Differential roles of eosinophils in cardiovascular disease.

Eosinophils are essential innate immune cells in allergic responses. Accumulating evidence indicates that eosinophils also participate in the pathogenesis of cardiovascular diseases (CVDs). In clinical studies, high blood eosinophil counts and eosinophil cationic protein levels have been associated with an increased risk of CVD, including myocardial infarction (MI), cardiac hypertrophy, atrial fibrillation, abdominal aortic aneurysm (AAA) and atherosclerosis. However, low blood eosinophil counts have also been reported to be a risk factor for MI, heart failure, aortic dissection, AAA, deep vein thrombosis, pulmonary embolism and ischaemic stroke. Although these conflicting clinical observations remain unexplained, CVD status, timing of eosinophil data collection, and tissue eosinophil phenotypic and functional heterogeneities might account for these discrepancies. Preclinical studies suggest that eosinophils have protective actions in MI, cardiac hypertrophy, heart failure and AAA. By contrast, cationic proteins and platelet-activating factor from eosinophils have been shown to promote vascular smooth muscle cell proliferation, vascular calcification, thrombomodulin inactivation and platelet activation and aggregation, thereby exacerbating atherosclerosis, atrial fibrillation, thrombosis and associated complications. Therefore, eosinophils seem to promote calcification and thrombosis in chronic CVD but are protective in acute cardiovascular settings. In this Review, we summarize the available clinical and preclinical data on the different roles of eosinophils in CVD.

The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors.

INTRODUCTION: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. METHODS: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. RESULT: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2-10 months). CONCLUSION: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia.

OBJECTIVE: Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients. METHODS: The robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification. RESULTS: The alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers. CONCLUSIONS: This study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

Heterogeneity of Multiple Pancreatic Neuroendocrine Tumors Identified by 68Ga-DOTANOC and 68Ga-Exendin-4 PET/CT in a Patient with Endogenous Hyperinsulinemic Hypoglycemia and Multiple Endocrine Neoplasia 1.

INTRODUCTION: Insulinomas are the most frequent functional pancreatic neuroendocrine tumors. In about 10% of cases, insulinomas are associated with hereditary syndromes, including multiple endocrine neoplasia 1 (MEN1). CASE PRESENTATION: Herein, we present a 44-year-old female with recurrent hypoglycemia. In December 1998, this patient underwent resection of two pancreatic lesions due to hypoglycemia and was diagnosed with insulinoma. After the operation, the symptoms of hypoglycemia disappeared. However, from 2021, hypoglycemic symptoms reappeared frequently, as did coma. In June 2023, enhanced CT showed multiple pancreatic lesions abundant with blood supply. Fasting serum blood glucose and insulin were 1.73 mmol/L and 15.2 U/L (2.6-11.8 U/L). Germline genes suggested MEN1 pathogenic mutations. 68Ga-DOTANOC PET/CT indicated there were multiple lesions located in the pancreas and duodenum with high expression of the somatostatin receptor (SSTR). 68Ga-exendin-4 PET/CT was added to localize the insulinoma. Most lesions with high expression of SSTR in the body and tail of the pancreas manifested parts of them with high uptake of 68Ga-exendin-4, and an additional lesion with high expression of glucagon-like peptide-1 receptor (GLP-1R) was only detected by 68Ga-exendin-4 PET/CT. It showed inter-tumor heterogeneity in the expression of SSTR and GLP-1R. From the distal pancreatectomy, a total of 5 tumors were found in the body and tail of the pancreas, which were diagnosed as neuroendocrine tumors (NETs). After the operation, all the symptoms related to hypoglycemia disappeared. Immunohistochemical results of SSTR2 and insulin were consistent with the imaging findings of dual-tracer PET/CT. CONCLUSION: From this case, a combination of 68Ga-DOTANOC and 68Ga-exendin-4 PET/CT was recommended in the patients with MEN1 and insulinoma to estimate the heterogeneity of multiple neuroendocrine tumors that contribute to detect all the NET lesions and locate the tumors with secretion of insulin.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.

BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS: We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy. RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.

Association Between Systemic Immune Inflammation Level and Poor Prognosis Across Different Glucose Metabolism Status in Coronary Artery Disease Patients.

Background: Blood glucose levels significantly affect the clinical prognosis of patients with coronary artery disease (CAD), and systemic immune inflammation is a common risk factor for both CAD and diabetes. However, the relationship between immune inflammation levels and poor prognosis in patients with CAD with different glucose metabolic statuses remains unclear. Methods: Between January 2007 and December 2020, we recruited 84,645 patients with CAD. The systemic immune inflammation index (SII) was used to comprehensively reflect the immune and inflammatory levels of patients and was calculated using the following formula: neutrophils × platelets/lymphocytes. The patients were classified into nine groups according to their glucose metabolism status (diabetes mellitus [DM], pre-diabetes mellitus [pre-DM], and normal glucose regulation [NGR]). Cox regression models and competing risk Fine and Gray models were used to investigate the association between SII and clinical outcomes. Results: During the follow-up period, 12,578 patients died, including 5857 cardiovascular-related and 1251 cancer-related deaths. The risk of all-cause and cause-specific mortality increased with increasing SII tertiles in CAD patients with NGR, pre-DM, and DM. When considering glucose metabolism status, the multivariate cox regression revealed that CAD patients with DM and SII-H levels had the highest risk of all-cause mortality (1.69 [1.56-1.83]), cardiovascular mortality (2.29 [2.02-2.59]), and cancer mortality (1.29 [1.01-1.66]). Moreover, incorporating the SII into traditional risk factor models significantly improved the C-index for predicting all-cause and cardiovascular mortality. Conclusion: Systemic immune inflammation levels on admission were correlated with a higher risk of all-cause and cause-specific mortality in patients with CAD, particularly in those with DM.

Establishment and assessment of a preclinical model of acute kidney injury induced by contrast media combined acute myocardial ischemia reperfusion surgery.

Acute kidney injury (AKI) is a common complication after acute myocardial infarction (AMI) in clinical practice, and the majority of previous preclinical models were induced by a single factor. The objective of the present study was to establish a stable preclinic model of AKI induced by contrast media (CM) with acute myocardial ischemia reperfusion surgery and to identify the effect of oxidative stress on kidney injury. Rats were treated individually or with CM or myocardial ischemia reperfusion surgery. Renal baseline and AKI parameters, the level of oxidative stress and histopathological images were examined along with AKI biomarkers. Results showed the incidence of AKI in the CM group and ischemia reperfusion injury (IRI) group was 40%, χ2 test (P<0.05 vs. CM-IRI) and 35%, χ2 test (P<0.05 vs. CM-IRI) and the combination group had the highest incidence rate 75%. IRI surgery combined with CM diminished kidney function and induced oxidative stress by increasing creatinine, blood urea nitrogen and reactive oxygen species levels. Western blotting showed that the early AKI biomarker of NGAL and KIM-1 increased and that the combination group had the highest value. Pathology damage exhibited severe kidney damage in the combination group compared with other control groups. The present research established a reliable preclinic model of post-AMI AKI with a stable and high postoperative AKI rate. Additionally, CM was demonstrated to exacerbate AKI caused by acute myocardial infarction through oxidative stress and, thus, oxidative stress may be a potential therapeutic target.

Enrichment and detection of VEGF165 in blood samples on a microfluidic chip integrated with multifunctional units.

In this paper, a multifunctional microfluidic chip integrated with a centrifugal separation zone, aqueous two-phase system (ATPS) mixing zone and enrichment detection zone was proposed and fabricated. An automatic and efficient separation and quantitative analysis method for vascular endothelial growth factor 165 (VEGF165) in whole blood samples was established with the designed microfluidic chip. A blood sample was divided into blood cells and plasma in the centrifugation zone. In the ATPS mixing zone, plasma was mixed with PEG/KH2PO4 aqueous two-phase solution containing Apt-Au NP nanoprobes. In the enrichment detection zone, the mixture was separated on CN140 modified with a ZnO NP-anti VEGF165 nanostructure. The VEGF165 captured by Apt-Au NPs was distributed in the PEG phase, concentrated at the front of CN140 and combined with anti-VEGF165 to form a sandwich structure. The sensitive detection of VEGF165 was achieved through fluorescence resonance energy transfer between rhodamine B and Au NPs on the nanoprobe. Under the optimized rotation program, capillary and centrifugal forces propelled the fluid in the whole process of pretreatment and detection. The detection linear range was between 1 pg mL-1 and 50 ng mL-1, the detection limit of VEGF165 in blood was 0.22 pg mL-1 and the enrichment efficiency was 983. It was illustrated that a convenient and reliable way for detection of tumor markers based on the multifunctional microfluidic chip was provided and it has a potential value for early screening and prognosis of clinical cancer.

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. METHODS: MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. RESULTS: MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. CONCLUSIONS: We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.

Elevated systemic immune inflammation level increases the risk of total and cause-specific mortality among patients with chronic kidney disease: a large multi-center longitudinal study.

BACKGROUND: Chronic kidney disease (CKD) is inherently a complex immune-inflammatory condition, and heightened inflammation and immune dysfunction are closely related to an increased risk of death. However, evidence regarding the relationship between immune-inflammatory levels and all-cause, cardiovascular, and cancer mortality among patients with CKD is scarce. METHODS: Patients with non-dialysis dependent CKD undergoing coronary angiography (CAG) were included from five Chinese tertiary hospitals. Systemic immune inflammation index (SII) was calculated by multiplying peripheral platelet count with neutrophil-to-lymphocyte ratio, and patients were categorized into four groups by SII quartiles. Cox regression models and competing risk Fine and Gray models were used to examining the relationships between SII levels and all-cause, cardiovascular, and cancer mortality. RESULTS: A total of the 19,327 patients (68.8 ± 10.03 years, female 32.0%) were included in this study. During a median follow-up of 4.5 years, 5,174 deaths occurred, including 2,861 cardiovascular deaths and 375 cancer deaths. Controlling for confounders, all-cause mortality (Q2, Q3, Q4: hazard ratio(HR) [95 CI%] = 1.15 [1.06-1.26], 1.30 [1.19-1.42], 1.48 [1.35-1.62], respectively; p for trend < 0.001) and cardiovascular mortality (Q2, Q3, Q4: HR [95 CI%] = 1.16 [1.03-1.31], 1.40 [1.24-1.58], 1.64 [1.44-1.85], respectively; p for trend < 0.001) increased with higher SII levels, and SII levels was related to cancer mortality comparing last quartile to first quartile of SII (Q2, Q3, Q4: HR [95 CI%] = 1.12 [0.83-1.52], 1.22 [0.90-1.67], 1.50 [1.09-2.08], respectively; p for trend < 0.001). CONCLUSION: Elevated immune inflammation level on admission was an independent risk factor for all-cause, cardiovascular, and cancer mortality among CKD patients. Further research is needed to validate the predictive value of SII for mortality risk among CKD patients.

Fibrinogen-to-Albumin Ratio and Long-Term Mortality in Coronary Artery Disease Patients with Different Glucose Metabolism Status.

Background: Abnormal glucose metabolism is present in most patients with coronary artery disease (CAD). Inflammation is considered to be a common risk factor for CAD and diabetes. Fibrinogen-to-albumin ratio (FAR), a novel inflammation biomarker, has been proposed as a predictor for cardiovascular disease. However, the relationship between the level of FAR and long-term mortality including all-cause, cardiovascular and cancer mortality, remains unknown in CAD patients, especially those with prediabetes. Methods: We enrolled 66,761 CAD patients from 2007 to 2020 from a multi-center registry cohort study. The primary outcomes were the all-cause, cardiovascular and cancer mortality. FAR was calculated using the following formula: Fibrinogen (g/L)/Albumin (g/L). Patients were divided into three groups by FAR tertile (low FAR (FAR-L), median FAR (FAR-M), high FAR (FAR-H)), and further categorized into 9 groups according to FAR and glucose metabolism status (normal glucose regulation (NGR), prediabetes mellitus (PreDM), diabetes mellitus (DM)). Cox regression models and competing risk models were used to examine the relationships between FAR and clinical outcomes. Results: 66,761 patients (63.1 ± 11.0 years, 75.3% male) were enrolled. During the follow-up, 10,534 patients died, including 4991 cardiovascular deaths and 1092 cancer deaths. After adjusting for confounders, higher FAR was associated with increased risk of all-cause and cause-specific mortality in CAD patients with NGR, PreDM and DM. The risk of all-cause and cardiovascular mortality was highest in FAR-H with DM (HR (95% CI) = 1.71 (1.58-1.86), 2.11 (1.86-2.38), respectively; p < 0.001). FAR-H with PreDM was significantly associated with the highest risk of cancer mortality (HR (95% CI) = 2.27 (1.70-3.02), p < 0.001). Adding FAR to the original model significantly improved the prediction of long-term mortality. Conclusions: Increased FAR was significantly associated with higher risk of all-cause and cause-specific mortality in CAD patients with NGR, PreDM and DM. Abnormal glucose metabolism augments the relationship between FAR and mortality. Clinical Trial Registration: ClinicalTrials.gov NCT05050877.

Strain level microbial detection and quantification with applications to single cell metagenomics.

Computational identification and quantification of distinct microbes from high throughput sequencing data is crucial for our understanding of human health. Existing methods either use accurate but computationally expensive alignment-based approaches or less accurate but computationally fast alignment-free approaches, which often fail to correctly assign reads to genomes. Here we introduce CAMMiQ, a combinatorial optimization framework to identify and quantify distinct genomes (specified by a database) in a metagenomic dataset. As a key methodological innovation, CAMMiQ uses substrings of variable length and those that appear in two genomes in the database, as opposed to the commonly used fixed-length, unique substrings. These substrings allow to accurately decouple mixtures of highly similar genomes resulting in higher accuracy than the leading alternatives, without requiring additional computational resources, as demonstrated on commonly used benchmarking datasets. Importantly, we show that CAMMiQ can distinguish closely related bacterial strains in simulated metagenomic and real single-cell metatranscriptomic data.

Non-Destructive Detection of Moldy Walnuts Based on Hyperspectral Imaging Technology.

Walnuts with their shells are a popular agricultural product in China. However, mildew from growth can sometimes be processed into foods. It is difficult to visually determine which walnuts have mildew without breaking the shells. A non-destructive method for detecting walnuts with mildew was studied by combining spectral data with image information. A total of 120 "Lüling" walnuts with shells were used for the mildew experiment. The characteristics of the spectral data from six surfaces of all samples were collected in the range of 370-1042 nm on days 0, 15, and 30. The spectrum was pretreated using SNV, and the feature bands were extracted using PCA and modeled using a support vector machine (SVM). The results show that the overall classification accuracy was 93%, with an of accuracy of 100% for INEN walnuts (normal internally and externally). The accuracy for IMEM walnuts (mildew internally and externally) reached 87.29%. There was an accuracy of 78.6% for IMEN walnuts (mildew internally and normal externally). The non-destructive detection of mildewed walnuts can be undertaken using hyperspectral imaging technology, which provides a new technique for exploring the mechanisms of walnuts with mildew.

ImmunoTyper-SR: A computational approach for genotyping immunoglobulin heavy chain variable genes using short-read data.

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which are critical for the structure of antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype when using standard short-read sequencing technologies. Here, we introduce ImmunoTyper-SR, an algorithmic tool for the genotyping and CNV analysis of the germline IGHV genes on Illumina whole-genome sequencing (WGS) data using a combinatorial optimization formulation that resolves ambiguous read mappings. We have validated ImmunoTyper-SR on 12 individuals, whose IGHV allele composition had been independently validated, as well as concordance between WGS replicates from nine individuals. We then applied ImmunoTyper-SR on 585 COVID patients to investigate the associations between IGHV alleles and anti-type I IFN autoantibodies, which were previously associated with COVID-19 severity.

Tongxinluo-pretreated mesenchymal stem cells facilitate cardiac repair via exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway.

BACKGROUND: Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. METHODS: MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. RESULTS: Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. CONCLUSIONS: This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation.

Elevation of Preprocedural Systemic Immune Inflammation Level Increases the Risk of Contrast-Associated Acute Kidney Injury Following Coronary Angiography: A Multicenter Cohort Study.

Background: Inflammation and immune responses play an important role in the pathophysiology of contrast-associated acute kidney injury (CA-AKI), and systemic immune inflammation index (SII) has recently emerged as a new parameter for immune and inflammatory response evaluation. However, limited research has been undertaken to explore the relationship between SII and CA-AKI following coronary angiography (CAG). Patients and Methods: From January 2007 to December 2020, 46,333 patients undergoing CAG were included from 5 Chinese tertiary hospitals. SII was calculated as total peripheral platelets count × neutrophil-to-lymphocyte ratio. Patients were categorized by preprocedural SII quartiles: Q1 ≤404.5, Q2 >404.5 and ≤631.7, Q3 >631.7 and ≤1082.8, Q4 >1082.8. Univariable and multivariable logistic regression were used to reveal the link between preprocedural SII and CA-AKI. Results: A total of the 46,333 patients (62.9 ± 11.5 years, female 28.1%) were included in the study. The incidence of CA-AKI was 8.4% in Q1 group, 8.7% in Q2 group, 9.4% in Q3 group, 15.1% in Q4 group. In the multivariable model, comparing the highest (Q4 group) to lowest (Q1 group) SII level categories, preprocedural SII was related to a higher risk of CA-AKI after fully adjusting for well-known confounders, and there was no statistically difference in the other two SII level categories (Q2 and Q3 groups) compared with Q1 group (adjusted model 3: Q2 group: OR: 0.98, 95% CI: 0.87-1.11, P = 0.771; Q3 group: OR: 1.04, 95% CI: 0.92-1.18, P = 0.553; Q4: OR: 1.65, 95% CI: 1.45-1.88, p < 0.001; P for trend < 0.001). Similar results were found for all the subgroups analysis except for patients undergoing PCI, and the interaction analyses for age, PCI and AMI were significant. In addition, Kaplan-Meier curves demonstrated that the lowest quartile group showed the worst all-cause mortality in a significant SII level-dependent manner among the four groups (Log rank test; p < 0.0001). Conclusion: Elevated preprocedural SII level was a significant and independent risk factor for CA-AKI following CAG. Higher-quality prospective studies are needed to validate the predictive value of SII for CA-AKI.