Visualizing the crucial roles of plasma membrane and peroxynitrite during abdominal aortic aneurysm using two-photon fluorescence imaging.

Peroxynitrite (ONOO-) and cell plasma membrane (CPM) are two key factors in cell pyroptosis during the progression of abdominal aortic aneurysm (AAA). However, their combined temporal and spatial roles in initiating AAA pathogenesis remain unclear. Herein, we developed a two-photon fluorescence probe, BH-Vis, enabling real-time dynamic detection of CPM and ONOO- changes, and revealing their interplay in AAA. BH-Vis precisely targets CPM with reduced red fluorescence intensity correlating with diminished CPM tension. Concurrently, a blue shift of the fluorescence signal of BH-Vis occurs in response to ONOO- offering a reliable ratiometric detection mode with enhanced accuracy by minimizing external testing variables. More importantly, two photon confocal imaging with palmitic acid (PA) and ganglioside (GM1) manipulation, which modulating cell pyroptosis, showcases reliable fluorescence fluctuations. This groundbreaking application of BH-Vis in a mouse AAA model demonstrates its significant potential for accurately identifying cell pyroptosis levels during AAA development.

131I Induced In Vivo Proteolysis by Photoswitchable azoPROTAC Reinforces Internal Radiotherapy.

Photopharmacology, incorporating photoswitches such as azobenezes into drugs, is an emerging therapeutic method to realize spatiotemporal control of pharmacological activity by light. However, most photoswitchable molecules are triggered by UV light with limited tissue penetration, which greatly restricts the in vivo application. Here, this study proves that 131I can trigger the trans-cis photoisomerization of a reported azobenezen incorporating PROTACs (azoPROTAC). With the presence of 50 µCi mL-1 131I, the azoPROTAC can effectively down-regulate BRD4 and c-Myc levels in 4T1 cells at a similar level as it does under light irradiation (405 nm, 60 mW cm-2). What's more, the degradation of BRD4 can further benefit the 131I-based radiotherapy. The in vivo experiment proves that intratumoral co-adminstration of 131I (300 µCi) and azoPROTC (25 mg kg-1) via hydrogel not only successfully induce protein degradation in 4T1 tumor bearing-mice but also efficiently inhibit tumor growth with enhanced radiotherapeutic effect and anti-tumor immunological effect. This is the first time that a radioisotope is successfully used as a trigger in photopharmacology in a mouse model. It believes that this study will benefit photopharmacology in deep tissue.

Sensitivity analysis and point mutations in BcSDHB confer cyclobutrifluram resistance in Botrytis cinerea from China.

Botrytis cinerea is one of the most destructive pathogens worldwide. It can damage over 200 crops, resulting in significant yield and quality losses. Cyclobutrifluram, a new generation of succinate dehydrogenase inhibitors, exhibits excellent inhibitory activity against B. cinerea. However, the baseline sensitivity and resistance of B. cinerea to cyclobutrifluram remains poorly understood. This study was designed to monitor the sensitivity frequency distribution, assess the resistance risk, and clarify the resistance mechanism of B. cinerea to cyclobutrifluram. The baseline sensitivity of B. cinerea isolates to cyclobutrifluram was 0.89 µg/mL. Cyclobutrifluram-resistant B. cinerea populations are present in the field. Six resistant B. cinerea isolates investigated in this study possessed enhanced compound fitness index compared to the sensitive isolates according to mycelial growth, mycelial dry weight, conidiation, conidial germination rate, and pathogenicity. Cyclobutrifluram exhibited no cross-resistance with tebuconazole, fludioxonil, cyprodinil, or iprodione. Sequence alignment revealed that BcSDHB from cyclobutrifluram-resistant B. cinerea isolates had three single substitutions (P225F, N230I, or H272R). Molecular docking verified that these mutations in BcSDHB conferred cyclobutrifluram resistance in B. cinerea. In conclusion, the resistance risk of B. cinerea to cyclobutrifluram is high, and the point mutations in BcSDHB (P225F, N230I, or H272R) confer cyclobutrifluram resistance in B. cinerea. This study provided important insights into cyclobutrifluram resistance in B. cinerea and offered valuable information for monitoring and managing cyclobutrifluram resistance in the future.

A novel fluorescence probe for ultrafast detection of SO2 derivatives/biogenic amines and its multi-application: Detecting food and fish freshness, fluorescent dye and bioimaging.

In this study, we have effectively prepared a novel fluorescent probe named HDXM based on benzopyran derivatives for the ultrafast detection (within 3 s) of SO2 derivatives or biogenic amines. HDXM showed a noticeable color change after the addition of SO2 derivatives (from purple to colorless) or biogenic amines (from purple to blue), indicating that HDXM can identify two analytes with the naked eye. It is worth noting that HDXM can be used to detect SO2 derivatives in actual sugar samples, and to image HSO3-/SO32- in living cells. More importantly, sensing labels (HDXM-loaded filter paper or agarose hydrogel) enable real-time visual monitoring of salmon freshness through colorimetric and fluorescence dual channels. Compared with the Chinese national standard method, the sensing label is an effective tool for evaluating the freshness of fish. Benefiting from its excellent solubility and fluorescence performance, HDXM can be used as a versatile fluorescent material in various applications, including flexible films, glass coatings, impregnating dyes, printing, and fingerprint ink. HDXM is expected to be a promising and valuable multifunctional tool for food safety and fluorescent materials.

Exploring the impact of high-altitude de-acclimatization on renal function: The roles of oxidative and endoplasmic reticulum stress in rat models.

BACKGROUND: High-altitude de-acclimatization (HADA) significantly impacts physiological functions when individuals acclimatize to high altitudes return to lower altitudes. This study investigates HADA's effects on renal function and structure in rats, focusing on oxidative and endoplasmic reticulum stress as potential mechanisms of renal injury. OBJECTIVE: To elucidate the pathophysiological mechanisms of renal damage in HADA and evaluate the efficacy of antioxidants Vitamin C (Vit C) and tauroursodeoxycholic acid (TUDCA) in mitigating these effects. METHODS: 88 male Sprague-Dawley rats were randomly divided into a control group, a high-altitude (HA) group, a high-altitude de-acclimatization (HADA) group, and a treatment group. The control group was housed in a sea level environment (500 m), while the HA, HADA, and treatment groups were placed in a simulated high-altitude chamber (5000 m) for 90 days. After this period, the HA group completed the modeling phase; the HADA group was further subdivided into four subgroups, each continuing to be housed in a sea level environment for 3, 7, 14, and 30 days, respectively. The treatment group was split into the Vit C group, the TUDCA group, and two placebo groups, receiving medication for 3 consecutive days, once daily upon return to the sea level. The Vit C group received 100 mg/kg Vit C solution via intravenous injection, the TUDCA group received 250 mg/kg TUDCA solution via intraperitoneal injection, and the placebo groups received an equivalent volume of saline similarly. Serum, urine, and kidney tissues were collected immediately after the modeling phase. Renal function and oxidative stress levels were assessed using biochemical and ELISA methods. Renal histopathology was observed with H&E, Masson's trichrome, PAS, and PASM staining. Transmission electron microscopy was used to examine the ultrastructure of glomeruli and filtration barrier. TUNEL staining assessed cortical apoptosis in the kidneys. Metabolomics was employed for differential metabolite screening and pathway enrichment analysis. RESULTS: Compared to the control and HA groups, the HADA 3-day group (HADA-3D) exhibited elevated renal function indicators, significant pathological damage, observable ultrastructural alterations including endoplasmic reticulum expansion and apoptosis. TUNEL-positive cells significantly increased, indicating heightened oxidative stress levels. Various differential metabolites were enriched in pathways related to oxidative and endoplasmic reticulum stress. Early intervention with Vit C and TUDCA markedly alleviated renal injury in HADA rats, significantly reducing the number of apoptotic cells, mitigating endoplasmic reticulum stress, and substantially lowering oxidative stress levels. CONCLUSION: This study elucidates the pivotal roles of oxidative and endoplasmic reticulum stress in the early-stage renal injury in rats undergoing HADA. Early intervention with the Vit C and TUDCA significantly mitigates renal damage caused by HADA. These findings provide insights into the pathophysiological mechanisms of HADA and suggest potential therapeutic strategies for its future management.

Robust Graphene-based Aerogel for Integrated 3D Asymmetric Supercapacitors with High Energy Density.

Three-dimensional asymmetric supercapacitors (3D ASC) have garnered significant attention due to their high operating window, theoretical energy density, and circularity. However, the practical application of 3D electrode materials is limited by brittleness and excessive dead volume. Therefore, we propose a controlled contraction strategy that regulates the pore structure of 3D electrode materials, eliminates dead volume in the 3D skeleton structure, and enhances mechanical strength. In this study to obtain reduced graphene oxide/manganese dioxide (rGO/MnO2) and reduced graphene oxide/carbon nanotube (rGO/CNT) composite aerogels with a stable and compact structure. MnO2 and CNT as nanogaskets, preventing the self-stacking of graphene nanosheets during the shrinkage process. Additionally, the high specific capacitor nanogaskets significantly enhance the specific energy density of the rGO aerogel electrode. The prepared rGO/MnO2//rGO/CNT 3D ASC exhibits a high mass-specific capacitance of 216.15 F g-1, a high mass energy density of 74 Wh kg-1 at 3.5 A g-1, and maintains a retention rate of capacitance at 99.89 % after undergoing 10,000 cycles of charge and discharge at 5 A g-1. The versatile and integrated assembly of 3D ASC units is achieved through the utilization of the robust mechanical structure of rGO-based aerogel electrodes, employing a mortise and tenon structural design.

Potential roles of the interactions between gut microbiota and metabolites in LPS-induced intrauterine inflammation (IUI) and associated preterm birth (PTB).

BACKGROUND: Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in preterm birth (PTB) pathophysiology, increasing the incidence of neurodevelopmental disorders. Gut microbiota and metabolite profile alterations have been reported to be involved in PTB pathophysiology. METHOD AND RESULTS: In this study, IUI-exposed PTB mouse model was established and verified by PTB rate and other perinatal adverse reactions; LPS-indued IUI significantly increased the rates of PTB, apoptosis and inflammation in placenta tissue samples. LPS-induced IUI caused no significant differences in species richness and evenness but significantly altered the species abundance distribution. Non-targeted metabolomics analysis indicated that the metabolite profile of the preterm mice was altered, and differential metabolites were associated with signaling pathways including pyruvate metabolism. Furthermore, a significant positive correlation between Parasutterella excrementihominis and S4572761 (Nb-p-coumaroyltryptamine) and Mreference-1264 (pyruvic acid), respectively, was observed. Lastly, pyruvic acid treatment partially improved LPS-induced IUI phenotypes and decreased PTB rates and decreased the apoptosis and inflammation in placenta tissue samples. CONCLUSION: This study revealed an association among gut microbiota dysbiosis, metabolite profile alterations, and LPS-induced IUI and PTB in mice models. Our investigation revealed the possible involvement of gut microbiota in the pathophysiology of LPS-induced IUI and PTB, which might be mediated by metabolites such as pyruvic acid. Future studies should be conducted to verify the findings through larger sample-sized animal studies and clinical investigations.

Radioactive iodine therapy for follicular thyroid cancer: a 15 years follow-up study of Chinese patients.

PURPOSE: To identify long-term predictors of distant metastases (DM) and the overall survival (OS) of follicular thyroid cancer (FTC) patients who underwent radioactive iodine (RAI) therapy. And to expand the knowledge about the clinical course and experience of RAI treatment for FTC. MATERIALS: A total of 117 FTC patients who underwent RAI therapy at our institution from 2005 to 2020 were retrospectively studied. Patient characteristics, serum stimulating thyroglobulin (sTg) and thyroglobulin antibody levels, treatment process and follow-up data were collected until 26 April 2022. RESULTS: A total of 16 patients (13.7%) were lost to follow-up. A total of 23 (19.7%) patients with DM died and all FTC without DM were still alive. DM was seen in 58.4% (59/101) of patients. The most common location for metastatic lesions was the lung. Then was bone. The mean survival time of FTC with RAI was 156 months [95% confidence interval (CI): 142-171]. Five-year and 10-year cumulative survival rates of them were 88.8% and 67.4%, respectively. As for patients with DM were 80.4% and 41.3%, respectively. Age at diagnosis [odds ratio (OR) = 1.080, P  = 0.009], RAI therapy sessions (OR = 2.959, P  = 0.001) and sTg level (OR = 1.006, P  = 0.002) were predictive of DM occurrence in FTC with RAI. In the group of FTC with DM, survival analysis showed that males were more likely to have a lower OS than females ( P  = 0.039). CONCLUSION: Age, number of RAI therapy sessions, and sTg level were predictive of the occurrence of DM in FTC patients with RAI. Sex would influence the OS of FTC patients with DM.

A colorimetric and NIR fluorescent probe for ultrafast detecting bisulfite and organic amines and its applications in food, imaging, and monitoring fish freshness.

Herein, for the first time, we have successfully constructed a novel near-infrared (NIR) emission fluorescent probe Dpyt for ultrafast detecting (within 5 s) bisulfate and organic amines based on a 1,2-dihydrocyclopenta[b]chromene-barbiturate conjugation system. Upon addition of bisulfate or organic amines, Dpyt displayed a distinct color change from blue to colorless or from purple to blue, respectively, suggesting that the Dpyt can be used to detect two analytes by the naked eye. Based on quantum chemistry calculations, the fluorescence quenching of Dpyt after the addition of HSO3- is caused by the photoinduced electron transfer (PET) process of the adduct Dpyt-HSO3-. The fluorescence enhancement of Dpyt caused by most organic amines is due to the enhanced intramolecular charge transfer (ICT) process of deprotonated Dpyt. Notably, Dpyt can be applied for detecting HSO3- in actual food samples such as red wine and sugar, as well as for imaging of HSO3- and representative propylamine in living cells. And more importantly, indicator labels constructed by filter paper loaded with Dpyt can visually monitor the freshness of salmon in real-time by daylight and fluorescence dual-mode. The comparison with national standard method of China manifests that indicator labels are a valid tool to assess the freshness of seafood.

The RADAR technique in reconstruction of failed autologous arteriovenous fistulas due to juxta-anastomotic stenosis is equivalent to that with traditional surgery in maintenance hemodialysis patients.

OBJECTIVE: Autologous arteriovenous fistula (AVF) is recommended as superior vascular access for hemodialysis but has a high rate of failure, and juxta-anastomotic stenosis (JAS) is one of the predominant causes of fistula failure. The aim of this study was to compare the primary patency in reconstruction of failed AVFs due to JAS between the radial artery deviation and reimplantation (RADAR) technique and traditional surgery (end-vein to side-artery neo-anastomosis) in maintenance hemodialysis (MHD) patients. METHODS: A total of 1215 MHD patients with failed AVF were enrolled in this retrospective cohort study, and 614 patients with failed AVF received surgical intervention. Among these surgical interventions, 417 patients experienced AVF failure due to JAS. Finally, 25 patients who received the RADAR technique were enrolled. Controls of 50 patients received traditional surgery were randomly selected matched by age and sex. Clinical data such as age, sex, comorbidities, and blood biochemical indices were collected. Kaplan-Meier survival curves and Cox proportional hazards analyses were used to explore the difference between the RADAR group and the traditional group in reconstruction of failed AVFs. RESULTS: The RADAR group and the traditional group shared common baseline characteristics. The primary patencies of the reconstructed AVFs were 88.8%, 79.0%, 72.2%, 57.4%, and 38.3% at 12, 24, 36, 48, and 60 months among the 75 patients, respectively. Kaplan-Meier survival curve analysis demonstrated similar primary patencies in the two groups (log-rank test, p = 0.73). Compared with the traditional group, the RADAR group had no difference in predicting AVF failure after adjusting for potential confounders, with an HR of 0.92 (95% CI, 0.18-4.63). CONCLUSIONS: The primary patency of the RADAR technique and the traditional surgery in the reconstruction of failed AVFs due to JAS is almost equal in 5 years.

Predicting acute pancreatitis severity with enhanced computed tomography scans using convolutional neural networks.

This study aimed to evaluate acute pancreatitis (AP) severity using convolutional neural network (CNN) models with enhanced computed tomography (CT) scans. Three-dimensional DenseNet CNN models were developed and trained using the enhanced CT scans labeled with two severity assessment methods: the computed tomography severity index (CTSI) and Atlanta classification. Each labeling method was used independently for model training and validation. Model performance was evaluated using confusion matrices, areas under the receiver operating characteristic curve (AUC-ROC), accuracy, precision, recall, F1 score, and respective macro-average metrics. A total of 1,798 enhanced CT scans met the inclusion criteria were included in this study. The dataset was randomly divided into a training dataset (n = 1618) and a test dataset (n = 180) with a ratio of 9:1. The DenseNet model demonstrated promising predictions for both CTSI and Atlanta classification-labeled CT scans, with accuracy greater than 0.7 and AUC-ROC greater than 0.8. Specifically, when trained with CT scans labeled using CTSI, the DenseNet model achieved good performance, with a macro-average F1 score of 0.835 and a macro-average AUC-ROC of 0.980. The findings of this study affirm the feasibility of employing CNN models to predict the severity of AP using enhanced CT scans.

The influence of arm positions on mechanical dyssynchrony measured by gated myocardial perfusion imaging.

Background: In routine procedures, patient's arms are positioned above their heads to avoid potential attenuation artifacts and reduced image quality during gated myocardial perfusion imaging (G-MPI). However, it is difficult to achieve this action in the acute period following pacemaker implantation. This study aimed to explore the influence of arm positioning on myocardial perfusion imaging (MPI) in different types of heart disease. Methods: This study was conducted retrospectively. A total of 123 patients were enrolled and underwent resting G-MPI using a standard protocol with arms positioned above their heads and again with their arms at their sides. All individuals were divided into 3 groups: the normal group, the obstructive coronary artery disease (O-CAD) group, and the dilated cardiomyopathy (DCM) group. The G-MPI data were measured by QGS software and Emory Reconstruction Toolbox, including left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), end-systolic volume (ESV), extent, total perfusion deficit (TPD), summed rest score (SRS), scar burden, phase standard deviation (SD), and phase histogram bandwidth (BW). Results: In total, extent, TPD, EDV, ESV, LVEF, systolic SD, systolic BW, diastolic SD, and diastolic BW were all significantly different between the 2 arm positions (all P<0.01). On the Bland-Altman analysis, both EDV and ESV with the arm-down position were significantly underestimated (P<0.001). Meanwhile, TPD, extent, and LVEF with the arm-down position were significantly overestimated (P<0.05). Systolic SD, systolic BW, diastolic SD, and diastolic BW were systematically overestimated (P<0.001). In the DCM group (n=52), EDV, ESV, systolic SD, systolic BW, diastolic SD, and diastolic BW were identified as significantly different by the paired t-test between the 2 arm positions (P<0.05). In the O-CAD group (n=32), scar burden, ESV, LVEF, and diastolic BW were significantly different between the 2 arm positions (P<0.05). Conclusions: Systolic and diastolic dyssynchrony parameters and most left ventricular (LV) functional parameters were significantly influenced by arm position in both normal individuals and patients with heart failure (HF) with different pathophysiologies. More attention should be given to LV dyssynchrony data during clinical evaluation of cardiac resynchronization therapy (CRT) implantation procedure.

Containing anti-PLA2R IgG antibody induces podocyte injury in idiopathic membranous nephropathy.

Background: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear.Method: A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established in vitro podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed.Results: Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced (p = 0.016 and p = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group (p = 0.008).Conclusion: The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.

Role of lncRNAs in acute pancreatitis: pathogenesis, diagnosis, and therapy.

Acute pancreatitis (AP) is one of the most common acute abdominal diseases characterized by an injury and inflammatory disorder of the pancreas with complicated pathological mechanisms. Long non-coding RNAs (lncRNAs) have been shown to play an important role in various physiological and pathological processes in humans, and they have emerged as potential biomarkers of diagnosis and therapeutic targets in various diseases. Recently, accumulating evidence has shown significant alterations in the expression of lncRNAs, which are involved in the pathogenesis of AP, such as premature trypsinogen activation, impaired autophagy, inflammatory response, and acinar cell death. Moreover, lncRNAs can be the direct target of AP treatment and show potential as biomarkers for the diagnosis. Thus, in this review, we focus on the role of lncRNAs in the pathogenesis, diagnosis, and therapy of AP and emphasize the future directions to study lncRNAs in AP, providing new insight into understanding the cellular and molecular mechanisms of AP and seeking novel biomarkers for the diagnosis and therapeutic targets to improve clinical management in the future.

Alterations and potential roles of microbial population of pregnant mouse saliva and amniotic fluid.

PROBLEM: Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in PTB pathophysiology. However, the relationship between microflora and PTB is not fully elucidated. METHOD OF STUDY: In this study, we established an intrauterine inflammation mouse model via LPS intrauterine injection. The saliva and amniotic fluid were collected for 16s RNA gene sequencing. The levels of TNF-α and IL-1ß in mouse amniotic fluid were determined by ELISA assays. RESULTS: Up to 60% of the operational taxonomic units (OTUs) in the saliva and amniotic fluid of PBS-treated mice were overlapped. LPS treatment-induced changes in the abundance of oral and amniotic fluid microorganisms. Both immune-associated probiotics, salivarius and mastitidis, were still detected in saliva (at significantly increased levels) after LPS-induced intrauterine inflammation and almost no probiotics of any type were detected in amniotic fluid, suggesting that the uterine cavity seems to be more susceptible to LPS compared to the oral cavity. Moreover, the abundance of pathogenic bacteria Escherichia coli was increased in both saliva and amniotic fluid after LPS treatment. The level of TNF-α and IL-1ß in amniotic fluid is positively related to the amniotic fluid E. coli abundance. CONCLUSIONS: The microbial composition of saliva and amniotic fluid of pregnant mice was similar. LPS-induced intrauterine inflammation decreased the consistency of microbial composition in mouse saliva and amniotic fluid, increased the abundance of E. coli in saliva and amniotic fluid, and decreased the abundance of immune-associated probiotics, especially in amniotic fluid.

Hydrochemical analysis and groundwater suitability for drinking and irrigation in an arid agricultural area of the Northwest China.

Groundwater is the foremost water source in the arid and semiarid regions of Northwest China. Assessing groundwater's drinking and irrigation quality is essential for protecting these valuable groundwater resources. In this study, a total of 24 confined groundwater samples and 54 phreatic groundwater samples were collected in the southern and central Ningxia area for hydrochemical analysis and quality assessment. The hydrochemical results revealed that hydrochemical types of phreatic and confined groundwater consistently belonged to Na-SO4-Cl and Na-Mg-SO4-Cl types. The driving forces of groundwater chemistry were determined by gypsum dissolution, silicate dissolution, and positive cation exchange for phreatic and confined aquifers. The entropy-weighted water quality index (EWQI) and irrigation water quality index (IWQI) showed that the drinking water quality and irrigation quality were better in phreatic groundwater than in confined groundwater due to the Neogene-Paleogene groundwater system recharge and strong evaporation. Measures such as controlling groundwater extraction and optimizing well placement need to be implemented. The achievements would be helpful for groundwater management and protection in agricultural areas under semi-arid and arid climates.

ExoPD-L1: an assistant for tumor progression and potential diagnostic marker.

The proliferation and function of immune cells are often inhibited by the binding of programmed cell-death ligand 1 (PD-L1) to programmed cell-death 1 (PD-1). So far, many studies have shown that this combination poses significant difficulties for cancer treatment. Fortunately, PD-L1/PD-1 blocking therapy has achieved satisfactory results. Exosomes are tiny extracellular vesicle particles with a diameter of 40~160 nm, formed by cells through endocytosis. The exosomes are a natural shelter for many molecules and an important medium for information transmission. The contents of exosomes are composed of DNA, RNA, proteins and lipids etc. They are crucial to antigen presentation, tumor invasion, cell differentiation and migration. In addition to being present on the surface of tumor cells or in soluble form, PD-L1 is carried into the extracellular environment by tumor derived exosomes (TEX). At this time, the exosomes serve as a medium for communication between tumor cells and other cells or tissues and organs. In this review, we will cover the immunosuppressive role of exosomal PD-L1 (ExoPD-L1), ExoPD-L1 regulatory factors and emerging approaches for quantifying and detecting ExoPD-L1. More importantly, we will discuss how targeted ExoPD-L1 and combination therapy can be used to treat cancer more effectively.

Long non-coding RNA-XLOC_002383 enhances the inhibitory effects of THP-1 macrophages on Mycobacterium avium and functions as a competing endogenous RNA by sponging miR-146a-5p to target TRAF6.

The morbidity associated with infection by Mycobacterium avium (M. avium), a type of non-tuberculous mycobacteria (NTM), has increased in recent years due to infections that are easily missed, and thus, difficult to diagnose and treat. Here, we reported that miR-146a-5p was highly expressed, and XLOC_002383 and TRAF6 were downregulated in a time- and MOI-dependent manner in THP-1 macrophages infected with M. avium. In macrophages obtained from peripheral blood mononuclear cells, the expression levels of XLOC_002383 and TRAF6 were also decreased, and miR-146a-5p expression was increased following 24 h of infection with M. avium. miR-146a-5p was a target of XLOC_002383 and TRAF6 mRNA was a target of miR-146a-5p, and XLOC_002383 regulated TRAF6 expression by adsorbing miR-146a-5p, and further increased IL-6, TNF-α, IL-1ß and iNOS levels in THP-1 macrophages. The results of qPCR and CFU assays indicated that XLOC_002383 decreased the intracellular M. avium loads. Overall, the present study demonstrated that XLOC_002383 may function as a competing endogenous RNA and interacts with miR-146a-5p to increase THP-1 macrophage inflammatory factors and microbicidal mediators iNOS. This enhanced the inhibitory effects of THP-1 macrophages on M. avium, which improved the understanding of the pathogenesis and host defenses in the process of NTM infectious diseases.

Single-cell transcriptomics reveals the drivers and therapeutic targets of lymph node metastasis in lung adenocarcinoma.

Lymph node metastasis (LNM) is usually the most common metastatic pathway in lung adenocarcinoma (LUAD) and is associated with a poorer prognosis and higher possibility of recurrence. Therefore, discovering the drivers and therapeutic targets of LNM is important for early and non-invasive detection of patients with a high risk of LNM and guiding individualized therapy. Various cell constitutions of the primary tumor and lymph node microenvironment was characterized based on scRNA-seq data. The copy number variation (CNV) analysis was performed to probe clonal structures and origins of metastatic lymph nodes, and found 6q loss and 20q gain may drive LNM in LUAD. Then a LNM-related cell subset, named Scissor+ cells, was identified using the Scissor algorithm. And cell-cell communication network among Scissor+ cells and microenvironment was further analyzed. Besides, a pro-LNM signature was subsequently constructed based on 27 genes using pseudotime trajectory analysis and gene set variation analysis. The pro-LNM signature showed a significant correlation with N stage and a good predictive ability of LUAD survival. At last, we identified that erastin and gefitinib could potentially inhibit LNM by targeting Scissor+ cells based on the drug sensitivity data of the cancer cell lines, which provided new insights for LUAD therapy.

Phytophthora RxLR effector PcSnel4B promotes degradation of resistance protein AtRPS2.

Phytophthora capsici deploys effector proteins to manipulate host immunity and facilitate its colonization. However, the underlying mechanisms remain largely unclear. In this study, we demonstrated that a Sne-like (Snel) RxLR effector gene PcSnel4 is highly expressed at the early stages of P. capsici infection in Nicotiana benthamiana. Knocking out both alleles of PcSnel4 attenuated the virulence of P. capsici, while expression of PcSnel4 promoted its colonization in N. benthamiana. PcSnel4B could suppress the hypersensitive reaction (HR) induced by Avr3a-R3a and RESISTANCE TO PSEUDOMONAS SYRINGAE 2 (AtRPS2), but it did not suppress cell death elicited by Phytophthora infestin 1 (INF1) and Crinkler 4 (CRN4). COP9 signalosome 5 (CSN5) in N. benthamiana was identified as a host target of PcSnel4. Silencing NbCSN5 compromised the cell death induced by AtRPS2. PcSnel4B impaired the interaction and colocalization of Cullin1 (CUL1) and CSN5 in vivo. Expression of AtCUL1 promoted the degradation of AtRPS2 and disrupted HR, while AtCSN5a stabilized AtRPS2 and promoted HR, regardless of the expression of AtCUL1. PcSnel4 counteracted the effect of AtCSN5 and enhanced the degradation of AtRPS2, resulting in HR suppression. This study deciphered the underlying mechanism of PcSnel4-mediated suppression of HR induced by AtRPS2.