Atherosis-associated lnc_000048 activates PKR to enhance STAT1-mediated polarization of THP-1 macrophages to M1 phenotype.

JOURNAL/nrgr/04.03/01300535-202419110-00029/figure1/v/2024-03-08T184507Z/r/image-tiff Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE-/- mice. However, little is known about the role of lnc_000048 in classically activated macrophage (M1) polarization. In this study, we established THP-1-derived testing state macrophages (M0), M1 macrophages, and alternately activated macrophages (M2). Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages. Flow cytometry was used to detect phenotypic proteins (CD11b, CD38, CD80). We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048. Flow cytometry, western blot, and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response, while over-expression of lnc_000048 led to the opposite effect. Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization. Moreover, catRAPID prediction, RNA-pull down, and mass spectrometry were used to identify and screen the protein kinase RNA-activated (PKR), then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR. Immunofluorescence (IF)-RNA fluorescence in situ hybridization (FISH) double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage. We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation, leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression. Taken together, these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.

Embolic stroke of undetermined source: Focusing on atrial cardiopathy and patent foramen ovale.

BACKGROUND: Atrial cardiopathy(AC) and patent foramen ovale (PFO) are two etiologies of embolic strokes of undetermined source (ESUS). We aimed to explore the relationship between them in ESUS. METHODS: A total of 1146 participants were included from January 2019 to June 2022, which included the ESUS group and non-embolic stroke which includes LAA(large arterial atherosclerosis) + SAO(small artery occlusion) group. AC was defined as the presence of at least one of the following: PTFV1(P-wave terminal force in lead V1) > 4000 µV*ms in the electrocardiograms, NT-proBNP(N-terminal probrain natriuretic peptide) > 250 pg/mL in laboratory tests or LAD(left atrial diameter) > 3.8 cm for women and > 4.0 cm for men in cardiac ultrasound. The presence of PFO was assessed by transthoracic echocardiography, transcranial Doppler ultrasound, transesophageal echocardiography or cardiac MRI. PFO was considered pathogenic if the RoPE score was 7 to 10. RESULTS: The prevalence of AC and PFO was higher in the ESUS group than the LAA + SAO group. The prevalence of AC was lower in ESUS patients with pathogenic PFO (37.9%) than those without PFO (68.4%) and with incidental PFO (64.0%) (p = 0.006). The prevalence of pathogenic PFO was lower in ESUS patients with AC than those without AC (6.0% vs. 17.8%, p = 0.006). The AUC(area under the curve) of PTFV1 for predicting ESUS was 0.724 [95%CI (0.686-0.762), p < 0.05)], indicating that PTFV1 the most valuable AC biomarker. CONCLUSIONS: The prevalence of AC is inversely related to the prevalence of pathogenic PFO in ESUS patients. PTFV1 was the most valuable index to predict ESUS among the AC biomarkers.

Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma.

OBJECTIVE: We investigated the prognostic value of cyclin-dependent kinase 5 (CDK5) in a true population-based cohort of patients with colon cancer. METHODS: 1. Immunohistochemical (IHC) staining was used to retrospectively analyse the expression of CDK5 in colon cancer tissue samples of 296 patients. The χ2 test, Kaplan-Meier method and Cox proportional regression model were used to analyse the difference between the patients with differential expression of CDK5 and with different stages (metastatic and nonmetastatic); 2. The number of tumour-infiltrating lymphocytes (TILs) in tumour sections was determined, and its relationship with prognosis was explored. RESULTS: 1. Among 296 patients stained for CDK5, 18 cases (6.09%) showed negative expression, 77 cases (26.01%) showed weak expression (+1), 124 cases (41.89%) showed medium positive expression (2+), and 77 cases (26.01%) showed strong positive expression (3+). The expression of CDK5 was neither related to mismatch repair nor TILs (p > .05). In non-metastatic patients, longer progression-free survival (PFS) and cancer-specific survival (CSS) were observed in patients with high CDK5 expression (2+ or 3+) than low CDK5 expression (- or 1+), while in metastatic disease, the opposite was true (p < .001). 2. TILs in 226 patients were detected in the study. Among them, 115 cases (50.88%) showed a low number of TILs (TILs-L), and 111 cases (49.12%) showed a high number of TILs (TILs-H). Patients with a TIL ratio greater than .2 had a significantly better CSS (p < .001) or PFS (p = .008) than patients with a lower TIL ratio. By multivariate analysis, TILs-H was a protective factor for CSS, however failed to reach a significant difference (hazard ratio: .59, 95% CI: .33∼1.06, p = .079), and so was the PFS (HR: .65, 95% CI: .29∼1.43, p = .279). CONCLUSION: High expression of CDK5 indicates a good prognosis in nonmetastatic colon cancer, while it is the opposite in metastatic colon cancer, and the expression of CDK5 is unrelated to TILs. Patients with TIL-H have a better prognosis, with a proper cut-off value of 20% for colon cancer.

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease.

Background: Cerebral small vessel disease (CSVD) with an insidious onset can cause overall neurological dysfunction and dementia, bringing a massive burden to society. However, the pathogenesis of CSVD is complex and reliable non-invasive biomarkers for diagnosis are still not available at present. Our study aimed to investigate abnormal exosomal miRNA patterns via microarray analysis and identify candidate biomarkers for CSVD. Methods: We isolated exosomes from the plasma of all subjects and identified exosomes via currently universally accepted methods. The miRNAs were profiled through microarrays, and then the expression of selected differentially expressed miRNAs was validated through RT-PCR. GO and KEGG analysis predicted possible functions of differentially expressed miRNAs. Receiver operating characteristic (ROC) curve was employed to observe the diagnostic value of selective miRNAs. Finally, the relationship between the expression of miR-320e and the CSVD burden was analyzed. Results: A total of 14 miRNAs displayed differential enrichment levels with |fold change|≥1.5 and p<0.05 through miRNA microarray analysis. The RT-PCR analysis validated that exosomal miR-320e was significantly downregulated in CSVD patients (p<0.0001). ROC curve analysis of exosomal miR-320e showed the area under the curve of 0.752. According to the multivariable analysis, miR-320e was an independent predictor of white matter hyperintensity ([aOR]= 0.452, 95% confidence interval [CI]= 0.258-0.792, p=0.006) and exhibited a negative correlation with the load of periventricular white matter hyperintensities (p=0.0021) and deep white matter hyperintensities (p=0.0018), respectively. In addition, it exhibited a negative correlation with total CSVD burden score (r=-0.276, p=0.001). Conclusion: In our study, plasma exosomal miR-320e has a certain diagnostic value for CSVD, and a significant correlation with imaging burden of CSVD. Overall, exosomal miR-320e has the potential to be a novel biomarker for CSVD, but further research with a large sample size is necessary to assess its clinical utility.

Resection of primary lesion with chemotherapy improves the survival of patients with metastatic colorectal neuroendocrine carcinoma.

OBJECTIVE: To evaluate the effect of resection of primary lesion and chemotherapy on survival of patients with metastatic colorectal neuroendocrine carcinoma (CRNEC). METHODS: Clinical data of 393 patients with metastatic CRNECs between January 2010 and December 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, including 171 patients who received resection of primary lesion and 221 patients who did not undergo surgery. With the propensity score matching method 172 non-operated patients were selected as controls. Kaplan-Meier method and Log-rank test were used to evaluate the survival differences, while the prognostic factors were analyzed by Cox proportional-hazards model. Metastatic CRNEC patients from January 2001 to December 2021 in Affiliated Jinhua Hospital, Zhejiang University School of Medicine were selected for validation. RESULTS: Compared with non-operated patients, patients who received resection had longer cause-specific survival ( P<0.05). Patients with resected positive lymph nodes>8 had a poorer prognosis compared to those with resected positive lymph nodes≤8 ( P<0.05). Multivariate analysis showed that gender, location of primary lesion and treatments were independent risk factors for cause-specific survival in patients with metastatic CRNEC (all P<0.05). For metastatic CRNEC patients with resection of primary lesion, rectal neuroendocrine carcinoma, positive resected lymph nodes≤8 and resection of primary lesion combined with chemotherapy were associated with better cause-specific survival (all P<0.05). CONCLUSIONS: Patients with metastatic CRNEC may benefit from resection of primary lesion, and resection of primary lesion combined with chemotherapy might be the better strategy for metastatic CRNECs. The number of positive lymph nodes resected is correlated with the prognosis of patients.

An R-Based Landscape Validation of a Competing Risk Model.

The Cox proportional hazard model is widely applied for survival analyses in clinical settings, but it is not able to cope with multiple survival outcomes. Different from the traditional Cox proportional hazard model, competing risk models consider the presence of competing events and their combination with a nomogram, a graphical calculating device, which is a useful tool for clinicians to conduct a precise prognostic prediction. In this study, we report a method for establishing the competing risk nomogram, that is, the evaluation of its discrimination (i.e., concordance index and area under the curve) and calibration (i.e., calibration curves) abilities, as well as the net benefit (i.e., decision curve analysis). In addition, internal validation using bootstrap resamples of the original dataset and external validation using an external dataset of the established competing risk nomogram were also performed to demonstrate its extrapolation ability. The competing risk nomogram should serve as a useful tool for clinicians to predict prognosis with the consideration of competing risks.

Increased level of FAM19A5 is associated with cerebral small vessel disease and leads to a better outcome.

Objective: FAM19A5 plays an essential role in the development and acute or chronic inflammation of the central nervous system. The present study aimed to explore the association between FAM19A5 and cerebral small vessel disease (cSVD). Methods: A total of 344 recent small subcortical infarct (RSSI) patients and 265 healthy controls were included in this study. The difference in the FAM19A5 level between the two groups was compared and the correlation between FAM19A5 and cerebral infarction volume was analyzed. Also, the association between FAM19A5 and the total magnetic resonance imaging (MRI) burden with its imaging characteristics was explored. Moreover, the correspondence of FAM19A5 with the outcome was assessed via Δ National Institutes of Health Stroke Scale score (NIHSS) and the percentage of NIHSS improvement. Results: FAM19A5 was highly expressed in the RSSI group (P = 0.023), showing a positive correlation with cerebral infarction volume (P < 0.01). It was positively correlated with total MRI cSVD burden (P < 0.001) and reflected the severity of white matter hyperintensity (WMH) (P < 0.01) and enlarged perivascular space (EPVS) (P < 0.01), but did not show any association with cerebral microbleed (CMB) and lacune. Moreover, FAM19A5 suggested a larger Δ NIHSS (P = 0.021) and NIHSS improvement percentage (P = 0.007). Conclusion: Serum FAM19A5 was increased in RSSI and positively correlated with the infarct volume. It also reflects the total MRI burden of cSVD, of which the imaging characteristics are positively correlated with WMH and EPVS. In addition, higher FAM19A5 levels reflect better outcomes in RSSI patients.

miR-155 activates the NLRP3 inflammasome by regulating the MEK/ERK/NF-κB pathway in carotid atherosclerotic plaques in ApoE-/- mice.

Atherosclerosis is an inflammatory disease. The NLRP3 inflammasome and miR-155 are significant components of inflammation and atherosclerosis. The aim of this research was to explore the possible mechanism by which miR-155 mediates the formation of carotid atherosclerotic plaques via the NLRP3 inflammasome. Fifty 6-week-old male ApoE-/- mice were randomly divided into 5 groups. They are the blank group, the negative control (NC) group, the miR-155 mimic group, the miR-155 inhibitor group, and the miR-155 mimic and ERK inhibitor group. The blood lipid levels were measured by the enzyme method Oil red O, HE, and immunohistochemical staining were used to observe the degree of carotid plaque formation. PCR was used to measure the expression of miR-155. The blood lipid levels were measured by the enzyme method. Western blotting was used to measure the expression of NLRP3 inflammasome-related proteins, interleukin-1ß, interleukin-18, and MEK/ERK/NF-κB signaling pathway-related proteins. Compared with those of the NC group, the expression of miR-155 in the miR-155 mimic group increased significantly (P < 0.05), the degree of carotid plaque formation increased, the plasma levels of TC and LDL also increased significantly (P < 0.05); the expression levels of NLRP3 inflammasome-related proteins, interleukin-1ß, interleukin-18, and MEK/ERK/NF-κB signaling pathway-related proteins were also significantly increased. Injection of ERK inhibitors into miR-155 mimic mice reduced the expression levels of p-NF-κB, NLRP3 inflammasome-related proteins, and inflammatory cytokines. In conclusion, miR-155 can promote the formation of atherosclerotic plaque in ApoE-/- mice, which may be achieved by regulating the MEK/ERK/NF-κB pathway to activate the NLRP3 inflammasome. HIGHLIGHTS: • In ApoE-/- mice, miR-155 promotes atherosclerotic plaque formation. • The NLRP3 inflammasome has an important role in the inflammatory process of atherosclerosis. • miR-155 activates the NLRP3 inflammasome by regulating the MEK/ERK/NF-κB pathway in carotid atherosclerotic plaques of ApoE-/- mice.

Sex-specific relationship between serum uric acid levels and the prevalence of large vessel occlusion in acute ischemic stroke.

PURPOSE: Previous studies have found that uric acid (UA) plays a neuroprotective role in ischemic stroke patients. However, the relationship between serum UA of acute ischemic stroke (AIS) and large vessel occlusion (LVO) strokes is unclear. METHODS: In this retrospective study, 1318 AIS patients were enrolled. All patients underwent imaging examinations to assess the intracranial and carotid vessels. Multivariate logistic regression analysis was conducted to evaluate the relationship between UA levels and the prevalence of LVO. RESULTS: The 1318 enrolled AIS patients were comprised of 287 LVO and 1031 non-LVO patients. UA levels in males were higher than females (321.04 ± 91.28 vs. 274.43 ± 82.11, p < .001). The association between serum UA levels and LVO was modified by sex (p = .007). When serum UA levels were continuous, after adjusting for related risk factors, higher serum UA levels were still associated with a lower prevalence of LVO in males (odds ratio (OR) 0.997, 95% confidence interval (CI) 0.994-0.999), but not in female subjects (OR 0.998, 95% CI 0.995-1.001). When serum UA levels were divided into tertiles, higher UA levels had a lower risk of LVO than the moderate (p = .006) and lower tertiles of UA levels (p = .010) in males, but not in females (p = .402 and p = .206 for moderate and low tertiles, respectively). CONCLUSIONS: AIS patients with higher serum UA levels tend to be associated with a lower risk of LVO in males, but not in females.

The Combined Regulation of Long Non-coding RNA and RNA-Binding Proteins in Atherosclerosis.

Atherosclerosis is a complex disease closely related to the function of endothelial cells (ECs), monocytes/macrophages, and vascular smooth muscle cells (VSMCs). Despite a good understanding of the pathogenesis of atherosclerosis, the underlying molecular mechanisms are still only poorly understood. Therefore, atherosclerosis continues to be an important clinical issue worthy of further research. Recent evidence has shown that long non-coding RNAs (lncRNAs) and RNA-binding proteins (RBPs) can serve as important regulators of cellular function in atherosclerosis. Besides, several studies have shown that lncRNAs are partly dependent on the specific interaction with RBPs to exert their function. This review summarizes the important contributions of lncRNAs and RBPs in atherosclerosis and provides novel and comprehensible interaction models of lncRNAs and RBPs.

Association between uric acid and the prognosis of acute ischemic stroke: A systematic review and meta-analysis.

AIMS: Meta-analysis was performed to assess the value of serum uric acid in the prognosis of ischemic stroke. DATA SYNTHESIS: We searched the databases of PubMed, Embase, and Web of Science. The literature we searched was published from the establishment of the database to January 2021. The references of the included literature were also collected. Two researchers sifted through the literature according to the inclusion and exclusion criteria and extracted the data. Stata 16.0 software was used for meta-analysis, and funnel plots were used to evaluate publication bias. Ten studies fulfilled the research criteria and were eventually included, and the analysis results showed that there was no significant association between serum uric acid and the functional outcome (OR = 0.99, 95% CI; 0.97-1.10), poor outcome (OR = 1.07, 95% CI; 0.99-1.15), vascular events (OR = 0.86, 95% CI; 0.52-1.41), and mortality (OR = 1.08, 95% CI; 0.93-1.24) related to ischemic stroke. CONCLUSIONS: There was no significant correlation between serum uric acid level and prognosis of ischemic stroke.

Comprehensive Analysis of Peripheral Exosomal circRNAs in Large Artery Atherosclerotic Stroke.

Exosomes are crucial vehicles in intercellular communication. Circular RNAs (circRNAs), novel endogenous noncoding RNAs, play diverse roles in ischemic stroke. Recently, the abundance and stability of circRNAs in exosomes have been identified. However, a comprehensive analysis of exosomal circRNAs in large artery atherosclerotic (LAA) stroke has not yet been reported. We performed RNA sequencing (RNA-Seq) to comprehensively identify differentially expressed (DE) exosomal circRNAs in five paired LAA and normal controls. Further, quantitative real-time PCR (qRT-PCR) was used to verify the RNA-Seq results in a cohort of stroke patients (32 versus 32). RNA-Seq identified a total of 462 circRNAs in peripheral exosomes; there were 25 DE circRNAs among them. Additionally, circRNA competing endogenous RNA (ceRNA) network and translatable analysis revealed the potential functions of the exosomal circRNAs in LAA progression. Two ceRNA pathways involving 5 circRNAs, 2 miRNAs, and 3 mRNAs were confirmed by qRT-PCR. In the validation cohort, receiver operating characteristic (ROC) curve analysis identified two circRNAs as possible novel biomarkers, and a logistic model combining two and four circRNAs increased the area under the curve compared with the individual circRNAs. Here, we show for the first time the comprehensive expression of exosomal circRNAs, which displayed the potential diagnostic and biological function in LAA stroke.

Development and validation of a predictive model algorithm to identify anaphylaxis in adults with type 2 diabetes in U.S. administrative claims data.

PURPOSE: To use medical record adjudication and predictive modeling methods to develop and validate an algorithm to identify anaphylaxis among adults with type 2 diabetes (T2D) in administrative claims. METHODS: A conventional screening algorithm that prioritized sensitivity to identify potential anaphylaxis cases was developed and consisted of diagnosis codes for anaphylaxis or relevant signs and symptoms. This algorithm was applied to adults with T2D in the HealthCore Integrated Research Database (HIRD) from 2016 to 2018. Clinical experts adjudicated anaphylaxis case status from redacted medical records. We used confirmed case status as an outcome for predictive models developed using lasso regression with 10-fold cross-validation to identify predictors and estimate the probability of confirmed anaphylaxis. RESULTS: Clinical adjudicators reviewed medical records with sufficient information from 272 adults identified by the anaphylaxis screening algorithm, which had an estimated Positive Predictive Value (PPV) of 65% (95% confidence interval [CI]: 60%-71%). The predictive model algorithm had a c-statistic of 0.95. The model's probability threshold of 0.60 excluded 89% (84/94) of false positives identified by the screening algorithm, with a PPV of 94% (95% CI: 91%-98%). The model excluded very few true positives (15 of 178), and identified 92% (95% CI: 87%-96%) of the cases selected by the screening algorithm. CONCLUSIONS: Predictive modeling techniques yielded an accurate algorithm with high PPV and sensitivity for identifying anaphylaxis in administrative claims. This algorithm could be considered in future safety studies using similar claims data to reduce potential outcome misclassification.

Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study.

BACKGROUND: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. METHODS: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. RESULTS: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4). CONCLUSIONS: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A.

Atherosclerosis is a chronic inflammatory disease associated with the development of plaques that can be converted into an acute clinical event by thrombosis or plaque rupture. Mesenchymal stem cells (MSCs) exhibit therapeutic effects for the treatment of various diseases, including atherosclerosis. In this study, we show that microRNA-145 (miR-145) is associated with atherosclerosis by microRNA sequencing and bioinformatics analysis. MSC-derived miR-145-rich exosomes could efficiently deliver miR-145 from MSCs to human umbilical vein endothelial cells (HUVECs). Treatment of miR-145-rich exosomes could downregulate JAM-A, inhibit migration in vitro, and reduce atherosclerotic plaque in vivo. Our study suggests that MSC-derived miR-145-rich exosomes have great potential for atherosclerosis prevention.

A real-world study on characteristics, treatments and outcomes in US patients with advanced stage ovarian cancer.

BACKGROUND: Detailed epidemiologic descriptions of large populations of advanced stage ovarian cancer patients have been lacking to date. This study aimed to describe the patient characteristics, treatment patterns, survival, and incidence rates of health outcomes of interest (HOI) in a large cohort of advanced stage ovarian cancer patients in the United States (US). METHODS: This cohort study identified incident advanced stage (III/IV) ovarian cancer patients in the US diagnosed from 2010 to 2018 in the HealthCore Integrated Research Database (HIRD) using a validated predictive model algorithm. Descriptive characteristics were presented overall and by treatment line. The incidence rates and 95% confidence intervals for pre-specified HOIs were evaluated after advanced stage diagnosis. Overall survival, time to treatment discontinuation or death (TTD), and time to next treatment or death (TTNT) were defined using treatment information in claims and linkage with the National Death Index. RESULTS: We identified 12,659 patients with incident advanced stage ovarian cancer during the study period. Most patients undergoing treatment received platinum agents (75%) and/or taxanes (70%). The most common HOIs (> 24 per 100 person-years) included abdominal pain, nausea and vomiting, anemia, and serious infections. The median overall survival from diagnosis was 4.5 years, while approximately half of the treated cohort had a first-line time to treatment discontinuation or death (TTD) within the first 4 months, and a time to next treatment or death (TTNT) from first to second-line of about 6 months. CONCLUSIONS: This study describes commercially insured US patients with advanced stage ovarian cancer from 2010 to 2018, and observed diverse treatment patterns, incidence of numerous HOIs, and limited survival in this population.

Ferroelectric resistance switching in Pt/Fe/BiFeO3/SrRuO3/SrTiO3 heterostructures.

BiFeO3 (BFO)-based heterostructures have been widely studied to develop high-speed, high-density and low-consumption nonvolatile memory. In this study, the resistive switching (RS) behavior in metal/BFO/SrRuO3 (SRO) heterostructures was investigated. The I-V curves of Pt/Fe/BFO/SRO and Pt/BFO/SRO heterostructures demonstrate that the RS behavior in the Pt/Fe/BFO/SRO heterostructures results from the fact that ferroelectric polarization modulated the depletion layer width around the BFO/SRO interface. According to the fitting results of the I-V curves, the conductivity mechanisms are the interface-limited Fowler-Nordheim tunneling mechanism in the negative bias and the space-charge-limited conduction mechanism in the positive bias. Compared with the memory performance in the Pt/BFO/SRO heterostructures, the memory performance in the Pt/Fe/BFO/SRO heterostructures evidently improved. The Fe layer with a work function similar to that of the BFO layer can decrease the barrier height and reduce the accumulation of the injected charges at the top-electrode/BFO interface, which further improves the ferroelectric performance of the BFO layer.

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

Inflammation, especially involving the NLRP3 inflammasome, is critical to atherosclerotic plaque formation. Enhanced autophagy can inhibit the development of atherosclerosis, and recent studies have revealed that NLRP3 inflammasome can be degraded by autophagy in atherosclerosis. In the present study, we established a foam-cell model to investigate the impact of oxidized low density lipoproteins (ox-LDLs) on autophagy and the inflammasome in atherosclerosis-related inflammation. We observed that ox-LDLs activated NLRP3 inflammasomes in macrophages and restricted autophagy in a time-and dose-dependent manner. We further observed through immunoprecipitation and siRNA knockdown that autophagic degradation of the NLRP3 inflammasome is dependent on K63 polyubiquitation of its NLRP3 subunit and subsequent binding by the adaptor protein p62. Our findings uncover a mechanism by which autophagy inhibits inflammation in atherosclerosis and the role of K63 in that process.