A Comparative Study of Human Pluripotent Stem Cell-Derived Macrophages in Modeling Viral Infections.

Macrophages play multiple roles in innate immunity including phagocytosing pathogens, modulating the inflammatory response, presenting antigens, and recruiting other immune cells. Tissue-resident macrophages (TRMs) adapt to the local microenvironment and can exhibit different immune responses upon encountering distinct pathogens. In this study, we generated induced macrophages (iMACs) derived from human pluripotent stem cells (hPSCs) to investigate the interactions between the macrophages and various human pathogens, including the hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Streptococcus pneumoniae. iMACs can engulf all three pathogens. A comparison of the RNA-seq data of the iMACs encountering these pathogens revealed that the pathogens activated distinct gene networks related to viral response and inflammation in iMACs. Interestingly, in the presence of both HCV and host cells, iMACs upregulated different sets of genes involved in immune cell migration and chemotaxis. Finally, we constructed an image-based high-content analysis system consisting of iMACs, recombinant GFP-HCV, and hepatic cells to evaluate the effect of a chemical inhibitor on HCV infection. In summary, we developed a human cell-based in vitro model to study the macrophage response to human viral and bacterial infections; the results of the transcriptome analysis indicated that the iMACs were a useful resource for modeling pathogen-macrophage-tissue microenvironment interactions.

Clinical data mining: challenges, opportunities, and recommendations for translational applications.

Clinical data mining of predictive models offers significant advantages for re-evaluating and leveraging large amounts of complex clinical real-world data and experimental comparison data for tasks such as risk stratification, diagnosis, classification, and survival prediction. However, its translational application is still limited. One challenge is that the proposed clinical requirements and data mining are not synchronized. Additionally, the exotic predictions of data mining are difficult to apply directly in local medical institutions. Hence, it is necessary to incisively review the translational application of clinical data mining, providing an analytical workflow for developing and validating prediction models to ensure the scientific validity of analytic workflows in response to clinical questions. This review systematically revisits the purpose, process, and principles of clinical data mining and discusses the key causes contributing to the detachment from practice and the misuse of model verification in developing predictive models for research. Based on this, we propose a niche-targeting framework of four principles: Clinical Contextual, Subgroup-Oriented, Confounder- and False Positive-Controlled (CSCF), to provide guidance for clinical data mining prior to the model's development in clinical settings. Eventually, it is hoped that this review can help guide future research and develop personalized predictive models to achieve the goal of discovering subgroups with varied remedial benefits or risks and ensuring that precision medicine can deliver its full potential.

Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis.

INTRODUCTION: The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). METHODS: A retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. RESULTS: The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. CONCLUSIONS: FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

Proprotein convertase subtilisin/kexin type 9 inhibitor ameliorates cerebral ischemia in mice by inhibiting inflammation.

OBJECTIVES: To investigate the potential protective effects of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, on ischemic stroke and its underlying mechanisms. MATERIALS AND METHODS: We established a mouse model with distal middle cerebral artery occlusion. We evaluated the therapeutic effects through neurological function and infarct size, while the underlying mechanisms were elucidated using western blotting and real-time polymerase chain reaction. RESULTS: Evolocumab improved neurological recovery, reduced the infarct volume, suppressed the activation of Toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB), and attenuated the increased levels of IL-1ß and TNF-α after cerebral ischemia. CONCLUSION: Evolocumab protects against cerebral ischemic injury by inhibiting inflammation. Therefore, the TLR4/NF-кB pathway may represent a major mechanism in ischemic stroke.

Association between increased C-reactive protein and cardiovascular disease among patients with rectal cancer.

Purpose: This study aimed to investigate the association between increased C-reactive protein (CRP) and cardiovascular disease (CVD) in individuals with rectal cancer, as well as to understand the effect of chemotherapy for cancer on increasing CRP and its underlying mechanisms. Patients and methods: From January 1, 2010 to December 31, 2020, individuals with rectal cancer were evaluated at the First Affiliated Hospital of Gannan Medical University. Then, in patients with rectal cancer, the relationship between increased CRP and CVD attributes was summarized, and the impact of chemotherapy on CRP levels was qualitatively assessed. For further investigation into potential regulatory mechanisms of CRP, differentially expressed genes (DEGs), GO and KEGG enrichment analyses were conducted. Results: A total of 827 individuals were included in the study, including 175 with CVD (21.16%) and 652 without CVD. A significant association between increased CRP and CVD events was observed in rectal cancer patients (p < 0.01), and it significantly improved the classification performance of the CVD predictive model in the AUC (0.724 vs 0.707) and NRI (0.069, 95% CI 0.05-0.14). Furthermore, a comparison of CRP levels before and after chemotherapy revealed a significant increase among rectal cancers post-treatment (p < 0.001). Analysis of differentially expressed genes and co-expression indicated that 96 DEGs were involved in the pathophysiology of increased CRP after chemotherapy, and three hub genes were implicated in atherosclerotic susceptibility. Conclusion: In conclusion, our findings indicated that increased CRP levels following chemotherapy profoundly impacted CVD events in individuals with rectal cancer, and may be beneficial in promoting CVD prediction in clinical practice.

Fabrication of mesopore-rich HZSM-5 to boost the degradation of plastic wastes.

Plastic waste is causing serious environment pollution and its efficient disposal is attracting more and more attention. The use of catalysts not only reduced the degradation temperature of plastic wastes but also facilitated the production of valuable chemicals. Herein, mesopores were introduced into HZSM-5 zeolites by alkali and acid treatment, which was expected to eliminate the diffusion resistance caused by bulky polymer molecules and improve the catalytic activity. It was found that HZSM-5 zeolites enhanced PE, PP and PS degradation, and an increase of mesopore volume further improved the catalytic activity and reduced the activation energy. For example, the use of HZSM-5 in PP degradation decreased the activation energy from 146.9 kJ mol-1 to 93.1 kJ mol-1, and mesopore-rich HZSM-5 further decreased the activation energy to 84.0 kJ mol-1. The molecular diameter of the PP fragment was obtained by theoretical calculations, and it was close to 1.6 nm, which was significantly higher than the micropore diameter of HZSM-5 zeolites (0.5-0.6 nm) while lower than the mesopore diameter. It was concluded that the presence of mesopores provided the place and space for plastics degradation.

Progress in the diagnosis of lymph node metastasis in rectal cancer: a review.

Historically, the chief focus of lymph node metastasis research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen a rapid accumulation of massive omics and imaging data catalyzed by the rapid development of advanced technologies. This rapid increase in data has driven improvements in the accuracy of diagnosis of lymph node metastasis, and its analysis further demands new methods and the opportunity to provide novel insights for basic research. In fact, the combination of omics data, imaging data, clinical medicine, and diagnostic methods has led to notable advances in our basic understanding and transformation of lymph node metastases in rectal cancer. Higher levels of integration will require a concerted effort among data scientists and clinicians. Herein, we review the current state and future challenges to advance the diagnosis of lymph node metastases in rectal cancer.

Hydrogen-Rich Saline-A Novel Neuroprotective Agent in a Mouse Model of Experimental Cerebral Ischemia via the ROS-NLRP3 Inflammasome Signaling Pathway In Vivo and In Vitro.

BACKGROUND: Our previous research revealed that inflammation plays an important role in the pathophysiology of cerebral ischemia. The function of the NOD-like receptor protein 3 (NLRP3) inflammasome is to activate the inflammatory process. Recent findings suggest that reactive oxygen species (ROS) are essential secondary messengers that activate the NLRP3 inflammasome. Hydrogen-rich saline (HS) has attracted attention for its anti-inflammatory properties. However, the protective effect and possible mechanism of HSin brain ischemia have not been well elucidated. METHODS: To test the therapeutic effect of HS, we established a mouse model of distal middle cerebral artery occlusion (dMCAO) and an in vitro model of BV2 cells induced by lipopolysaccharide (LPS). The ROS scavenger N-acetylcysteine (NAC) was used to investigate the underlying mechanisms of HS. RESULTS: HS significantly improved neurological function, reduced infarct volume, and increased cerebral blood flow in a dMCAO mouse model. ROS, NLRP3, Caspase-1, and IL-1ß expression increased after cerebral ischemia, and this was reversed by HS treatment. In BV2 cells, the application of NAC further demonstrated that HS could effectively inhibit the expression of the ROS-activated NLRP3 inflammasome. CONCLUSIONS: HS, as a novel therapeutic option, could exert protect the brain by inhibiting the activation of the ROS-NLRP3 signaling pathway after cerebral ischemia.

An immuno-score signature of tumor immune microenvironment predicts clinical outcomes in locally advanced rectal cancer.

Background and purpose: Accumulating evidence indicates that neoadjuvant chemoradiotherapy(nCRT) success has an immune-associated constituent in locally advanced rectal cancer (LARC). The immune-associated configuration of the tumor microenvironment associated with responses to treatment was explored in LARC in this study. Material and methods: A novel analytic framework was developed based on within-sample relative expression orderings for identifying tumor immune-associated gene pairs and identified an immuno-score signature from bulk transcriptome profiling analysis of 200 LARC patients. And sequencing and microarray analysis of gene expression was conducted to investigate the association between the signature and response to nCRT, immunotherapy, and cell function of CD4 and CD8. The results were validated using 111 pretreated samples from publicly available datasets in multiple aspects and survival analyses. Results: The immuno-score signature of 18 immune-related gene pairs (referred to as IPS) was validated on bulk microarray and RNA-Seq data. According to the model's immune score, LARC patients were divided into high- and low-score groups. The patients with high-score were greater sensitivity to nCRT and immunotherapy, gaining a significantly improved prognosis. In addition, the immune-score gene pair signature was associated with type I anti-tumor T cell responses, positive regulators of T cell functions, and chromosomal instability while reflecting differences between CD8+ T cell subtypes. Conclusion: The immuno-score signature underlines a key role of tumor immune components in nCRT response, and predicts the prognosis of LARC patients as well.

Changes in the BTK/NF-κB signaling pathway and related cytokines in different stages of neuromyelitis optica spectrum disorders.

OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis; their pathogenesis is still not fully elucidated. Although it has been determined that Bruton tyrosine kinase (BTK) and NF-κB are associated with NMOSD, the changes that occur in different periods remain unknown. The study aimed to demonstrate the changes in the BTK/NF-κB pathway and related chemokines in different stages of NMOSDs. METHODS: A total of 32 patients with NMOSD were selected as the experimental group, and 32 healthy volunteers were included in the control group. In this study, the BTK/NF-κB pathway and related chemokines in the cerebrospinal fluid and peripheral blood samples of patients with NMOSD were analyzed in the acute or remission phase. RESULTS: BTK, NF-κB, PI3K, IKK, CXCL2, and CXCL12 levels in the NMOSD group in the acute or remission phase were significantly higher than those in the control group (p < 0.05). CONCLUSION: The BTK/NF-κB pathway plays a vital role in the progression of NMOSD pathology. Our results shed light on its important role as a therapeutic target for NMOSD.

Liraglutide Ameliorates Cerebral Ischemia in Mice via Antipyroptotic Pathways.

It was recently shown that pyroptosis, an inflammatory form of programmed cell death, is critically involved in the pathogenesis of ischemic stroke. Liraglutide (Lg) is a novel long-acting analog of glucagon-like peptide-1 that has potential protective effects against stroke. However, the relationship between Lg and pyroptosis in the brain is not well defined. In this study, we found that injection of Lg significantly improved the recovery of motor function, increased cerebral blood flow and ameliorated cerebral damage in a mouse model of focal cerebral cortical ischemia. Our results revealed that Lg treatment significantly reduced the levels of NLRP3, Caspase1, IL-1ß and the pore-forming protein gasdermin D in microglial cells in vitro, suggesting that the neuroprotective effect of Lg may be achieved through the inhibition of pyroptosis. Furthermore, by using a specific inhibitor of NOD-like receptor protein 3 (NLRP3), we confirmed that the antipyroptotic mechanism of Lg may be mediated by NLRP3 in vivo. Our present study unveils a novel neuroprotective mechanism through which Lg alleviates ischemia by exerting NLRP3-dependent antipyroptotic effects.

Mixed Triboelectric and Flexoelectric Charge Transfer at the Nanoscale.

The triboelectric effect is a ubiquitous phenomenon in which the surfaces of two materials are easily charged during the contact-separation process. Despite the widespread consequences and applications, the charging mechanisms are not sufficiently understood. Here, the authors report that, in the presence of a strain gradient, the charge transfer is a result of competition between flexoelectricity and triboelectricity, which could enhance charge transfer during triboelectric measurements when the charge transfers of both effects are in the same direction. When they are in the opposite directions, the direction and amount of charge transfer could be modulated by the competition between flexoelectric and triboelectric effects, which leads to a distinctive phenomenon, that is, the charge transfer is reversed with varying forces. The subsequent results on the electrical power output signals from the triboelectrification support the proposed mechanism. Therefore, the present study emphasizes the key role of the flexoelectric effect through experimental approaches, and suggests that both the amount and direction of charge transfer can be modulated by manipulating the mixed triboelectric and flexoelectric effects. This finding may provide important information on the triboelectric effect and can be further extended to serve as a guideline for material selection during a nanopatterned device design.

Identification of blood-derived candidate gene markers and a new 7-gene diagnostic model for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease with a high disability rate. Modern molecular biology techniques have identified a number of key genes and diagnostic markers to MS, but the etiology and pathogenesis of MS remain unknown. RESULTS: In this study, the integration of three peripheral blood mononuclear cell (PBMC) microarray datasets and one peripheral blood T cells microarray dataset allowed comprehensive network and pathway analyses of the biological functions of MS-related genes. Differential expression analysis identified 78 significantly aberrantly expressed genes in MS, and further functional enrichment analysis showed that these genes were associated with innate immune response-activating signal transduction (p = 0.0017), neutrophil mediated immunity (p = 0.002), positive regulation of innate immune response (p = 0.004), IL-17 signaling pathway (p < 0.035) and other immune-related signaling pathways. In addition, a network of MS-specific protein-protein interactions (PPI) was constructed based on differential genes. Subsequent analysis of network topology properties identified the up-regulated CXCR4, ITGAM, ACTB, RHOA, RPS27A, UBA52, and RPL8 genes as the hub genes of the network, and they were also potential biomarkers of MS through Rap1 signaling pathway or leukocyte transendothelial migration. RT-qPCR results demonstrated that CXCR4 was obviously up-regulated, while ACTB, RHOA, and ITGAM were down-regulated in MS patient PBMC in comparison with normal samples. Finally, support vector machine was employed to establish a diagnostic model of MS with a high prediction performance in internal and external datasets (mean AUC = 0.97) and in different chip platform datasets (AUC = (0.93). CONCLUSION: This study provides new understanding for the etiology/pathogenesis of MS, facilitating an early identification and prediction of MS.

Identification of blood-derived candidate gene markers and a new 7-gene diagnostic model for multiple sclerosis

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease with a high disability rate. Modern molecular biology techniques have identified a number of key genes and diagnostic markers to MS, but the etiology and pathogenesis of MS remain unknown. RESULTS: In this study, the integration of three peripheral blood mononuclear cell (PBMC) microarray datasets and one peripheral blood T cells microarray dataset allowed comprehensive network and pathway analyses of the biological functions of MS-related genes. Differential expression analysis identified 78 significantly aberrantly expressed genes in MS, and further functional enrichment analysis showed that these genes were associated with innate immune response-activating signal transduction (p = 0.0017), neutrophil mediated immunity (p = 0.002), positive regulation of innate immune response (p = 0.004), IL-17 signaling pathway (p < 0.035) and other immune-related signaling pathways. In addition, a network of MS-specific protein-protein interactions (PPI) was constructed based on differential genes. Subsequent analysis of network topology properties identified the up-regulated CXCR4, ITGAM, ACTB, RHOA, RPS27A, UBA52, and RPL8 genes as the hub genes of the network, and they were also potential biomarkers of MS through Rap1 signaling pathway or leukocyte transendothelial migration. RT-qPCR results demonstrated that CXCR4 was obviously up-regulated, while ACTB, RHOA, and ITGAM were down-regulated in MS patient PBMC in comparison with normal samples. Finally, support vector machine was employed to establish a diagnostic model of MS with a high prediction performance in internal and external datasets (mean AUC = 0.97) and in different chip platform datasets (AUC = (0.93). CONCLUSION: This study provides new understanding for the etiology/pathogenesis of MS, facilitating an early identification and prediction of MS.

Recent Progress in the Nanoscale Evaluation of Piezoelectric and Ferroelectric Properties via Scanning Probe Microscopy.

Piezoelectric and ferroelectric materials have garnered significant interest owing to their excellent physical properties and multiple potential applications. Accordingly, the need for evaluating piezoelectric and ferroelectric properties has also increased. The piezoelectric and ferroelectric properties are evaluated macroscopically using laser interferometers and polarization-electric field loop measurements. However, as the research focus is shifted from bulk to nanosized materials, scanning probe microscopy (SPM) techniques have been suggested as an alternative approach for evaluating piezoelectric and ferroelectric properties. In this Progress Report, the recent progress on the nanoscale evaluation of piezoelectric and ferroelectric properties of diverse materials using SPM-based methods is summarized. Among the SPM techniques, the focus is on recent studies that are related to piezoresponse force microscopy and conductive atomic force microscopy; further, the utilization of these two modes to understand piezoelectric and ferroelectric properties at the nanoscale level is discussed. This work can provide guidelines for evaluating the piezoelectric and ferroelectric properties of materials based on SPM techniques.

MiR-503 suppresses hypoxia-induced proliferation, migration and angiogenesis of endothelial progenitor cells by targeting Apelin.

Endothelial progenitor cells (EPCs) are of great importance in the process of endogenous blood vessel repair to maintain endothelial integrity and have been applied in a wide range of models of ischemic diseases. MicroRNAs represent a class of non-protein coding endogenous RNAs with 19-24 nucleotides in length and serve an important role in multiple physiological and pathological processes, including angiogenesis. It has been reported that miR-503 reduces angiogenesis in tumorigenesis. However, to our knowledge, the precise role of miR-503 in the regulation of EPCs remains unclear. In the current study, we found that the expression of miR-503 was decreased in mouse bone marrow derived EPCs under the hypoxic condition. Importantly, upregulation of miR-503 suppressed the proliferation, migration and capillary-like tube formation of EPCs induced by hypoxia. Furthermore, a dual luciferase reporter assay showed that Apelin, an endogenous ligand of the G protein-coupled receptor APJ, was a direct target of miR-503 and overexpression of miR-503 significantly inhibited the protein level of Apelin in EPCs. Moreover, hypoxia treatment enhanced the expression of Apelin in EPCs. Meanwhile ectopic expression of Apelin promoted cellular proliferation, migration and tube formation of EPCs in vitro. In summary, our results indicate that miR-503 regulates proliferation, migration and angiogenesis of EPCs by targeting Apelin.

Nap1l1 Controls Embryonic Neural Progenitor Cell Proliferation and Differentiation in the Developing Brain.

The precise function and role of nucleosome assembly protein 1-like 1 (Nap1l1) in brain development are unclear. Here, we find that Nap1l1 knockdown decreases neural progenitor cell (NPC) proliferation and induces premature neuronal differentiation during cortical development. A similar deficiency in embryonic neurogenesis was observed in Nap1l1 knockout (KO) mice, which were generated using the CRISPR-Cas9 system. RNA sequencing (RNA-seq) analysis indicates that Ras-associated domain family member 10 (RassF10) may be the downstream target of Nap1l1. Furthermore, we found that Nap1l1 regulates RassF10 expression by promoting SETD1A-mediated H3K4 trimethylation at the RassF10 promoter. Nap1l1 KO defects may be rescued by RassF10 overexpression, suggesting that Nap1l1 controls NPC differentiation through RassF10. Our findings reveal an essential role for the Nap1l1 histone chaperone in cortical neurogenesis during early embryonic brain development.

DISC1 regulates astrogenesis in the embryonic brain via modulation of RAS/MEK/ERK signaling through RASSF7.

Disrupted in schizophrenia 1 (DISC1) is known as a high susceptibility gene for schizophrenia. Recent studies have indicated that schizophrenia might be caused by glia defects and dysfunction. However, there is no direct evidence of a link between the schizophrenia gene DISC1 and gliogenesis defects. Thus, an investigation into the involvement of DISC1 (a ubiquitously expressed brain protein) in astrogenesis during the late stage of mouse embryonic brain development is warranted. Here, we show that suppression of DISC1 expression represses astrogenesis in vitro and in vivo, and that DISC1 overexpression substantially enhances the process. Furthermore, mouse and human DISC1 overexpression rescued the astrogenesis defects caused by DISC1 knockdown. Mechanistically, DISC1 activates the RAS/MEK/ERK signaling pathway via direct association with RASSF7. Also, the pERK complex undergoes nuclear translocation and influences the expression of genes related to astrogenesis. In summary, our results demonstrate that DISC1 regulates astrogenesis by modulating RAS/MEK/ERK signaling via RASSF7 and provide a framework for understanding how DISC1 dysfunction might lead to neuropsychiatric diseases.

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin.

Abnormalities in parvalbumin (PV)-expressing interneurons cause neurodevelopmental disorders such as epilepsy, autism, and schizophrenia. Unlike other types of neurons that can be efficiently differentiated from pluripotent stem cells, PV neurons were minimally generated using a conventional differentiation strategy. In this study we developed an adenovirus-based transdifferentiation strategy that incorporates an additional chemical compound for the efficient generation of induced PV (iPV) neurons. The chemical compound forskolin combined with Ascl1 induced ∼80% of mouse fibroblasts to iPV neurons. The iPV neurons generated by this procedure matured 5-7 days post infection and were characterized by electrophysiological properties and known neuronal markers, such as PV and GABA. Our studies, therefore, identified an efficient approach for generating PV neurons.

Autophagy-related gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex.

Astrocyte differentiation is essential for late embryonic brain development, and autophagy is active during this process. However, it is unknown whether and how autophagy regulates astrocyte differentiation. Here, we show that Atg5, which is necessary for autophagosome formation, regulates astrocyte differentiation. Atg5 deficiency represses the generation of astrocytes in vitro and in vivo. Conversely, Atg5 overexpression increases the number of astrocytes substantially. We show that Atg5 activates the JAK2-STAT3 pathway by degrading the inhibitory protein SOCS2. The astrocyte differentiation defect caused by Atg5 loss can be rescued by human Atg5 overexpression, STAT3 overexpression, and SOCS2 knockdown. Together, these data demonstrate that Atg5 regulates astrocyte differentiation, with potential implications for brain disorders with autophagy deficiency.