Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis.

Background: The cardinal feature of systemic sclerosis (SSc) is skin thickening and tightening. Targetable mechanisms for skin features remain elusive. Drugs successful in treating internal organ manifestations have failed efficacy in skin. Dermal white adipose tissue (DWAT) is amongst the understudied contributors to skin manifestations. This study proposes the role of sine oculis homeobox homolog 1 ( SIX1 ), a gene previously unrecognized as a contributor to dermal lipoatrophy characteristic of early skin fibrosis in SSc. Methods: Skin gene expression of SIX1 was analyzed in the GENISOS and PRESS SSc cohorts. Correlation analysis was performed with Spearman rank analysis. Novel mouse models were developed using the Cre-loxp system to knock out Six1 in all cells and mature adipocytes. Subcutaneous bleomycin was used to model early DWAT atrophy and dermal fibrosis characteristic of SSc. Findings: SIX1 was upregulated in SSc skin, the expression of which correlates with adipose-associated genes and molecular pathways. Genetic deletion of Six1 in all cells in mice challenged with bleomycin abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage. Adipocyte specific Six1 deletion was able to attenuate the early increase in skin thickness, a hallmark of experimental skin fibrosis. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. Interpretation: This work identifies SIX1 as an early marker of skin fibrosis in SSc. We also demonstrate a causative role of Six1 in skin fibrosis by promoting adipocyte loss and show that deletion of Six1 in adipocytes has the potential of impacting early disease progression. Research in context: Evidence before this study: Skin thickening and tightening are leading causes of morbidity in systemic sclerosis (SSc). The authors previously reported that the aberrantly expressed developmental transcription factor sine oculis homeobox homology 1 (SIX1) drives pulmonary fibrosis. However, the contribution of SIX1 to skin fibrosis and associated dermal fat loss remains unknown.Added value of this study: The role of dermal fat loss in skin fibrosis is not fully understood. Studies have shown that adipocytes can transition to mesenchymal cells promoting fibrosis, consistent with loss of the dermal white adipose layer. Our research provides insight into a novel molecular mechanism of lipodystrophy important for skin fibrosis in SSc. We identified the upregulation of SIX1 in adipocytes in skin from patients with SSc which was associated with the progression of skin fibrosis. We found elevated Six1 in mouse dermal adipocytes of early fibrotic skin. Ubiquitous and adipose-specific loss of Six1 decreased markers of experimental skin fibrosis in mice which recapitulate cardinal features of SSc dermal fibrosis. Increased SIX1 expression is linked with elevated levels of Serpine1 the gene that codes for the protein plasminogen activator inhibitor (PAI)-1. This is important since PAI-1 is a known pro-fibrotic agent in the skin that contributes to the deposition of extracellular matrix (ECM) products. Implications of all the available evidence: Fat atrophy may represent a targetable contributor to early systemic sclerosis manifestations. This is as it precedes skin fibrosis and the use of topical agent which are usually lipophilic can help us target dermal adipocytes. Our results show that SIX1 could be an important early marker for skin fibrosis in SSc that can also be targeted therapeutically.

Causal relationship between inflammatory proteins and glioblastoma: a two-sample bi­directional mendelian randomization study.

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors. Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms. Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms. Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.

The association of systemic inflammatory response index and neutrophil-to-high-density lipoprotein ratio mediated by fasting blood glucose with 90-day prognosis in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: The contribution of individual and combined inflammatory markers for the prognosis of acute ischemic stroke (AIS) remains elusive. This study investigated the effect of systemic inflammatory response index (SIRI), and neutrophil to high-density lipoprotein ratio (NHR), which is mediated by fasting blood glucose (FBG), on 90-day prognosis of patients with AIS. METHODS: In this pre-specified substudy of an observational cohort study, 2828 patients with AIS were enrolled from the Nanjing Stroke Registry between January 2017 to July 2021. Peripheral venous blood was collected from patients fasting for at least 8 hours within 24 hours of admission to gather information on the following parameters: neutrophil count, lymphocyte count, monocyte count, HDL level, and fasting blood glucose level. Then, the SIRI and NHR values were calculated. Following this, the correlation among SIRI, NHR, and modified Rankin Scale (mRS) scores 90d after onset was examined via univariate and multivariate logistic analyses. Lastly, mediation analysis was performed to examine the relationship between systematic inflammatory response and study outcomes mediated by FBG. RESULTS: SIRI and NHR were both negatively correlated with clinical outcomes (p < 0.05). Logistic regression analysis revealed that SIRI and NHR were independently associated with poor outcomes after adjusting for potential confounders. Subgroup analyses further validated these correlations. Meanwhile, mediation analysis corroborated that FBG partially mediated the associations between SIRI and a poor prognosis at 90d (indirect effect estimate = 0.0038, bootstrap 95% CI 0.001 to 0.008; direct effect estimate = 0.1719, bootstrap 95% CI 0.1258 to 0.2179). Besides, FBG also played a mediating role between NHR and poor outcomes (indirect effect estimate = 0.0066, bootstrap 95% CI 0.002 to 0.120; direct effect estimate = 0.1308, bootstrap 95% CI 0.0934 to 0.1681). CONCLUSIONS: Our study demonstrated that SIRI and NHR are positively associated with poor clinical and mortality outcomes at 90d in AIS patients, which was partially mediated by FBG.

Functional identification of DNA demethylase gene CaROS1 in pepper (Capsicum annuum L.) involved in salt stress.

Pepper, which is a widely cultivated important vegetable, is sensitive to salt stress, and the continuous intensification of soil salinization has affected pepper production worldwide. However, genes confer to salt tolerance are rarely been cloned in pepper. Since the REPRESSOR OF SILENCING 1 (ROS1) is a DNA demethylase that plays a crucial regulatory role in plants in response to various abiotic stresses, including salt stress. We cloned a ROS1 gene in pepper, named CaROS1 (LOC107843637). Bioinformatic analysis showed that the CaROS1 protein contains the HhH-GPD glycosylase and RRM_DME domains. qRT-PCR analyses showed that the CaROS1 was highly expressed in young and mature fruits of pepper and rapidly induced by salt stress. Functional characterization of the CaROS1 was performed by gene silencing in pepper and overexpressing in tobacco, revealed that the CaROS1 positively regulates salt tolerance ability. More detailly, CaROS1-silenced pepper were more sensitive to salt stress, and their ROS levels, relative conductivity, and malondialdehyde content were significantly higher in leaves than those of the control plants. Besides, CaROS1-overexpressing tobacco plants were more tolerant to salt stress, with a higher relative water content, total chlorophyll content, and antioxidant enzyme activity in leaves compared to those of WT plants during salt stress. These results revealed the CaROS1 dose play a role in salt stress response, providing the theoretical basis for salt tolerance genetic engineering breeding in pepper.

Hot-water soluble fraction of starch as particle-stabilizers of oil-in-water emulsions: Effect of dry heat modification.

Dry heat treatment (DHT) ranging from 130 to 190 °C was employed to modify corn starch. The hot-water soluble fraction (HWS) of the DHT-modified starch was isolated, and its capacity and mechanism for stabilizing O/W emulsions were investigated. Corn starch underwent a significant structural transformation by DHT at 190 °C, characterized by a 7.3 % reduction in relative crystallinity, a tenfold decrease in weight-average molecular weight from 95.21 to 8.11 × 106 g/mol, and a degradation of over one-third of the extra-long chains of amylopectin (DP > 36) into short chains (DP 6-12). These structural modifications resulted in a substantial formation of soluble amylopectin, leading to a sharp increase in the HWS content of corn starch from 3.16 % to 85.06 %. This augmented HWS content surpassed the critical macromolecule concentration, prompting the formation of HWS nanoaggregates. These nanoaggregates, with an average particle size of 33 nm, functioned as particle stabilizers, ensuring the stability of the O/W emulsion through the Pickering mechanism. The O/W emulsion stabilized by HWS nanoaggregates exhibited noteworthy centrifugal and storage stability, with rheological properties remaining nearly unchanged over a storage period of 180 days. Given its straightforward preparation process, the HWS of DHT-modified starch could be a promising natural emulsifier.

ScRNA-seq reveals novel immune-suppressive T cells and investigates CMV-TCR-T cells cytotoxicity against GBM.

BACKGROUND: Glioblastoma (GBM) is a fatal primary brain malignancy in adults. Previous studies have shown that cytomegalovirus (CMV) is a risk factor for tumorigenesis and aggressiveness for glioblastoma. However, little is known about how CMV infection affects immune cells in the tumor microenvironment of GBM. Furthermore, there has been almost no engineered T-cell receptor (TCR)-T targeting CMV for GBM research to date. METHODS: We evaluated the CMV infection status of patients with GBM's tumor tissue by immune electron microscopy, immunofluorescence, and droplet digital PCR. We performed single-cell RNA sequencing for CMV-infected GBM to investigate the effects of CMV on the GBM immune microenvironment. CellChat was applied to analyze the interaction between cells in the GBM tumor microenvironment. Additionally, we conducted single-cell TCR/B cell receptor (BCR) sequencing and Grouping of Lymphocyte Interactions with Paratope Hotspots 2 algorithms to acquire specific CMV-TCR sequences. Genetic engineering was used to introduce CMV-TCR into primary T cells derived from patients with CMV-infected GBM. Flow cytometry was used to measure the proportion and cytotoxicity status of T cells in vitro. RESULTS: We identified two novel immune cell subpopulations in CMV-infected GBM, which were bipositive CD68+SOX2+ tumor-associated macrophages and FXYD6+ T cells. We highlighted that the interaction between bipositive TAMs or cancer cells and T cells was predominantly focused on FXYD6+ T cells rather than regulatory T cells (Tregs), whereas, FXYD6+ T cells were further identified as a group of novel immunosuppressive T cells. CMV-TCR-T cells showed significant therapeutic effects on the human-derived orthotopic GBM mice model. CONCLUSIONS: These findings provided an insight into the underlying mechanism of CMV infection promoting the GBM immunosuppression, and provided a novel potential immunotherapy strategy for patients with GBM.

Integrated single-cell and spatial transcriptomic analysis reveals YBX1 drives immune regulation in GBM progression.

The RNA modification 5-methylcytosine (m5C) is widespread across various RNA types, significantly impacting RNA stability and translational efficiency. Accumulating evidence highlights its significant role within the tumorigenesis and progression of multiple malignancies. Nevertheless, the specific process through m5C is implicated in Glioblastoma (GBM) remains unclear. We conducted acomprehensive analysis of m5C expression distribution in single-cell GBM data. Our findings revealed elevated m5C scores in GBM single-cell data compared to the normal group. Additionally, multiple tumors exhibited significantly higher m5C scores than the normal group. Moreover, there was a positive correlation observed between the m5C score and inflammation score. m5C regulatory factor YBX1 exhibited a heightened expression in GBM, correlating closely with metastatic tendencies and an unfavorable prognosis across various cancer types. YBX1 has different biological functions in myeloid cells 1 and myeloid cells 2. YBX1 may act as immunosuppressive regulator by inhibiting the NF-κB pathway and inflammatory response in myeloid cells 1. YBX1 is essential for immune infiltrates, which creates a highly immunosuppressive tumor microenvironment by TNF signaling pathway in myeloid cells 2. YBX1+ neoplastic cells promote cell proliferation by NF-κB pathway. APOE mediates the interaction of YBX1+ myeloid cells and neoplastic cells by NF-κB.

Correlation of Peripheral Blood Inflammatory Indicators to Prognosis After Intravenous Thrombolysis in Acute Ischemic Stroke: A Retrospective Study.

Purpose: According to many previous studies, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and hypersensitive C-reactive protein (CRP) are commonly used as important indicators to assess the prognosis of intravenous thrombolysis in AIS patients. Based on this, we used two novel biomarkers C-NLR (CRP/neutrophil-to-lymphocyte ratio) and C-LMR (CRP×lymphocyte-to-monocyte ratio) to investigate their correlation with 90-day outcomes in AIS patients after intravenous thrombolysis. Patients and Methods: A total of 204 AIS patients who received intravenous thrombolysis at the Stroke Center of Jiangsu Province Hospital of Chinese Medicine from January 2021 to December 2022 were retrospectively included. All patients were followed up 90 days after thrombolysis to assess their prognosis. Patients with a modified Rankin scale score (mRS) of 3-6 were included in the unfavorable outcome group, and those with a score of 0-2 were included in the favorable outcome group. Logistic regression analysis, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival curve were used to investigate the association between C-NLR, C-LMR, and 90-day prognosis in AIS patients treated with early intravenous thrombolysis. Results: C-NLR (OR=1.586, 95% CI=1.098~2.291, P=0.014) and C-LMR (OR=1.099, 95% CI=1.025~1.179, P=0.008) were independent risk factors for 90-day prognosis of AIS patients treated with early intravenous thrombolysis. The higher C-NLR and C-LMR were associated with unfavorable prognosis. Conclusion: C-NLR and C-LMR can be used as biomarkers to predict prognosis of AIS patients treated with early intravenous thrombolysis.

Electronic structure modulation of iron sites with fluorine coordination enables ultra-effective H2O2 activation.

Electronic structure modulation of active sites is critical important in Fenton catalysis as it offers a promising strategy for boosting H2O2 activation. However, efficient generation of hydroxyl radicals (•OH) is often limited to the unoptimized coordination environment of active sites. Herein, we report the rational design and synthesis of iron oxyfluoride (FeOF), whose iron sites strongly coordinate with the most electronegative fluorine atoms in a characteristic moiety of F-(Fe(III)O3)-F, for effective H2O2 activation with potent •OH generation. Results demonstrate that the fluorine coordination plays a pivotal role in lowering the local electron density and optimizing the electronic structures of iron sites, thus facilitating the rate-limiting H2O2 adsorption and subsequent peroxyl bond cleavage reactions. Consequently, FeOF exhibits a significant and pH-adaptive •OH yield (~450 µM) with high selectivity, which is 1 ~ 3 orders of magnitude higher than the state-of-the-art iron-based catalysts, leading to excellent degradation activities against various organic pollutants at neutral condition. This work provides fundamental insights into the function of fluorine coordination in boosting Fenton catalysis at atomic level, which may inspire the design of efficient active sites for sustainable environmental remediation.

Hierarchical Porous Fibers for Intrinsically Thermally Insulated and Self-Sensing Integrated Smart Textile.

Here, stretchable hierarchical porous polyurethane fibers were designed, fabricated, and employed as a three-dimensional hierarchical interconnected framework for conductive networks interwoven with silver nanoparticles and carbon nanotubes. The fiber possessed favorable thermal insulation, strain sensing, and electric heating properties. The core-shell layered porous structure of fiber made the fiber have high heat insulation performance (the difference value of temperature |ΔT| = 3.54, 8.9, and 12.7 °C at heating stage temperatures of 35, 50, and 65 °C) and ultrahigh elongation at break (813%). Importantly, after conductive filler decoration, the fiber could exhibit real-time strain-sensing capacities with a high gauge factor. In addition, the fibers could be heated at low voltage, like an electrical heater. The development of flexible, stretchable, and multifunctional porous fibers had great potential applications in intelligent wearable devices for integrated thermal management, strain sensing, and intrinsic self-warming capability.

Design and synthesis of pyrene-based probes and their fluorescent detection of Sb(III).

A series of pyrene-based fluorescent (FL) probes for Sb(III) were designed and synthesized. All of them exhibited luminescence by pyrene excimers in the mixture of DMSO and water and showed enhanced emission with the addition of Sb(III). By comparing their FL response to Sb(III), the effects of intramolecular hydrogen bond, inductive effect, and steric effect were investigated. Meanwhile, the FL enhancement factor of the best performing probe reached 10.28 and the detection limit was calculated to be 0.0535 mg/L, indicating that it might be used as a potential candidate for the treatment of Sb(III) in printing and dyeing wastewater.

Relationship of Day-by-Day Blood Pressure Variability and Admission Stroke Severity in Acute Ischemic Stroke.

OBJECTIVES: Research on the association between stroke severity and day-by-day blood pressure variability (BPV) in acute ischemic stroke (AIS) is rare as the majority focus on the blood pressure (BP) or the short-term BPV. Our study aims to explore the exact roles of daily BPV through the 7-day commencement on stroke severity in AIS. METHODS: The study included 633 patients with AIS, defining AIS as the time from the beginning of symptom up to 7 days with recording BP twice a day as well as calculating the daily BPV, and then matching them to the stroke severity. The logistic regression models were used to evaluate associations between stroke severity and day-by-day BPV. We used the smooth curve fitting to identify whether there was a nonlinear association. In addition, the subgroup analyses were performed using the logistic regression. RESULTS: According to the modified National Institutes of Health Stroke Scale score, 301 (47.5%) patients were allocated to the mild stroke group and 332 (52.5%) to the moderate-to-severe stroke group. In terms of stroke categories, we found no significant difference between BP at admission or mean BP. However, the moderate-to-severe stroke group exhibited higher daily BPV. The multiple logistic regression analysis indicated that day-by-day BPV was positively correlated to stroke severity [odds ratio (OR)=1.05, 95% CI:1.01-1.1, P=0.03 for SBP-SD; OR=1.08, 95% CI:1.01-1.15, P=0.03 for SBP-CV; OR=1.04, 95% CI:1.01-1.07, P=0.015 for SBP-SV). CONCLUSIONS: High day-by-day BPV in AIS was associated with more severe stroke independent of BP levels.

Global research trends on innate lymphoid cells in the brain, gut and lung field: a bibliometric and visualized analysis.

Background: ILCs play important roles in the brain, gut, and lungs. Researchers are attempting to establish a research framework on the brain-gut-lung axis using ILCs. However, no one has yet conducted a bibliometric analysis to summarize the findings. In this study, we utilized bibliometrics to analyze the emerging trends and focal areas of ILCs in the brain, intestine, and lung. We aim to provide references for future research on the brain-gut-lung axis. Methods: To conduct a comprehensive bibliometric analysis on ILCs in the fields of brain, intestine, and lung, we utilized software such as HistCite, VOSviewer, and CiteSpace. Our analysis focused on various aspects, including the number of publications, countries, authors, journals, co-cited documents, and keywords. This approach allowed us to gain valuable insights into the research landscape surrounding ILCs in these specific fields. Results: A total of 8411 articles or reviews on ILCs in the fields of brain, intestine, and lung were included. The number of published articles has shown a consistent upward trend since 2003. A total of 45279 authors from 99 countries have contributed to these articles. The United States has the highest number of publications (n=3044) and the most cited articles (TGCS=210776). The top three published authors in this field are David Artis, Marco Colonna and Andrew NJ McKenzie. The journal Immunity is the most authoritative choice for researchers. The main research focuses in this field include NK cell, ILC2, tumor immunity, multiple sclerosis, inflammatory bowel disease, airway inflammation, RORγT, and immunotherapy. In recent years, cancer and tumor microenvironment have emerged as hot keywords, particularly immunotherapy, PD-1 related directions, indicating a potential shift in research focus. Conclusion: European and American countries have been pivotal in conducting research on ILCs, while China has produced a significant number of publications, its impact is still limited. Tumors are likely to emerge as the next focal points in this field. The connection and regulation between the brain and the lung are not yet fully understood, and further investigation is necessary to explore the role of ILCs in the brain-lung axis.

Insight into deep learning for glioma IDH medical image analysis: A systematic review.

BACKGROUND: Deep learning techniques explain the enormous potential of medical image analysis, particularly in digital pathology. Concurrently, molecular markers have gained increasing significance over the past decade in the context of glioma patients, providing novel insights into diagnosis and more personalized treatment options. Deep learning combined with imaging and molecular analysis enables more accurate prognostication of patients, more accurate treatment plan proposals, and accurate biomarker (IDH) prediction for gliomas. This systematic study examines the development of deep learning techniques for IDH prediction using histopathology images, spanning the period from 2019 to 2023. METHOD: The study adhered to the PRISMA reporting requirements, and databases including PubMed, Google Scholar, Google Search, and preprint repositories (such as arXiv) were systematically queried for pertinent literature spanning the period from 2019 to the 30th of 2023. Search phrases related to deep learning, digital pathology, glioma, and IDH were collaboratively utilized. RESULTS: Fifteen papers meeting the inclusion criteria were included in the analysis. These criteria specifically encompassed studies utilizing deep learning for the analysis of hematoxylin and eosin images to determine the IDH status in patients with gliomas. CONCLUSIONS: When predicting the status of IDH, the classifier built on digital pathological images demonstrates exceptional performance. The study's predictive effectiveness is enhanced with the utilization of the appropriate deep learning model. However, external verification is necessary to showcase their resilience and universality. Larger sample sizes and multicenter samples are necessary for more comprehensive research to evaluate performance and confirm clinical advantages.

Zuogui Pill Promotes Neurite Outgrowth by Regulating OPN/ IGF-1R/PTEN and Downstream mTOR Signaling Pathway.

AIM AND OBJECTIVE: Zuogui pill (ZGP) is the traditional Chinese medicine for tonifying kidney yin. Clinical and animal studies have shown that ZGP effectively enhances neurologic impairment after ischemic stroke, which may be related to promoting neurite outgrowth. This investigation aimed to prove the pro-neurite outgrowth impact of ZGP and define the underlying molecular pathway in vitro. MATERIALS AND METHODS: The major biochemical components in the ZGP were investigated using UPLC-QTOF-MS. All-trans retinoic acid (ATRA) was employed to stimulate SH-SY5Y cells to develop into mature neurons, followed by oxygen-glucose deprivation and reoxygenation damage (OGD/R). Then the cells were supplemented with different concentrations of ZGP, and cell viability was identified by CCK-8. The neurites' outgrowth abilities were detected by wound healing test, while immunofluorescence staining of ß-III-tubulin was used to label neurites and measure their length. Western blot was employed to discover the changes in protein levels. RESULTS: ZGP improved the cell viability of differentiated SH-SY5Y cells following OGD/R damage, according to the CCK-8 assay. Concurrently, ZGP promoted neurite outgrowth and improved neurite crossing and migration ability. Protein expression analysis showed that ZGP upregulated the expression of GAP43, OPN, p-IGF-1R, mTOR, and p-S6 proteins but downregulated the expression of PTEN protein. Blocking assay with IGF-1R specific inhibitor Linstinib suggested IGF-1R mediated mTOR signaling pathway was involved in the pro-neurite outgrowth effect of ZGP. CONCLUSION: This work illustrated the molecular mechanism underpinning ZGP's action and offered more proof of its ability to promote neurite outgrowth and regeneration following ischemic stroke.

Predictive Panel for Immunotherapy in Low-Grade Glioma.

BACKGROUND: The main treatment of low-grade glioma (LGG) is still surgical resection followed by radiotherapy and/or chemotherapy, which has certain limitations, including side effects and drug resistance. Immunotherapy is a promising treatment for LGG, but it is generally hindered by the tumor microenvironment with the limited expression of tumor antigens. METHODS: We integrated RNA sequencing data sets and clinical information and conducted consistent cluster analysis to explore the most suitable patients for immune checkpoint therapy. Gene set enrichment analysis, UMAP analysis, mutation correlation analysis, TIMER analysis, and TIDE analysis were used to identify the immune characteristics of 3 immune subtypes and the feasibility of 5 antigens as immune checkpoint markers. RESULTS: We analyzed the isolation and mutation of homologous recombination repair genes (HRR) of the 3 immune subtypes, and the HRR genes of the 3 subtypes were obviously segregated. Among them, the IS2 subtype has a large number of HRR gene mutations, which increases the immunogenicity of tumors-this is consistent with the results of tumor mutation load analysis of 3 immune subtypes. Then we evaluated the immune cell infiltration of immune subtypes and found that IS2 and IS3 subtypes were rich in immune cells. It is worth noting that there are many Treg cells and NK cells in the IS1 subtype. In addition, when analyzing the immune checkpoint gene expression of the 3 subtypes, we found that they were upregulated most in IS2 subtypes compared with other subtypes. Then when we further confirmed the role of immune-related genes in LGG; through TIDE analysis and TISIDB analysis, we obtained 5 markers that can predict the efficacy of ICB in patients with LGG. In addition, we confirmed that they were associated with poor prognosis through survival analysis. CONCLUSIONS: We obtained 3 reliable immune subtypes, and patients with the IS2 subtype are suitable for immunotherapy, in which NAMPT, SLC11A1, TNC, VIM, and SPP1 are predictive panel markers for ICB in the LGG group. Our findings provide a rationale for immunotherapy selection and prediction of patient prognosis in LGG patients.

Chronic stress as an emerging risk factor for the development and progression of glioma.

ABSTRACT: Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system. Compared with patients with other cancers, glioma patients often suffer from increased levels of psychological stress, such as anxiety and fear. Chronic stress (CS) is thought to impact glioma profoundly. However, because of the complex mechanisms underlying CS and variability in individual tolerance, the role of CS in glioma remains unclear. This review suggests a new proposal to redivide the stress system into two parts. Neuronal activity is dominant upstream. Stress-signaling molecules produced by the neuroendocrine system are dominant downstream. We discuss the underlying molecular mechanisms by which CS impacts glioma. Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

Cand2 inhibits CRL-mediated ubiquitination and suppresses autophagy to facilitate pathogenicity of phytopathogenic fungi.

The ubiquitin-proteasome system and the autophagy system are the two primary mechanisms used by eukaryotes to maintain protein homeostasis, and both are closely related to the pathogenicity of the rice blast fungus. In this research, we identified MoCand2 as an inhibitor of ubiquitination in Magnaporthe oryzae. Through this role, MoCand2 participates in the regulation of autophagy and pathogenicity. Specifically, we found that deletion of MoCand2 increased the ubiquitination level in M. oryzae, whereas overexpression of MoCand2 inhibited the accumulation of ubiquitinated proteins. Interaction analyses showed that MoCand2 is a subunit of Cullin-RING ligases (CRLs). It suppresses ubiquitination by blocking the assembly of CRLs and downregulating the expression of key CRL subunits. Further research indicated that MoCand2 regulates autophagy through ubiquitination. MoCand2 knockout led to over-ubiquitination and over-degradation of MoTor, and we confirmed that MoTor content was negatively correlated with autophagy level. In addition, MoCand2 knockout accelerated the K63 ubiquitination of MoAtg6 and strengthened the assembly and activity of the phosphatidylinositol-3-kinase class 3 complex, thus enhancing autophagy. Abnormal ubiquitination and autophagy in ΔMocand2 resulted in defects in growth, conidiation, stress resistance, and pathogenicity. Finally, sequence alignment and functional analyses in other phytopathogenic fungi confirmed the high conservation of fungal Cand2s. Our research thus reveals a novel mechanism by which ubiquitination regulates autophagy and pathogenicity in phytopathogenic fungi.

Association of fasting blood glucose level with 90-day unfavorable outcome in acute ischemic stroke patients.

OBJECTIVES: Fasting blood glucose (FBG) is a risk factor for Acute Ischemic Stroke (AIS). We aimed to systematically assess the association of FBG level and 90-day unfavorable outcome in AIS patients. METHODS: FBG levels and related information of the patients were collected at admission. The unfavorable outcome was defined as 90-day mRS 3-6. FBG levels were analyzed as continuous variables and tertiles (Q1-Q3). Odds ratios and 95% confidence intervals were calculated by using multivariate logistic regression analysis. RESULTS: Overall, 677 AIS patients were included. FBG were significantly associated with unfavorable outcome at 90 days (adjusted OR 1.15 [95%Cl, 1.05-1.25], P = 0.002). Participants were categorized based on the FBG tertile cut-off points, the Odds ratios was 2.55-fold higher in Q3 than those in Q1 after adjusting (OR 2.55[95%Cl, 1.23-5.3], p = 0.012). Threshold effect analysis showed when FBG ≥ 5.5 mmol/L, the correlation between FBG and 90-day unfavorable outcome increased significantly. Subgroup analysis showed that there was no significant interaction between FBG and 90-day unfavorable outcome. Non-diabetic AIS patients with hyperglycemia (FBG ≥ 7 mmol/L) have a worse prognosis in comparison to those with normal glucose (FBG ˂ 5.6 mmol/L) (OR 8.59 [ 95%Cl, 2.24-32.97], p = 0.002). CONCLUSION: FBG is an independent predictor of 90-day unfavorable outcome after stroke in AIS patients. When FBG ≥ 5.5 mmol/L, the risk of 90-day unfavorable outcome increases significantly.

[Effect and mechanism of Zuogui Pills on neural function recovery in ischemic stroke mice based on OPN/IGF-1/mTOR].

To explore the effect and mechanism of Zuogui Pills in promoting neural tissue recovery and functional recovery in mice with ischemic stroke. Male C57BL/6J mice were randomly divided into a sham group, a model group, and low-, medium, and high-dose Zuogui Pills groups(3.5, 7, and 14 g·kg~(-1)), with 15 mice in each group. The ischemic stroke model was established using photochemical embolization. Stiker remove and irregular ladder walking behavioral tests were conducted before modeling and on days 7, 14, 21, and 28 after medication. Triphenyl tetrazolium chloride(TTC) staining was performed on day 3 after modeling, and T2-weighted imaging(T2WI) and diffusion-weighted imaging(DWI) were performed on day 28 after medication to evaluate the extent of brain injury. Hematoxylin-eosin(HE) staining was performed to observe the histology of the cerebral cortex. Axonal marker proteins myelin basic protein(MBP), growth-associated protein 43(GAP43), mammalian target of rapamycin(mTOR), and its downstream phosphorylated s6 ribosomal protein(p-S6), as well as mechanism-related proteins osteopontin(OPN) and insulin-like growth factor 1(IGF-1), were detected using immunofluorescence and Western blot. Zuogui Pills had a certain restorative effect on the neural function impairment caused by ischemic stroke in mice. TTC staining showed white infarct foci in the sensory-motor cortex area, and T2WI imaging revealed cystic necrosis in the sensory-motor cortex area. The Zuogui Pills groups showed less brain tissue damage, fewer scars, and more capillaries. The number of neuronal axons in those groups was higher than that in the model group, and neuronal activity was stronger. The expression of GAP43, OPN, IGF-1, and mTOR proteins in the Zuogui Pills groups was higher than that in the model group. In summary, Zuogui Pills can promote the recovery of neural function and axonal growth in mice with ischemic stroke, and its mechanism may be related to the activation of the OPN/IGF-1/mTOR signaling pathway.