuclear factor, there is no previous evidence of cytoplasmic distribution of γ-H2AX. However, the present findings demonstrated that EVA71 encouraged the localization of γ-H2AX to the cytoplasm. Of note, γ-H2AX formed a complex with structural protein VP3, non-structural protein 3D, and the viral genome. Treatment with an inhibitor or CRISPR/Cas9 technology to decrease or silence the expression of γ-H2AX decreased viral genome replication in host cells; this effect was accompanied by decreased viral protein expression and virions. In animal experiments, caffeine was used to inhibit DDR; the results revealed that caffeine protected neonatal mice from death after infection with EVA71, laying the foundation for new therapeutic applications of caffeine. More importantly, in children with HFMD, γ-H2AX was upregulated in peripheral blood lymphocytes. The consistent in vitro and in vivo data on γ-H2AX from this study suggested that caffeine or other inhibitors of DDR might be novel therapeutic agents for HFMD.

The gut-brain axis has been shown to play a vital role in the prognosis and recovery of ischemic stroke (IS), which is associated with gut microbiota dysfunction and changes in the gastrointestinal system and epithelial barrier integrity. In turn, gut microbiota and its derived metabolites can influence stroke outcomes. In this review, we first describe the relationship between IS (clinical and experimental IS) and the gut microbiota. Second, we summarize the role and specific mechanisms of microbiota-derived metabolites in IS. Further, we discuss the roles of natural medicines targeting the gut microbiota. Finally, the potential use of the gut microbiota and derived metabolites as a promising therapeutic opportunity for stroke prevention, diagnosis, and treatment is explored.

Accurate and timely monitoring of biochemical and biophysical traits associated with crop growth is essential for indicating crop growth status and yield prediction for precise field management. This study evaluated the application of three combinations of feature selection and machine learning regression techniques based on unmanned aerial vehicle (UAV) multispectral images for estimating the bio-parameters, including leaf area index (LAI), leaf chlorophyll content (LCC), and canopy chlorophyll content (CCC), at key growth stages of winter wheat. The performance of Support Vector Regression (SVR) in combination with Sequential Forward Selection (SFS) for the bio-parameters estimation was compared with that of Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest (RF) regression with internal feature selectors. A consumer-grade multispectral UAV was used to conduct four flight campaigns over a split-plot experimental field with various nitrogen fertilizer treatments during a growing season of winter wheat. Eighteen spectral variables were used as the input candidates for analyses against the three bio-parameters at four growth stages. Compared to LASSO and RF internal feature selectors, the SFS algorithm selects the least input variables for each crop bio-parameter model, which can reduce data redundancy while improving model efficiency. The results of the SFS-SVR method show better accuracy and robustness in predicting winter wheat bio-parameter traits during the four growth stages. The regression model developed based on SFS-SVR for LAI, LCC, and CCC, had the best predictive accuracy in terms of coefficients of determination (R2), root mean square error (RMSE) and relative predictive deviation (RPD) of 0.967, 0.225 and 4.905 at the early filling stage, 0.912, 2.711 μg/cm2 and 2.872 at the heading stage, and 0.968, 0.147 g/m2 and 5.279 at the booting stage, respectively. Furthermore, the spatial distributions in the retrieved winter wheat bio-parameter maps accurately depicted the application of the fertilization treatments across the experimental field, and further statistical analysis revealed the variations in the bio-parameters and yield under different nitrogen fertilization treatments. This study provides a reference for monitoring and estimating winter wheat bio-parameters based on UAV multispectral imagery during specific crop phenology periods.

Drilling cores, the most direct and accurate first-hand data reflecting the subsurface geological information, are of unclear orientation for most boreholes. The image feature comparison method is one of the most widely used methods for core orientation. However, this method is mainly conducted by manual comparison, which is labor-intensive, time-consuming and inaccurate. In this paper, we propose an automatic core orientation method by comparing the planar geologic features (one of the most common features) in drill-core scans and microresistivity images. This method first automatically detects planar geologic features by combing the vertical gradient-based Otsu threshold segmentation, Hough transform and optimal sinusoid extraction and then determines correction difference of the core orientation by comparing the dip azimuths of the optimal sinusoids from the two types of images. This method is successfully applied to actual data. The automatic core orientation results are compared with the manual core orientation results. The results show that this method can eliminate human errors and has higher accuracy, especially for core scan images with non-distinct features. The proposed method has wide application potential in the fields of hydrocarbon exploration and development, scientific drilling research, and basic geological surveys.

Ferroptosis is a novel form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which causes membrane injury. Under the catalysis of iron ions, cells deficient in glutathione peroxidase (GPX4) cannot preserve the balance in lipid oxidative metabolism, and the buildup of reactive oxygen species on the membrane lipids leads to cell death. An increasing body of evidence suggests that ferroptosis plays a significant role in the development and occurrence of cardiovascular diseases. In this paper, we mainly elaborated on the molecular mechanisms regulating ferroptosis and its impact on cardiovascular disease to lay the groundwork for future studies on the prophylaxis and treatment of this patient population.

DnaJ proteins are key molecular chaperones that act as a part of the stress response to stabilize plant proteins, thereby maintaining protein homeostasis under stressful conditions. Herein we used transgenic plants to explore the role of the tomato (Solanum lycopersicum) SlDnaJ20 chloroplast DnaJ protein in to the resistance of these proteins to cold. When chilled, transgenic plants exhibited superior cold resistance, with reduced growth inhibition and cellular damage and increased fresh mass and chlorophyll content relative to control. These transgenic plants further exhibited increased Fv/Fm, P700 oxidation, φRo, and δRo relative to control plants under chilling conditions. Under these same cold conditions, these transgenic plants also exhibited higher levels of core proteins in the photosystem I (PSI) and II (PSII) complexes (PsaA and PsaB; D1 and D2) relative to control wild-type plants. Together these results suggested that the overexpression of SlDnaJ20 is sufficient to maintain PSI and PSII complex stability and to alleviate associated photoinhibition of these complexes, thereby increasing transgenic plant resistance to cold stress.

Ischemic stroke is one of the major contributors to death and disability worldwide. Thus, there is an urgent need to develop early brain tissue perfusion therapies following acute stroke and to enhance functional recovery in stroke survivors. The morbidity, therapy, and recovery processes are highly orchestrated interactions involving the brain with other tissues. Exosomes are natural and ideal mediators of intercellular information transfer and recognized as biomarkers for disease diagnosis and prognosis. Changes in exosome contents express throughout the physiological process. Accumulating evidence demonstrates the use of exosomes in exploring unknown cellular and molecular mechanisms of intercellular communication and organ homeostasis and indicates their potential role in ischemic stroke. Inspired by the unique properties of exosomes, this review focuses on the communication, diagnosis, and therapeutic role of various derived exosomes, and their development and challenges for the treatment of cerebral ischemic stroke.

Abstract Tumor‐derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre‐metastatic niche that facilitates organotropic metastasis. Identifying the organ‐specific molecular determinants of EVs can develop potential anti‐metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer‐derived EVs, are found to play a crucial role in facilitating bone‐tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre‐metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP‐associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV‐integrin. VAPA‐enriched LOs‐induced pre‐metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs‐delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott–Aldrich syndrome protein (N‐WASP) via dual mechanisms, consequently resulting in ARP2/3 complex‐mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N‐WASP inhibitor 187‐1‐packaged LOs (LOs/187‐1) dramatically abolishes the inductive effect of VAPA‐enriched LOs on pre‐metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone‐tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.

Abstract That the high frequency and good replication capacity of strains with reduced susceptibility to neuraminidase inhibitors (NAIs) in highly pathogenic avian influenza H7N9 (HPAI H7N9) virus made it a significance to further study its drug resistance. HPAI H7N9 viruses bearing NA I222L or E119V substitution and two mutations of I222L-E119V as well as their NAIs-sensitive counterpart were generated by reverse genetics for NA inhibition test and replication capability evaluation in vitro. The attenuated H7N9/PR8 recombinant viruses were developed to study the pathogenicity and drug resistance brought by the above substitutions to mice. The IC50 fold change of oseltamivir to HPAI H7N9 with NA222L-119V is 306.34 times than that of its susceptible strain, and 3.5 times than the E119V mutant virus. HPAI H7N9 bearing NA222L-119V had good replication ability with peak value of more than 6log10 TCID50/ml in MDCK cells. H7N9/PR8 virus bearing NA222L-119V substitutions leaded to diffuse pneumonia, significant weight loss and fatality in mice. NA E119V made H7N9/PR8 virus resistant to oseltamivir, and I222L-E119V had synergistic resistance to oseltamivir in mice. Due to the good fitness of drug resistant strains of HPAI H7N9 virus, it is necessary to strengthen drug resistance surveillance and new drug research.

Atherosclerosis is the pathological basis of various vascular diseases, including those with high mortality, such as myocardial infarction and stroke. However, its pathogenesis is complex and has not been fully elucidated yet. Over the past few years, single-cell RNA sequencing (scRNA-seq) has been developed and widely used in many biological fields to reveal biological mechanisms at the cellular level and solve the problems of cellular heterogeneity that cannot be solved using bulk RNA sequencing. In this review, we briefly summarize the existing scRNA-seq technologies and focus on their application in atherosclerosis research to provide insights into the occurrence, development and treatment of atherosclerosis.

Diabetic retinopathy (DR), a leading cause of vision loss and blindness worldwide, is caused by retinal neurovascular unit dysfunction, and its cellular pathology involves at least nine kinds of retinal cells, including photoreceptors, horizontal and bipolar cells, amacrine cells, retinal ganglion cells, glial cells (Müller cells, astrocytes, and microglia), endothelial cells, pericytes, and retinal pigment epithelial cells. Its mechanism is complicated and involves loss of cells, inflammatory factor production, neovascularization, and BRB impairment. However, the mechanism has not been completely elucidated. Drug treatment for DR has been gradually advancing recently. Research on potential drug targets relies upon clear information on pathogenesis and effective biomarkers. Therefore, we reviewed the recent literature on the cellular pathology and the diagnostic and prognostic biomarkers of DR in terms of blood, protein, and clinical and preclinical drug therapy (including synthesized molecules and natural molecules). This review may provide a theoretical basis for further DR research.

Abstract Background Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Methods Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. Results We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. Conclusion We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

This study examined whether firms’ external financing demands affect the impression management of carbon information disclosure; we also considered the moderating role of media attention in this relationship. The sample consisted of firms in eight energy-intensive industries included in the State Council of China’s “Notice on the Pilot Work of Carbon Emission Trading.” The findings are as follows: (1) A positive correlation existed between external financing demand and the impression management of carbon information disclosure; that is, compared to firms without external financing demand, those with external financing demand had greater impression management of carbon information disclosure. (2) Media attention partially weakened the effect of external financing demand on the impression management of carbon information disclosure. These findings are shown to be robust. Further test indicated that, compared to state-owned enterprises (SOEs), the effect of external financing demand on the impression management of carbon information disclosure was more pronounced in non-SOEs. Our findings enrich the literature on carbon information disclosure. They also provide ideas for governments to formulate carbon information disclosure standards, for investors to effectively identify firm’s impression management of carbon information disclosure, and for firms to better carry out carbon management.

Multiple sevoflurane exposure may result in cognitive deficits in neonatal animals. This study attempted to investigate the potential mechanism of sevoflurane-induced neurotoxicity in developing hippocampus. Neonatal animals received sevoflurane anesthesia, then the behavioral tests and Golgi-Cox staining were employed to detect the effect of sevoflurane inhalation in adult mice. And the mitochondrial function was evaluated using MitoSOX staining, Fluo calcium indicators, mitochondrial permeability transition pore (mPTP) assay, and JC-1 probe after sevoflurane administration. Meanwhile, mitochondrial lipid hydroperoxide and ferroptosis were measured by MitoPeDPP and Mito-FerroGreen signals following sevoflurane exposure. Moreover, the ferroptosis and behavioral performance were assessed after deferiprone (DFP) treatment. The results showed that sevoflurane administration induced cognitive impairment accompanied by reducing dendritic length, density, and nodes. Additionally, sevoflurane exposure elevated mitochondrial ROS production and cytoplasm calcium levels, triggered the opening of mPTP, and decreased the mitochondrial membrane potential (MMP). However, supplement of elamipretide (SS-31) effectively reversed mitochondrial dysfunction. Mitochondrial lipid hydroperoxide production was increased after sevoflurane administration, whereas Fer-1 treatment reduced lipid hydroperoxide formation. Sevoflurane exposure induced mitochondrial iron overload, whereas Mito-Tempo treatment reduced iron accumulation. Prussian blue staining showed that the hippocampal iron deposition was apparently increased after sevoflurane inhalation. Additionally, the ferroptosis-related protein expression (including ACSL4, COX2, GPX4, and FTH1) was significantly changed, whereas DFP effectively suppressed ferroptosis and enhanced sevoflurane-induced behavioral malfunction. These findings demonstrated that sevoflurane administration elicited mitochondrial dysfunction and iron dyshomeostasis and eventually resulted in cognitive impairments, whereas protecting mitochondrial function and chelating neurotoxic iron effectively reversed these pathological processes.

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.

Bone metastasis is one of the most common distant metastasis of breast cancer, which could cause serious skeletal disease and increased cancer-related death. Therefore, identification of novel target(s) to develop therapeutics would improve patient outcomes. The role of NKX2-8 in modulation of bone remodeling was determined using osteoclastogenesis and micro-CT assays. The expression of NKX2-8 was examined via immunohistochemistry analysis in 344 breast cancer tissues. The mechanism underlying NKX2-8-mediated PTHrP downregulation was investigated using biotinylated deactivated Cas9 capture analysis, chromatin immunoprecipitation, co-immunoprecipitation assays. A bone-metastatic mouse model was used to examine the effect of NKX2-8 dysregulation on breast cancer bone metastasis and the impact of three PTHrP inhibitor on prevention of breast cancer bone metastasis. The downregulated expression of NKX2-8 was significantly correlated with breast cancer bone metastasis. In vivo bone-metastatic mouse model indicated that silencing NKX2-8 promoted, but overexpressing NKX2-8 inhibited, breast cancer osteolytic bone metastasis and osteoclastogenesis. Mechanistically, NKX2-8 directly interacted with HDAC1 on the PTHrP promoter, which resulted in a reduction of histone H3K27 acetylation, consequently transcriptionally downregulated PTHrP expression in breast cancer cells. Furthermore, targeting PTHrP effectively inhibited NKX2-8-downregulation-mediated breast cancer bone metastasis. Taken together, our results uncover a novel mechanism underlying NKX2-8 downregulation-mediated breast cancer bone metastasis and represent that the targeting PTHrP might be a tailored treatment for NKX2-8 silencing-induced breast cancer bone metastasis.

Pyroptosis is a pro-inflammatory cell death executed by gasdermin family proteins that involve the formation of pores on cells, recognition of danger signals, and release of pro-inflammatory cytokines IL-1β and IL-18. Pyroptosis modulates mucosal innate immunity and enteropathogenic bacterial infection. Similarly, the gasdermin family has been reported to be involved in the defense of the intestinal epithelium against bacterial infection and in the regulation of intestinal inflammation. Pyroptosis initiates damage signals that activate multiple pathways to cause inflammation, which may be a potential cause of chronic intestinal inflammation. In this review, we discuss the impact of pyroptosis on inflammatory bowel disease (IBD), with a focus on the executive proteins of pyroptosis (GSDMB, GADMD, and GSDME) and IBD-related endogenous damage-associated molecular patterns (DAMPs) produced by pyroptosis.

Makingmistakes is an inevitable part of leadership, but little is known about how and when leaders benefit from reflecting on their missteps. In this paper, we propose that mistakes, when reflected upon, have the potential to increase a leader's expressed humility. We detail how having leaders recall past mistakes can help them formulate plans for learning and encourage them to express humility. We also argue that this positive relationship is strengthened when leaders have a promotion focus. We detail downstream benefits, as increased levels of leaders' expressed humility are expected to increase their teams' improvement-oriented behaviors and, subsequently, team performance. Across multiple studies and using varied methods (i.e., scenario-based experimentswith 955 managerial leaders, a laboratory experiment with 210 student leaders and team members, and a daily field experiment with 85 managers), we empirically test the proposed relationships. Our studies contribute to the literature by identifying leaders' recall of learning from mistakes as an important intervention to elicit their expressed humility. [ABSTRACT FROM AUTHOR]

Newcastle disease is a kind of avian infectious disease caused by Newcastle disease virus (NDV). The virulence of NDV is dependent mainly on the fusion (F) protein and hemagglutinin-neuraminidase (HN) protein. The genomes of 2 viruses, NDV-Blackbird and NDV-Dove, are 99.9% similar, while NDV-Blackbird is a velogenic virus, and NDV-Dove is a lentogenic virus. Further analysis revealed that the F proteins of the 2 strains were identical, and only 5 amino acid sites on the HN proteins were inconsistent. Five different HN mutant plasmids were constructed and analyzed in this study. The results showed that the mutation F110L caused a significant increase in fusion-promotion activity caused by an increase in neuraminidase activity. Because of the increase in receptor-binding activity caused by G116R, there was a significant increase in fusion-promotion activity. The mutation G54S resulted in a slight decrease in the fusion-promotion activity caused by a slight decrease in receptor-binding activity. The slight increase in the fusion-promotion activity caused by A469V was associated with a significant increase in neuraminidase activity. Therefore, the amino acids L110 and R116 played a key role in determining the virulence difference between NDV-Blackbird and NDV-Dove, which could lay a foundation for illuminating the virulence differences of NDV strains, as well as the development of attenuated vaccines.

Abstract Porcine growth hormone (pGH) is a class of peptide hormones secreted from the pituitary gland, which can significantly improve growth and feed utilization of pigs. However, it is unstable and volatile in vitro. It needs to be encapsulated in liposomes when feeding livestock, whose high cost greatly limits its application in pig industry. Therefore we attempted to express pGH as intracellular soluble protein in Pichia pastoris and feed these yeasts with partial wall-breaking for swine, which could release directly pGH in intestine tract in case of being degraded in intestinal tract with low cost. In order to improve the intracellular soluble expression of pGH protein in Pichia pastoris and stability in vitro, we optimized the pGH gene, and screened molecular chaperones from E. coli and Pichia pastoris respectively for co-expressing with pGH. In addition, we had also explored conditions of mechanical crushing and fermentation. The results showed that the expression of intracellular soluble pGH protein was significantly increased after gene optimized and co-expressed with Ssa1–Sis1 chaperone from Pichia pastoris. Meanwhile, the optimal conditions of partial wall-breaking and fermentation of Pichia pastoris were confirmed, the data showed that the intracellular expression of the optimized pGH protein co-expressed with Ssa1–Sis1 could reach 340 mg/L with optimal conditions of partial wall-breaking and fermentation. Animal experiments verified that the optimized pGH protein co-expression with Ssa1–Sis1 had the best promoting effects on the growth of piglets. Our study demonstrated that Ssa1–Sis1 could enhance the intracellular soluble expression of pGH protein in Pichia pastoris and that partial wall-breaking of yeast could prevent pGH from degradation in vitro, release targetedly in the intestine and play its biological function effectively. Our study could provide a new idea to cut the cost effectively, establishing a theoretical basis for the clinic application of unstable substances in vitro.

For efficient replication, viruses have developed multiple strategies to evade host antiviral innate immunity. Paramyxoviruses are a large family of enveloped RNA viruses that comprises diverse human and animal pathogens which jeopardize global public health and the economy. The accessory proteins expressed from the P gene by RNA editing or overlapping open reading frames (ORFs) are major viral immune evasion factors antagonizing type I interferon (IFN-I) production and other antiviral innate immune responses. However, the antagonistic mechanisms against antiviral innate immunity by accessory proteins differ among viruses. Here, we summarize the current understandings of immune evasion mechanisms by paramyxovirus accessory proteins, specifically how accessory proteins directly or indirectly target the adaptors in the antiviral innate immune signaling pathway to facilitate virus replication. Additionally, some cellular responses, which are also involved in viral replication, will be briefly summarized.

Prohibiting the unsafe sale of livestock that have died in production and harmlessly disposing of them are key measures to control and prevent outbreaks of zoonotic diseases and exert a great significance for maintaining meat-derived food and public health safety. However, under the strict implementation of governmental initiatives, some farmers still choose to sell dead livestock unsafely in developing countries such as China, Brazil, Mexico, and Kenya, which have become an important hidden danger in preventing and controlling zoonotic diseases. Based on data from 496 pig farmers in Hebei, Henan, and Hubei, China, the Double Hurdle Model was employed to explore the impact of governmental initiatives on the willingness and proportion of dead pigs sold unsafely by farmers. Besides, based on the heterogeneity of organization participation and breeding scale, the impact of governmental initiatives on different scale farmers' unsafely selling behaviors is also discussed. The results showed that the harmless disposal subsidy significantly reduces farmers' willingness to unsafely sell dead pigs (SW, RC = −0.0666, and SE = 0.0261). Still, the impact on the proportion is weak (SP, RC = −0.0502, and SE = 0.0474). Though the effect of supervision punishment is greatly weakened (SW, RC =−0.0381, and SE = 0.0324; SP, RC = −0.0204 and SE = 0.0263), it can significantly enhance the effect of harmless disposal subsidy by creating a good law-abiding environment (SW, RC = −0.1370, and SE = 0.0374; SP, RC = −0.0820, and SE = 0.0431). Governmental initiatives have an undue impact on the unsafe sale of dead livestock by farmers participating in cooperatives. The effects of these measures on different scale farmers' unsafe sale of dead pigs are highly heterogeneous. In addition, the study also found that food and public health safety risk perceptions are important endogenous drivers for curbing farmers selling dead pigs. This research can also provide important inspiration for other countries. The government should raise farmers' risk perception level of food and public safety, optimize governmental initiatives, play the key role of cooperative organization, increase the proportion of dead pigs harmlessly disposed of, and finally eliminate new hidden dangers in the prevention and control of zoonotic diseases.

Ischemic stroke (IS) is a disease that is characterized by high mortality and disability. Recent studies have shown that LncRNA-mediated competing endogenous RNA (ceRNA) networks play roles in the occurrence and development of cerebral I/R injury by regulating different signaling pathways. However, no systematic analysis of ceRNA mechanisms in IS has been reported. In this review, we discuss molecular mechanisms of LncRNA-mediated ceRNA networks under I/R injury. The expression levels of LncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) and their effects in four major cell types of the neurovascular unit (NVU) are also involved. We further summarize studies of LncRNAs as biomarkers and therapeutic targets. Finally, we analyze the advantages and limitations of using LncRNAs as therapeutics for IS.

It is known that genotoxic stress induces high levels of ROS and deplete cellular glutathione stores. Here, Cao et al. uncover a β-catenin-dependent TCF/LEF-independent mechanism that promotes histone-mediated transcriptional activation of glutathione synthesis.

Background: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2–8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). Methods: The deletion frequency and expression of NKX2–8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2–8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2–8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. Findings: NKX2–8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2–8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2–8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2–8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. Interpretation: Our results demonstrate that NKX2–8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2–8-deleted EOC. Fund: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities. Keywords: NKX2–8, Chemoresistance, Fatty acid oxidation, Metabolic reprogram, Epithelial ovarian cancer

Abstract Background and Aims H9N2 subtype avian influenza virus (AIV) has low‐pathogenicity but causes respiratory symptoms and drop in egg production in chicken with long‐term virus shedding, resulting in great economic losses due to high mortality related to secondary infection with other pathogens. In recent years, H9N2 viruses have been posing a threat to public health, causing human infection in China. Compared to studies on other AIV subtypes, there are relatively few studies on the pathogenic mechanism of the H9N2 virus in mammals. H9N2 subtype AIV has been circulating worldwide in many avian species and transmitting with high efficiency in poultry. It can provide internal genes for other subtypes to produce new viruses, causing a pandemic risk. It is important to carry out long‐term surveillance and pathogenic characteristics of the H9N2 virus. In this study, we conducted environmental surveillance of live poultry markets in Anhui province from 2013 to 2018, and 33 representative environmental isolates were selected and studied systematically. Methods The genomic RNA of Anhui H9N2 isolates was subjected to RT‐PCR amplification followed by sequencing analysis. Results Thirty‐three strains were isolated from the embryonated eggs of specific‐pathogen‐free chickens. Phylogenetic analysis indicated that h9.4.2.5‐like H9N2 viruses were predominant during 2013‐2018 and acquired multiple specific amino acid mutations that may have increased their affinity for mammals and enhanced their infectivity and transmissibility. Additionally, six internal genes of H9N2 clustered together with the novel human‐lethal reassortant viruses, such as the low‐pathogenicity H7N9, H10N8, and Anhui H5N6 viruses, and even HPAI H7N9. Conclusion Because H9N2 viruses may be the donors of internal genes that lead to the generation of novel reassortant viruses with enhanced pathogenicity in Anhui province, continuous environmental surveillance of live poultry markets, a key source of reassorted H9N2 and other avian influenza viruses, is of great importance.

Most neurological disorders are caused by abnormal gene translation. Generally, dysregulation of elements involved in the translational process disrupts homeostasis in neurons and neuroglia. Better understanding of how the gene translation process occurs requires detailed analysis of transcriptomic and proteomic profile data. However, a lack of strictly direct correlations between mRNA and protein levels limits translational investigation by combining transcriptomic and proteomic profiling. The much better correlation between proteins and translated mRNAs than total mRNAs in abundance and insufficiently sensitive proteomics approach promote the requirement of advances in translatomics technology. Translatomics which capture and sequence the mRNAs associated with ribosomes has been effective in identifying translational changes by genetics or projections, ribosome stalling, local translation, and transcript isoforms in the nervous system. Here, we place emphasis on the main three translatomics methods currently used to profile mRNAs attached to ribosome-nascent chain complex (RNC-mRNA). Their prominent applications in neurological diseases including glioma, neuropathic pain, depression, fragile X syndrome (FXS), neurodegenerative disorders are outlined. The content reviewed here expands our understanding on the contributions of aberrant translation to neurological disease development.

Improper handling of sick and dead pigs may seriously affect public health, socio-economic conditions, and eventually cause environmental pollution. However, effective promotion of sick and dead pig (SDP) waste recycling has become the prime focus of current rural governance. Therefore, the study explores the impact of commitment, rewards, and punishments to capture the recycling behavior of farmers’ sick and dead pig waste management. The study employs factor analysis, the probit model, and the moderating effect model to craft the findings. The study’s empirical setup comprises the survey data collected from the Hebei, Shandong, and Henan provinces, representing the major pig-producing provinces in China. The study found that the commitment, reward, and punishment mechanisms are essential factors affecting the farmers’ decision-making on recycling sick and dead pig waste. The marginal effect analysis found that the reward and punishment mechanism is more effective than the farmers’ commitment. The study confirmed that in the recycling treatment of sick and dead pig waste, the farmers’ commitment and the government’s reward and punishment policy are the main factors that influence farmers to manage sick and dead pig waste properly. Therefore, the government should highlight the importance of effective waste management, and training facilities should also be extended firmly. The government should impose strict rules and regulations to restrict the irresponsible dumping of farm waste. Monitoring mechanisms should be put in place promptly.

Adipic acid is one of the most important feedstocks for producing resins, nylons, lubricants, plasticizers. Current industrial petrochemical process, producing adipic acid from KA oil, catalyzed by nitric acid, has a serious pollution to the environment, due to the formation of waste nitrous oxide. Hence, developing cleaner methods to produce adipic acid has attracted much attention of both industry and academia. This mini-review article discussed advances on adipic acid synthesis from bio-renewable feedstocks, as well as most recent progress on cleaner technology from fossil fuels over novel catalytic materials. This work on recent advances in green adipic acid production will provide insights and guidance to further study of various other industrial processes for producing nylon precursors.