Leveraging a neutrophil-derived PCD signature to predict and stratify patients with acute myocardial infarction: from AI prediction to biological interpretation.

BACKGROUND: Programmed cell death (PCD) has recently been implicated in modulating the removal of neutrophils recruited in acute myocardial infarction (AMI). Nonetheless, the clinical significance and biological mechanism of neutrophil-related PCD remain unexplored. METHODS: We employed an integrative machine learning-based computational framework to generate a predictive neutrophil-derived PCD signature (NPCDS) within five independent microarray cohorts from the peripheral blood of AMI patients. Non-negative matrix factorization was leveraged to develop an NPCDS-based AMI subtype. To elucidate the biological mechanism underlying NPCDS, we implemented single-cell transcriptomics on Cd45+ cells isolated from the murine heart of experimental AMI. We finally conducted a Mendelian randomization (MR) study and molecular docking to investigate the therapeutic value of NPCDS on AMI. RESULTS: We reported the robust and superior performance of NPCDS in AMI prediction, which contributed to an optimal combination of random forest and stepwise regression fitted on nine neutrophil-related PCD genes (MDM2, PTK2B, MYH9, IVNS1ABP, MAPK14, GNS, MYD88, TLR2, CFLAR). Two divergent NPCDS-based subtypes of AMI were revealed, in which subtype 1 was characterized as inflammation-activated with more vibrant neutrophil activities, whereas subtype 2 demonstrated the opposite. Mechanically, we unveiled the expression dynamics of NPCDS to regulate neutrophil transformation from a pro-inflammatory phase to an anti-inflammatory phase in AMI. We uncovered a significant causal association between genetic predisposition towards MDM2 expression and the risk of AMI. We also found that lidoflazine, isotetrandrine, and cepharanthine could stably target MDM2. CONCLUSION: Altogether, NPCDS offers significant implications for prediction, stratification, and therapeutic management for AMI.

Identification of a novel LATS1 variant associated with familial cerebral cavernous malformations in a Chinese family.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic or hereditary vascular malformations in the central nervous system. CCM1-3 variants have been identified that are associated with the majority of familial cerebral cavernous malformations (FCCMs). However, there are still a few CCM1-3 wild-type FCCMs. The aim of the present study was to identify an additional pathogenic variant of FCCMs. METHODS: In this study, a large five-generation Chinese Han family affected by CCMs was recruited. Magnetic resonance imaging (MRI) was done for the detection of CCMs. Whole-exome sequencing (WES) was performed, and the identified variants were co-segregation analyzed by Sanger sequencing. The function of candidate variants was predicted in silico and experimental validated by angiogenesis assay in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: Twenty-four family members and one healthy spouse were enrolled. We found that CCMs were exhibited on MRI in nine family members. Overall, twenty-seven candidate variants were identified using WES, and no CCM1-3 variants were detected. The missense variant in LATS1 (c.821C > T, p.Thr274Ile) was verified to be associated with the clinical and pathological phenotype of FCCMs. CONCLUSION: Our findings indicated that the LATS1 variant could be a potential pathogenic factor for FCCMs in this Chinese family.

A population-based predictive model to identify patients with signet ring cell carcinoma of the stomach who are most suitable for primary tumor resection.

BACKGROUND: Though the survival benefit of primary tumor operation for patients with signet ring cell carcinoma of the stomach is known, the specific characteristics of those patients who would profit from the operation are yet to be determined. To this end, a predictive model was developed to identify the conjecture that the survival profit from primary tumor operation would only be obtained by patients. METHOD: The clinical data of the patients with signet ring cell carcinoma of the stomach were obtained from the Surveillance, Epidemiology, and End Results database, and then divided into operation and no-operation groups based on whether the patients underwent the primary tumor operation. To remove the confounding factors, propensity score matching was employed, and it was hypothesized that the patients who had been operated on and lived a longer life than the median cancer-specific survival time of those who hadn't must have profited from the surgery. To discuss the independent factors of cancer-specific survival time in the beneficial group and the non-beneficial group, the Cox model was used, and based on the various vital predictive factors, a nomogram was drawn using logistic regression. RESULT: The number of eligible patients was 12,484, with 43.9% (5483) of them having received surgery. After employing propensity score matching, the cancer-specific survival time of the operation group was found to be apparently longer (median: 21 vs. 5 months; p < 0.001) than the no-operation group. In the operation group, 4757 (86.7%) of the patients lived longer than five months (beneficial group). The six indexes (beneficial and non-beneficial group) included gender, age, Tumor Node Metastasis stage, histologic type, differentiation grade, and tumor position, and were used as predictors to draw the nomogram. The nomogram was used to divide the patients who had taken operations into two groups: the beneficial operation group and the non-beneficial operation group. The beneficial operation group, it was found, survived longer than the non-beneficial operation group (median cancer-specific survival time: 28 vs. 3 months, p < 0.001). Moreover, there was we could tell little difference in survival between the two groups (median cancer-specific survival time: 3 vs. 5 months). CONCLUSIONS: The predictive model created to select suitable candidates for surgical treatment from patients with signet ring carcinoma of the stomach could be adopted to identify certain patients benefiting from the primary tumor operation.

The phytotoxicity of microplastics to the photosynthetic performance and transcriptome profiling of Nicotiana tabacum seedlings.

Microplastics (MPs), as emerging "new generation" organic contaminants, have attracted extensive attention regarding their severe toxicity to aquatic and terrestrial organisms. However, the responses of plant photosynthesis to soil MP pollution are unclear. In this study, Nicotiana tabacum seedlings were grown in soils containing 0~1000 g·kg-1 polyethylene (PE)-MPs for 48 days. PE-MPs significantly increased the superoxide anion content by 15.3~44.8% but decreased the chlorophyll content and Rubisco activity by 4.3~14.0% and 4.23~30.9%, respectively. PE-MPs also inhibited RuBP carboxylation activation and regeneration, restrained light use efficiency, and prevented dark respiration, thereby reducing the light-saturated photosynthesis rate. The changed shape of OJIP transients indicated that PE-MP toxicity inhibited not only the primary photochemistry rate but also photoelectrochemical quenching, resulting in decreased quantum yields. RNA-Seq revealed thousands of differentially expressed genes (DEGs), among which 79 highly expressed DEGs were enriched in photosynthesis-related processes. Functional annotation revealed that the reduction in environment stress was mainly due to the repressed expression of light harvesting-, electron transport- and photosystem-related genes in chloroplasts. This study regarding the physiological and molecular responses of photosynthetic performance to soil PE-MP pollution provides a new viewpoint for exploring the plant photosynthesis regulating and protective mechanisms under soil MP stresses.

Long-term oncologic outcomes of natural orifice specimen extraction surgery versus conventional laparoscopic-assisted resection in the treatment of rectal cancer: a propensity-score matching study.

BACKGROUND: Natural orifice specimen extraction surgery (NOSES) has been increasingly applied in radical surgery of abdominal and pelvic organs, but it is still in the exploratory stage. There is insufficient evidence to prove its efficacy. METHODS: From January 2013 to June 2017, a total of 351 patients diagnosed with rectal cancer were eventually included in this study. Patients who underwent NOSES were assigned to the NOSES group, while patients undergoing conventional laparoscopic assisted resection were assigned as to the LAP group. Propensity score matching was used to align clinicopathological features between the two groups. RESULTS: From the perioperative data and postoperative follow-up results of both groups, patients in the NOSES group had less intraoperative bleeding (47.0 ± 60.4 ml vs 87.1 ± 101.2 ml, P = 0.011), shorter postoperative gastrointestinal recovery (50.7 ± 27.3 h vs 58.6 ± 28.5 h, P = 0.040), less postoperative analgesic use (36.8% vs 52.8%, P = 0.019), lower postoperative pain scores (P < 0.001), lower rate of postoperative complications (5.7% vs 15.5%, P = 0.020), more satisfaction with body image (P = 0.001) and cosmesis (P < 0.001) postoperatively. The NOSES group had a higher quality of life. Moreover, there was no significant difference in overall survival (OS) and disease-free survival (DFS) between the two groups. CONCLUSION: NOSES could be a safe and reliable technique for radical resection of rectal cancer, with better short-term outcomes than conventional laparoscopy, while long-term survival is not significantly different from that of conventional laparoscopic surgery.

Intravenous Lidocaine Infusion Reduce Post-operative Pain and Length of Hospital in Elderly Patients Undergoing Surgery: Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: It is debated wheter intravenous (IV) lidocaine improves post-operative pain and has other potential benefits in elderly patients. This systematic review and meta-analysis aimed to estimate the effect of perioperative continuous IV lidocaine in elderly patients undergoing surgery. METHOD: PubMed/Medline, Web of Science, Embase, and CENTRAL databases (through OVID SP) were searched independently until October 10, 2020 by two authors. We included all randomized controlled trials that compared the effect of continuous IV lidocaine and any placebo or no treatment in elderly patients after surgery. Primary outcomes were length of hospital stay and post-operative pain score. RESULTS: Eighteen studies (988 patients) were included. Meta-analysis suggested that IV lidocaine reduced the post-operative pain scores 2 hours (standardized mean difference [SMD]: -1.58, 95% confidence interval [CI]: -2.03 to -1.13), 4 hours (SMD:-1.20, 95% CI: -2.02 to -.39), 8 hours (SMD:-.82, 95% CI: -1.51 to -.13), 12 hours (SMD:-.66, 95% CI: -1.28 to -.04), and 24 hours (SMD:-.42, 95% CI: -.72 to -.12) post-operatively. Moreover, those patients given IV lidocaine had a shorter length of hospital stay (MD: -.24, 95% CI: -.71 to -.23) and required fewer opioid drugs (SMD: -.31, 95% CI: -.31 to -.01). CONCLUSION: The evidence suggested that IV lidocaine significantly reduced post-operative pain intensity and opioid consumption and shortened the length of hospital stay in elderly patients. IV lidocaine decreased the incidence of post-operative nausea while it could not reduce the incidence of post-operative vomiting and accelerate the recovery of gastrointestinal function.

Cloning, expression, and characterization of an arabitol dehydrogenase and coupled with NADH oxidase for effective production of L-xylulose.

A novel arabitol dehydrogenase (ArDH) gene was cloned from a bacterium named Aspergillus nidulans and expressed heterologously in Escherichia coli. The purified ArDH exhibited the maximal activity in pH 9.5 Tris-HCl buffer at 40 °C, showed Km and Vmax of 1.2 mg/mL and 9.1 U/mg, respectively. The ArDH was used to produce the L-xylulose and coupled with the NADH oxidase (Nox) for the regeneration of NAD+. In further optimization, a high conversion of 84.6% in 8 hours was achieved under the optimal conditions: 20 mM of xylitol, 100 µM NAD+ in pH 9.0 Tris-HCl buffer at 30 °C. The results indicated the coupling system with cofactor regeneration provides a promising approach for L-xylulose production from xylitol.

[Research Updates: Standardized Reporting and Evaluation Instruments for Postoperative Complications].

Postoperative complications are important indicators for evaluating surgical outcomes, and mortality and the incidence of various specific complications are often used to measure the efficacy of surgical and perioperative management strategies. With the progress of medical technology, there has been a dramatic decline in mortality and the incidence of complications. As a result, reporting and evaluation in the traditional methods no longer meets the actual needs of the world. There has arisen an urgent need for an instrument of standardized reporting and evaluation. The instrument should be aligned with the actual circumstances and should represent the patient's overall burden of postoperative complications. We herein reviewed the latest research findings on Clavien-Dindo Classification (CDC) system and comprehensive complication index (CCI), two instruments of standardized reporting and evaluation of postoperative complications, and discussed the space for improvement and prospects of application of CDC and CCI.

Claudin14 promotes colorectal cancer progression via the PI3K/AKT/mTOR pathway.

Colorectal cancer is the third leading cancer in the world in terms of incidence and mortality. The role of differentially expressed Claudin-14 (CLDN14) in CRC has not been reported. We observed that CLDN14 was associated with the progression of CRC. Our functional studies have shown that CLDN14 promoted the proliferation of CRC cells. In addition, CLDN14 also increased the migration and invasion of CRC cells. In vivo experiments also showed that CLDN14 promoted the growth of colorectal cancer via the PI3K/AKT/mTOR. In summary, our research suggests that CLDN14 promotes the progression of colorectal cancer. Our findings may provide new strategies for clinical management and patient prognosis of CRC.

Synaptotagmin 12 (SYT12) Gene Expression Promotes Cell Proliferation and Progression of Lung Adenocarcinoma and Involves the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway.

BACKGROUND This study aimed to use bioinformatics analysis to compare data from tissue microarrays from patients with lung adenocarcinoma (LUAD) and normal lung tissue, and human lung adenocarcinoma cells with normal lung epithelial cells in vitro to investigate the role of synaptotagmin 12 (SYT12) gene expression in LUAD. MATERIAL AND METHODS Human lung adenocarcinoma cell lines (A549, SPC-A-1, H1299, H1975, and PC9) and the normal HBE cell line were compared, and tumor xenografts were developed in mice. The Cancer Genome Atlas (TCGA) tissue microarray data were used to compare SYT12 expression and overall survival (OS). The in vivo and in vitro effects of down-regulation and upregulation of SYT12 were studied using short-interfering RNA (si-RNA) and overexpression plasmids, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and Western blot investigated the molecular mechanisms of SYT12 expression in LUAD. RESULTS SYT12 expression was increased in tissues from patients with LUAD from TCGA and was associated with advanced tumor stage and reduced prognosis. Knockdown of SYT12 suppressed the proliferation and migration of LUAD cells, and upregulation of SYT12 increased the proliferation and migration of LUAD cells in vitro. Phosphorylation of PIK3R3 activated the PI3K/AKT/mTOR pathway. In the mouse xenograft model, expression of SYT12 increased the volume and weight of the xenograft tumors. CONCLUSIONS Bioinformatics analysis, human LUAD cells, and mouse xenograft studies showed that SYT12 acted as a possible oncogene by phosphorylation of PIK3R3 to activate the PI3K/AKT/mTOR signaling pathway.

Cloning, Expression and Characterization of a Highly Active Alcohol Dehydrogenase for Production of Ethyl (S)-4-Chloro-3-Hydroxybutyrate.

A novel alcohol dehydrogenase from Bartonella apis (BaADH) was heterologous expressed in Escherichia coli. Its biochemical properties were investigated and used to catalyze the synthesis of ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE), which is a chiral intermediate of the cholesterol-lowering drug atorvastatin. The purified recombinant BaADH displayed 182.4 U/mg of the specific activity using ethyl 4-chloroacetoacetate as substrate under the conditions of 50 °C in pH 7.0 Tris-HCl buffer. It was stable in storage buffers of pH 7 to 9 and retains up to 96.7% of the initial activity after 24 h. The K m and V max values of BaADH were 0.11 mM and 190.4 µmol min-1 mg-1, respectively. Synthesis of (S)-CHBE catalyzed by BaADH was performed with a cofactor regeneration system using a glucose dehydrogenase, and a conversion of 94.9% can be achieved after 1 h reaction. Homology modeling and substrate docking revealed that a typical catalytic triad is in contact with local water molecules to form a catalytic system. The results indicated this ADH could contribute to the further enzymatic synthesis of (S)-CHBE.

Effect of distribution, interface property and density of hydrogel-embedded vertically aligned carbon nanotube arrays on the properties of a flexible solid state supercapacitor.

In this paper we fabricate a robust flexible solid-state supercapacitor (FSC) device by embedding a conductive poly(vinyl alcohol) hydrogel into aligned carbon nanotube (CNT) arrays. We carefully investigate the effect of distribution, interface properties and densification of CNTs in the gel matrix on the electrochemical properties of an FSC. The total electrochemical capacitance of the device is measured to be 227 mF cm-3 with a maximum energy density of 0.02 mWh cm-3, which is dramatically enhanced compared with a similar device composed of non-parallel CNTs. Additionally, controllable in situ electrochemical oxidation greatly improved the compatibility between the hydrophobic CNTs and the hydrophilic hydrogel, which decreased the resistance of the device and introduced extra pseudocapacitance. After such oxidation treatment the energy storage ability further doubled to 430 mF cm-3 with a maximum energy density of 0.04 mWh cm-3 . The FSCs based on densified CNT arrays exhibited a much higher volumetric capacitance of 1140 mF cm-3 and a larger energy density of 0.1 mWh cm-3, with a large power density of 14 mW cm-3. All devices show excellent stability of capacitance after at least 10 000 charge-discharge cycles with a loss of less than 2%. These easy-to-assemble hybrid arrays thus potentially provide a new method for manufacturing wearable devices and implantable medical devices.

Does chili pepper consumption affect BMI and obesity risk? A cross-sectional analysis.

Background: The effects of chili intake on overweight and obesity have attracted significant interest in recent years. This study aimed to investigate the correlation between chili consumption frequency, body mass index (BMI), and obesity prevalence in the American population. Methods: Data from participants in National Health and Nutrition Examination Survey (NHANES) 2003-2006 were collected. We enrolled 6,138 participants with complete information on chili intake and BMI in this cross-sectional study. Multivariate logistic regression and sensitivity analyses were conducted to explore the relationship between chili intake frequency and BMI and obesity. Subgroup analyses and interaction tests were employed to assess the stability of the observed correlation. Results: Increased chili consumption frequency was linked to higher BMI values and a greater prevalence of obesity. Compared to the non-consumption group, the highest frequency group had a multivariate-adjusted ß of 0.71 (95% CI: 0.05, 1.38) for BMI and an OR of 1.55 (95% CI: 1.22, 1.97) for obesity in the fully adjusted model. This positive association between chili intake frequency and obesity was more pronounced in females and older adults (≥ 60 years old). Conclusion: Our findings suggest a positive association between chili intake frequency and BMI and obesity in United States adults, suggesting that controlling chili intake frequency could potentially contribute to improved weight management in the general population.

Identifying OGN as a Biomarker Covering Multiple Pathogenic Pathways for Diagnosing Heart Failure: From Machine Learning to Mechanism Interpretation.

BACKGROUND: The pathophysiologic heterogeneity of heart failure (HF) necessitates a more detailed identification of diagnostic biomarkers that can reflect its diverse pathogenic pathways. METHODS: We conducted weighted gene and multiscale embedded gene co-expression network analysis on differentially expressed genes obtained from HF and non-HF specimens. We employed a machine learning integration framework and protein-protein interaction network to identify diagnostic biomarkers. Additionally, we integrated gene set variation analysis, gene set enrichment analysis (GSEA), and transcription factor (TF)-target analysis to unravel the biomarker-dominant pathways. Leveraging single-sample GSEA and molecular docking, we predicted immune cells and therapeutic drugs related to biomarkers. Quantitative polymerase chain reaction validated the expressions of biomarkers in the plasma of HF patients. A two-sample Mendelian randomization analysis was implemented to investigate the causal impact of biomarkers on HF. RESULTS: We first identified COL14A1, OGN, MFAP4, and SFRP4 as candidate biomarkers with robust diagnostic performance. We revealed that regulating biomarkers in HF pathogenesis involves TFs (BNC2, MEOX2) and pathways (cell adhesion molecules, chemokine signaling pathway, cytokine-cytokine receptor interaction, oxidative phosphorylation). Moreover, we observed the elevated infiltration of effector memory CD4+ T cells in HF, which was highly related to biomarkers and could impact immune pathways. Captopril, aldosterone antagonist, cyclopenthiazide, estradiol, tolazoline, and genistein were predicted as therapeutic drugs alleviating HF via interactions with biomarkers. In vitro study confirmed the up-regulation of OGN as a plasma biomarker of HF. Mendelian randomization analysis suggested that genetic predisposition toward higher plasma OGN promoted the risk of HF. CONCLUSIONS: We propose OGN as a diagnostic biomarker for HF, which may advance our understanding of the diagnosis and pathogenesis of HF.

Unveiling the Potential of Migrasomes: A Machine-Learning-Driven Signature for Diagnosing Acute Myocardial Infarction.

BACKGROUND: Recent studies have demonstrated that the migrasome, a newly functional extracellular vesicle, is potentially significant in the occurrence, progression, and diagnosis of cardiovascular diseases. Nonetheless, its diagnostic significance and biological mechanism in acute myocardial infarction (AMI) have yet to be fully explored. METHODS: To remedy this gap, we employed an integrative machine learning (ML) framework composed of 113 ML combinations within five independent AMI cohorts to establish a predictive migrasome-related signature (MS). To further elucidate the biological mechanism underlying MS, we implemented single-cell RNA sequencing (scRNA-seq) of cardiac Cd45+ cells from AMI-induced mice. Ultimately, we conducted mendelian randomization (MR) and molecular docking to unveil the therapeutic effectiveness of MS. RESULTS: MS demonstrated robust predictive performance and superior generalization, driven by the optimal combination of Stepglm and Lasso, on the expression of nine migrasome genes (BMP1, ITGB1, NDST1, TSPAN1, TSPAN18, TSPAN2, TSPAN4, TSPAN7, TSPAN9, and WNT8A). Notably, ITGB1 was found to be predominantly expressed in cardiac macrophages in AMI-induced mice, mechanically regulating macrophage transformation between anti-inflammatory and pro-inflammatory. Furthermore, we showed a positive causality between genetic predisposition towards ITGB1 expression and AMI risk, positioning it as a causative gene. Finally, we showed that ginsenoside Rh1, which interacts closely with ITGB1, could represent a novel therapeutic approach for repressing ITGB1. CONCLUSIONS: Our MS has implications in forecasting and curving AMI to inform future diagnostic and therapeutic strategies for AMI.